eLife Assessment

In this important study, Li and others identified cell membrane receptors for juvenile hormone (JH), a terpenoid hormone in insects that regulates their development and reproduction. While intracellular receptors for JH are well characterized, membrane receptors for JH have remained elusive for many years. The authors provide convincing evidence indicating that two receptor tyrosine kinases (RTKs), CAD96CA and FGFR1, modulate the genomic effects of JH by phosphorylating the intracellular receptors in the cotton bollworm, Helicoverpa armigera. Although differential functions of the two RTKs and potential effects of the other endogenous ligands of these RTKs on JH signaling remain unclear, this study lays a foundation for future studies.

eLife Assessment

In this valuable study, Li and others identified cell membrane receptors for juvenile hormone (JH), a terpenoid hormone in insects important for their development and reproduction. While intracellular receptors for JH have been well characterized, membrane receptors for JH remained elusive for many years. Although the authors provide solid evidence to indicate that the receptor tyrosine kinases they identified bind to JH in vitro and induce non-genomic responses in cultured cells, their loss-of-function phenotypes are not consistent with known JH functions, so additional work is required to define physiological roles of these receptors.

eLife Assessment

This is a fundamental body of work reporting anatomical, molecular, and functional mapping of the central complex in Drosophila. There were a few concerns of a minor nature, and all were addressed by the authors. The tools generated and the findings, which include characterization of neuromodulators used by different cells, will undoubtedly serve as a foundation for future studies of this brain region. The data are compelling and likely to have a major impact.

> for - addiction model - Marc Lewis - addiction diagram

> summary - Marc gives a good summary of everything - prefrontal cortex in control of judgment - striatum in charge of - attraction - desire - craving - midbrain - dopamine system - dopamine goes to the striatum and sets up localized feedback cycle so crave more - then the striatum becomes hyperactivated in the presence of cues - then you get that mechanism of now appeal - that narrowing of attraction to the immediate reward and - the loss of everything else - the other stuff falls off the radar - then the connection between - the prefrontal cortex and - the striatum starts to become compromised - resulting in ego fatigue - The prefrontal cortex simply becomes less effective at control

eLife Assessment

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

eLife Assessment

This important study presents a transcriptomic analysis of enterochromaffin cells in the intestine. The evidence supporting the authors' claims is solid, although the functional analysis is focused on the Piezo2-expressing subset in the colon. The work will be of interest to biologists working on intestinal mucosal biology.

eLife Assessment

This study combines mathematical models and experimental data to analyse the emergence of heterogeneity within clonal NK cell responses during antigen-specific cell expansion. Although it comprises different experimental data and tests different theoretical hypotheses, the main claims remain incomplete and would benefit from the consideration of several previous findings about clonal immune responses and corresponding mathematical approaches. The study presents valuable findings with the potential to provide key insights about NK cell development if proposed claims could be confirmed by additional analyses.

eLife Assessment

The study by Ma et al. provides fundamental findings and compelling evidence that Pyrotinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (PERSIST): A multicenter phase II trial. The findings enhance the understanding of HER2-positive breast cancer. The claims are fully supported by the types of experiments that were performed.

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 convincing evidence that this member of a larger tandemly duplicated gene family together with an upstream regulator contributes to salt tolerance. The manuscript will be of interest to plant biologists studying mechanisms of abiotic stress tolerance and gene family evolution.

eLife Assessment

The study conducted by Fang et al. offers significant and fundamental insights, notably enhancing our understanding of angiogenesis. While some of the claims are supported by convincing experimental approaches, others lack sufficient validation. Additionally, there are instances where critical experimental controls appear to be absent.

eLife Assessment

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

eLife Assessment

This study presents an important methodological advance to improve the sensitivity of PCR for detecting Trypanosoma cruzi in blood, combining DNA fragmentation, deep sampling, and blood cell pellet analysis. The findings offer solid evidence of enhanced detection sensitivity and shed light on parasite load dynamics during chronic infection in mammalian reservoirs. The evidence is sound for macaques and the method shows promise in expanding detection limits, but there is some variability in the limits of detection and small sample size of human samples. This work will be of interest to parasitologists, epidemiologists, and clinicians using molecular diagnostics to monitor responses to etiological treatments for Chagas disease.

eLife Assessment

This important study suggests that the composition of the extracellular matrix in a mouse model of liver fibrosis changes depending on the cause of liver fibrosis. The data could be used as a foundation for future antifibrotic therapies. The strength of evidence is convincing with respect to the use of animal models and proteomic analysis. The study provides a helpful inventory of proteins up or down-regulated.

eLife Assessment

This valuable study suggests that capsaicin nanoparticle administration in rats activates the transcription factor Nrf2 by directly binding to its repressor, KEAP1, leading to the induction of cytoprotective genes and preventing alcohol-induced gastric damage, offering a potential avenue for treating alcoholism-related gastric disorders. Although improvements were made following the first revision, the evidence supporting capsaicin as an Nrf2 activator remains incomplete, as some methodological aspects still require revision and the interpretation of key data needs further clarification.

eLife Assessment

This fundamental study reports the effects of the psychedelic drug psilocin on iPSC-derived human cortical neurons, analyzing different aspects of structural and functional neuronal plasticity. The evidence is convincing, integrating a comprehensive characterization of 5-HT2A expression and its subcellular distribution upon treatment with psilocin at different time points. The study supports the value of using iPSC-derived human cortical neurons for testing the potentially translational effects of psilocin and other psychedelic-related compounds.

eLife Assessment

The authors aimed to quantify feral pig interactions in eastern Australia to inform disease transmission networks. They used GPS tracking data from 146 feral pigs across multiple locations to construct proximity-based social networks and analyze contact rates within and between pig social units. This fundamental study shows that targeting adult males in feral pig control programs could help global efforts to contain disease. The methods are compelling and the paper should be of interest to the fields of veterinary medicine, public health, and epidemiology.

eLife Assessment

This is an important study demonstrating that anosmia in Parkinson's disease patients is due to dysfunction in cholinergic neurons. This study provides compelling evidence, using scRNA sequencing, that cholinergic olfactory projection neurons (OPN) are consistently affected in five different fruit fly models of Parkinson's disease, exhibiting synaptic dysfunction before the onset of motor deficits. Comparisons with scRNA sequencing of patients' human brain samples reveals similar synaptic gene deregulation in cholinergic neurons of patients. This study points the possibility that targeting cholinergic neurons could be a potential avenue for early diagnosis and intervention in PD.

eLife Assessment

This study provides important findings on the nature of eye movement choices by human subjects. The study uses a novel approach and provides relatively clear and convincing results of the relationship between pupil size and saccade production. The results should be of interest to a broad audience interested in sensorimotor integration and sensory-guided decision-making.

eLife Assessment

This manuscript presents valuable findings showing that rapamycin directly activates the cool-sensing ion channel, TRPM8, acting through a different binding site than other small-molecule cooling agents such as menthol. The use of Ca2+-imaging, electrophysiology, and computational biology provides solid evidence to support the finding. The authors also present a novel NMR-based method to help identify details of the binding site interactions. In this revised version, some analysis and the presentation have been corrected and improved. Their findings provide insights into TRP channel pharmacology and may indicate previously unknown physiological effects or therapeutic mechanisms of the immunosuppressant, rapamycin.

eLife Assessment

This important study by Liu et al. presents a comprehensive structure-function analysis of the presynaptic protein UNC-13, leading to new insights into how its distinct domains control neurotransmitter release. The methods, data, and analyses are convincing, and the genetic and electrophysiological approaches support many of their conclusions. The work will be of interest to neuroscientists studying synaptic transmission, as it provides a foundation for future mechanistic studies of Munc13/UNC-13 family proteins.

eLife Assessment

This important study uses advanced computational methods to elucidate how environmental dielectric properties influence the interaction strengths of tyrosine and phenylalanine in biomolecular condensates. The evidence supporting the claims of the authors is solid, as the simulations are performed rigorously providing mechanistic insights into the origin of the differences between the two aromatic amino acids considered. This study will be of broad interest to researchers studying biomolecular phase separation.

eLife Assessment

This study presents important methodologies for repeated brain ultrasound localization microscopy (ULM) in awake mice and a set of results indicating that wakefulness reduces vascularity and blood flow velocity. The data supporting these findings are solid. This study is relevant for scientists investigating vascular physiology in the brain.

eLife Assessment

This valuable paper explores the idea that transient modulations of neural gain promote switches between distinct perceptual interpretations of ambiguous stimuli. The authors provide solid evidence for this idea by pupillometry (an indirect proxy of neuromodulatory activity), fMRI, neural network modeling, and dynamical systems analyses. The highly integrative nature of this approach is rare in the field.

eLife Assessment

This useful study aimed to examine the relationship of spatial frequency selectivity of single macaque inferotemporal (IT) neurons to category selectivity. Interesting findings in this report suggest a shift in preferred spatial frequency during the response, from low to high spatial frequencies. This agrees with a coarse-to-fine processing strategy, which is in line with multiple studies in the early visual cortex. Some of the findings were difficult to evaluate because the methods are incomplete. The conclusion that single-unit spatial frequency selectivity can predict object coding requires further evidence to confirm.

eLife Assessment

This important study identifies species- and sex-specific neuronal cell types and gene expression in the preoptic area (POA) to help understand the evolutionary divergence of social behaviors. The evidence from single-nucleus RNA sequencing and immunostaining is compelling and suggests that cellular differences in the POA may contribute to behavioral variations such as mating and parental care that are apparent in two closely related deer mouse species. These rich observations provide an entry point for future hypothesis-driven experiments to demonstrate a causal role for these populations in sex- or species-variable behaviors in vertebrates. These data will be a resource that is of value to behavioral neuroscientists.

eLife Assessment

This is a valuable study, tackling the long-standing issue of the difficulty in imaging the inferior olive and addressing the most relevant questions with a rigorous approach. The technological advance allowed the authors to generate solid experimental evidence with high-quality data. The results are presented clearly and the analyses are rigorous.

eLife Assessment

This useful study presents findings on the developmental roles of Nup107, a key nucleoporin, in regulating the larval-to-pupal transition in Drosophila melanogaster through its involvement in ecdysone signaling. The evidence supporting the authors' claims is solid, with robust experimental approaches including RNAi knockdown and rescue experiments. The findings highlight Nup107's function in regulating ecdysone biosynthesis, specifically through the regulation of EcR levels and Halloween genes expression in the prothoracic gland; additionally, rescue experiments suggest that the RTK PTTH/Torso signaling pathway is disrupted upon Nup107 depletion, further emphasizing its role in ecdysone regulation. However, finding a mechanism, addressing potential off-target effects of RNAi, and exploring alternative mutant models would strengthen the findings as the currently proposed mechanism is not fully supported by the data.

eLife Assessment

This study investigates trial-by-trial inter-areal interactions in the visual cortex of the mouse and the monkey by analyzing two previously published datasets. The authors find that activity in one layer (in mice) or one area (in monkeys) can partially predict neural activity in another layer or area on the single-trial level in different experimental contexts. This valuable finding expands previously known contributions of stimulus-independent downstream activity to neural responses in the visual cortex by demonstrating how these change under varying visual stimuli as well as in the absence of visual stimulation. While the methodology is solid, the analysis for the monkey data is incomplete and would benefit from including a second animal.

eLife Assessment

This important study offers a molecular characterization of neurons and glia in the adult nervous system of the fruit fly Drosophila melanogaster. The study focuses on the progeny of a specific set of neural stem cells, called Type II neuroblasts that contribute to the central complex, a conserved brain region that plays key roles in sensorimotor integration. The data are convincing and collected using validated methodology, generating an invaluable resource for future studies. The study will be of interest to developmental neurobiologists.

eLife Assessment

The paper addresses the question of gene epistasis and asks what is the correct null model for which we should declare no epistasis. By reanalyzing synthetic gene array datasets regarding single and double-knockout yeast mutants, and considering two theoretical models of cell growth, the authors reach the valuable conclusion that the product function is a good null model. The analysis is still incomplete, as some assumptions and hypotheses are not fully justified. However, once verified, the results have the potential to be of value to the field of gene epistasis.

eLife Assessment

This study presents a valuable finding of novel markers that may potentially identify resident tendon stem/progenitor cells (TSPCs). The study also presents a comprehensive single-cell transcriptional dataset that will be of value to the field. The evidence supporting the identification of novel markers of a TSPC is incomplete, requiring clarification of current analyses, additional analyses between ages, and additional validation experiments to demonstrate that these markers are indeed specific and these cells are indeed TSPCs. This work will be of interest to biologists and engineers focused on tendons and ligaments.

eLife Assessment

This manuscript presents an interesting new framework (VARX) for simultaneously quantifying effective connectivity in brain activity during sensory stimulation and how that brain activity is being driven by that sensory stimulation. The reviewers thought the model was original and its conclusion that intrinsic connectivity is largely unaltered during sensory stimulation is very interesting, but that future use of the model could potentially be affected by false positive conclusions. Overall, this work is important with solid evidence for its conclusions - it will be of interest to neuroscientists working on brain connectivity and dynamics.

eLife Assessment

This study presents useful findings on the differences between male and hermaphrodite C. elegans connectomes and how they may result in changes in locomotory behavioural outputs. However, the study appears incomplete with respect to the relationship between sex-specific AVA wiring and male mate-finding. Another area of concern is that the analysis does not consider animal-to-animal variability in the wiring when attempting to identify significant differences between the male and hermaphrodite.

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 convincing with appropriate and validated methodology in line with current state-of-the-art. The significance of the findings is important in the context of Niemann-Pick Disease Type C as well as other subfields.

eLife Assessment

This revision of important work is a versatile addition to the chemical protein modifications and bioconjugation toolbox in synthetic biology. The technology developed cleverly uses Connectase to irreversibly fuse proteins of interest together so they can be studied in their native context, with compelling well-controlled data showing the technique works for various protein partners. This work will help multiple fields to explore multi-function constructs in basic synthetic biology. This work will also be of interest to those studying fusion oncoproteins commonly expressed in various human pathologies.

eLife Assessment

This manuscript addresses a mechanism by which dopamine (DA) regulates synaptic plasticity. The authors build upon their previous finding that DA applied after a timing pattern that ordinarily induces long-term depression (LTD) now induces long-term potentiation (LTP). The new findings that this "DA-dependent LTP" involves de novo protein synthesis, a cyclicAMP signalling pathway, and calcium-permeable AMPA receptors (CP-AMPARs) are of valuable significance. The conclusions are convincing and largely supported by the evidence provided.

eLife Assessment

Birdsong production depends on precise neural sequences in a vocal motor nucleus HVC. In this useful biophysical model, Daou and colleagues identify specific biophysical parameters that result in sparse neural sequences observed in vivo. While the model is presently incomplete because it is overfit to produce sequences and therefore not robust to real biological variation, the model has the potential to address some outstanding issues in HVC function.

eLife Assessment

This manuscript presents important findings on how structural color can be manipulated through a specific single-gene mutation in the motile bacterium Flavobacterium IR1. It provides a promising model to identify genes and molecular mechanisms supporting this widespread optical phenomenon. The story relies on convincing data with proteomic analysis and well-designed experiments, although it remains rather descriptive. This work will be of interest to biophysicists and microbiologists working on structural colors and Flavobacterium.

eLife Assessment

This fundamental research conducted a molecular comparison between smooth muscle cells and adjacent fibroblast cells within lung blood vessels affected by pulmonary arterial hypertension. The study identified distinct disease-related states in each cell type and provided deeper insights into their interactions and communication. While certain conclusions should be interpreted with caution due to inherent methodological limitations, the study's findings remain convincing and robust. This is supported by the use of advanced and complementary techniques, as well as the rare isolation of diseased lung blood vessel cells from the same donor, enabling direct comparison.

eLife Assessment

The paper presents a valuable theoretical treatment of the role of passage of time in optimal decision strategies in pursuit based tasks. The computational evidence and methodologies employed are novel, and the authors offer solid evidence for the majority of the claims.

eLife Assessment

This useful study by Gao et al identifies Hspa2 as a heterogeneous transcript in the early embryo and proposes a plausible mechanism showing interactions with Carm1. The authors propose that variability in HSPA2 levels among blastomeres at the 4-cell stage skews their relative contribution to the embryonic lineage. Given only 4 other heterogeneous transcripts/non-coding RNA have been proposed to act similarly at or before the 4-cell stage, this would be a key addition to our understanding of how the first cell fate decision is made. While this is a solid study, further data are needed to fully support the conclusions.

eLife Assessment

This important work addresses the relationship between the transdiagnostic compulsivity dimension and confidence as well as confidence-related behaviours like reminder setting. The relationship between confidence and compulsive disorders has recently received a lot of attention and has been considered to be a key cognitive change. The authors paired an elegant experimental design and pre-registration to give convincing evidence of the relationship between compulsivity, reminder setting, and confidence. In the revised version they thoroughly addressed the reviewer's comments, in particular adding new analyses clarifying how their findings relate to prediction error based learning as well as presenting additional recovery analyses and psychometric curves further strengthening the manuscript.

eLife Assessment

You et al. present an important study that applied a high-resolution transposon-based barcoding system to show the clonal contribution of hematopoietic stem and progenitor cells during aging, after 5-FU treatment, and upon transplantation. The results are convincing and show that there are different categories of multipotent progenitors that are either active or indolent, and that long-term fates are dominated by clones that either favor differentiation or self-renewal. This study will be of broad interest to stem-cell biologists and could reach an even wider audience with a clearer and more concise presentation and discussion of the results.

eLife Assessment

This study reports important advances in understanding how pyrazinamide, a first-line antibiotic for tuberculosis treatment, is effective in vivo. The experimental design and data provide solid evidence that the production of reactive oxygen species by host cells contributes to how pyrazinamide is more potent in the host than in culture conditions; however, additional experiments and controls would strengthen these conclusions. This work is of interest to the antibiotic drug development field.

eLife Assessment

This study demonstrated that the conditional knockout of afadin disrupts retinal laminar organization and reduced number of photoreceptors while preserving some of the structure and light responsiveness of retinal ganglion cells. These findings are solid and useful for understanding afadin's role in retinal cell generation, lamination, and functional organization. However, the study provides limited new insights into the relationship between retinal lamination defects and overall retinal function.

eLife Assessment

This useful study integrates experimental methods from materials science with psychophysical methods to investigate how frictional stabilities influence tactile surface discrimination. The authors argue that force fluctuations arising from transitions between frictional sliding conditions facilitate the discrimination of surfaces with similar friction coefficients. However, the reliance on friction data obtained from an artificial finger, together with the ambiguous correlative analyses relating these measurements to human psychophysics, renders the findings incomplete.

eLife Assessment

This valuable study offers insights into the role of Leiomodin-1 (LMOD1) in muscle stem cell biology, advancing our understanding of myogenic differentiation and indicating LMOD1 as a regulator of muscle regeneration, aging, and exercise adaptation. The integration of in vitro and in vivo approaches, complemented by proteomic and imaging methodologies, is solid. However, certain aspects require further attention to improve the clarity, impact, and overall significance of the work, particularly in substantiating the in vivo relevance. This work will provide a starting point that will be of value to medical biologists and biochemists working on LMOD and its variants in muscle biology.

eLife Assessment

ProtSSN is a valuable approach that generates protein embeddings by integrating sequence and structural information, demonstrating improved prediction of mutation effects on thermostability compared to competing models. The evidence supporting the authors' claims is compelling, with well-executed comparisons. This work will be of particular interest to researchers in bioinformatics and structural biology, especially those focused on protein function and stability.

eLife Assessment

This study describes the impact of mycobacterial genetic diversity on host-infection phenotypes by assessing the effect of different M. tuberculosis lineages on granulomatous inflammation using a 3D in vitro granuloma model. Despite being descriptive and showing mostly correlative relationships, the findings are useful and provide some solid support regarding the functional impact of M. tuberculosis's natural diversity on host-pathogen interactions. The study will interest researchers working on mycobacteria and motivate future studies to understand how genetic diversity influences virulence and immunity outcomes.

eLife Assessment

The study by Chen and Phillips provides evidence for a dynamic switch in the small RNA repertoire of the Argonaute protein NRDE-3 during embryogenesis in C. elegans. The work is supported by convincing experimental data, shedding light on RNA regulation during development. While the functional relevance of this process warrants further investigation, this study provides valuable insights into small RNA pathways with broader implications for developmental biology and gene regulation in other systems.

eLife Assessment

This useful study presents findings on the efficacy and mechanisms of linalool protection against Saprolegnia parasitica oomycetes in the grass carp model. The evidence presented is solid since the methods, data and analyses broadly support the claims with only minor weaknesses. This work will be of great interest to scientists within the fields of aquaculture, ichthyology, microbiology, and drug discovery.

eLife Assessment

This useful study uses a model of Streptococcus suis (a pig pathogen) infection in mice using an intranasal route, the natural route of infection ignored in most of the literature. The study aims to understand how capsular polysaccharides (CPS) contribute to neuropathology and virulence. The findings suggest that the olfactory route may lead to meningitis before bacteremia occurs and that CPS down-regulation may play a role in this process. However, the study remains incomplete as presented.

eLife Assessment

This valuable study reports the link between a disruption in testicular mineral (phosphate) homeostasis, FGF23 expression, and Sertoli cell dysfunction. The data supporting the conclusion are solid. This work will be of interest to biomedical researchers working on testis biology and male infertility. The assessment is based on the editors' critical evaluation of the authors' responses.

eLife Assessment

This study investigates a dietary intervention that employs a smartphone app to promote meal regularity, findings that have theoretical or practical implications for a subfield and may be clinically useful. The intervention to entice participants to adhere to specific meal times represents a restrictive diet (even though it does not ask to limit caloric intake) similar to a time-restricted feeding diet, while the control subjects are not experiencing or adhering to dietary restrictions. The authors report significant weight loss but did not rigorously assess caloric intake which remains a weakness of this study as food diaries are notoriously unreliable. While the concept is very interesting, the study is considered incomplete, and the rigor of the results should be strengthened in follow-up studies to add more stringent methods to assess caloric intake. Additionally, the study hypothesizes that the intervention resets the circadian clock. However, the study needs an objective method for assessing circadian rhythms, such as actigraphy, in addition to a subjective questionnaire.

eLife Assessment

This study provides a comprehensive exploration of the role of IL-1β signaling during development of lung injury induced by a combination of underlying inflammation and mechanical ventilation. The data are convincing, and while the translatability of the findings related to therapeutic hypothermia may be somewhat complicated, they have the potential to be very valuable to the field.

eLife Assessment

This study highlights ITCH as a regulator of SARS-CoV-2 replication by promoting K63-linked ubiquitination of M and E proteins. While the findings are potentially useful, the approaches are overly reliant on ectopic expression models and lack direct mechanistic evidence that ubiquitination of M and E has functional relevance. Accordingly, the strength of evidence is incomplete, as further experiments are needed to validate the findings and address potential confounding factors.

eLife Assessment

NCX1 is an important cardiac Ca2+/Na+ exchanger whose activity is tightly regulated. This manuscript describes the structural basis of activation by the lipid PIP2 and inhibition by binding of a small molecule to NCX1. These results provide key insights into NCX1 regulation and cellular Ca2+ signaling, but the evidence presented is still incomplete.

eLife Assessment

This valuable paper reports machine learning-based image analysis pipelines for the automated segmentation of micronuclei and the detection and sorting of micronuclei-containing cells. These are powerful new tools for researchers who study micronuclei and their physiologic consequences. The analysis of the new tools and their benchmarking is rigorous and convincing; applications and remaining limitations are well explained in the paper.

eLife Assessment

This valuable study introduces a new method for detecting RNA modification. Since it does not rely on chemical modification of RNA, which often results in RNA degradation and therefore loss of RNA molecules, it complements other approaches for detecting RNA modification, and it might be of particular interest for sites where modifications are found in only a minority of interrogated molecules. The information provided is incomplete, however, to allow for comparison with other methods, since there is uncertainty regarding false positive and false negative rates.

eLife Assessment

This important study shows how genetic variation is associated with fecundity following a period of reproductive diapause in female Drosophila. The work identifies the olfactory system as central to successful diapause with associated changes in longevity and fecundity. While the methods used are convincing, a limitation of the study, as of any other laboratory-based investigation is the challenge of demonstrating how well measures for fitness related to diapause and its recovery correlates with realities encountered during development in the wild.

eLife Assessment

This useful manuscript reports mechanisms behind the increase in fecundity in response to sub-lethal doses of pesticides in the crop pest, the brown plant hopper. The authors hypothesize that the pesticide works by inducing the JH titer, which through the JH signaling pathway induces egg development. Evidence for this is, however, incomplete.

eLife Assessment

This valuable study confirms the association between the human leukocyte antigen (HLA)-II region and tuberculosis (TB) susceptibility in genetically admixed South African populations, specifically identifying a near-genome-wide significant association in the HLA-DPB1 gene, which originates from KhoeSan ancestry. The evidence supporting the association between the HLA-II region and TB susceptibility is solid, and the work will be of interest to those studying the genetic basis of tuberculosis susceptibility/infection resistance.

eLife Assessment

Studying several allergens in different mouse strains, the authors assessed the role of IgM in airway inflammatory responses and show that IgM deficient mice have reduced airway hyperresponsiveness. Although the findings are useful and interesting and among others show the expression of a protein that regulates actin in smooth cells, the study remains incomplete as the data and analyses only partly support their primary claim.

eLife Assessment

This important study describes how a single effector of the Type Six Secretion System (T6SS) has two distinct functions, which may contribute to bacterial survival and the development of novel antibacterials. The authors utilized various methods in biochemistry, microbiology, and microscopy to produce convincing data supporting their claims about the protein's function; however, they could clarify the implications for non-experts to enhance the accessibility of this work. This manuscript is of interest to those studying T6SS, particularly those interested in effectors and bacterial enzymes.

eLife Assessment

This manuscript reports an important new statistical method for calculating the significance of correlations between two time-series, which provides more accuracy than other methods when the data has few replicates. The proposed method solves a real-life problem that is frequently encountered and is broadly applicable to many realistic datasets in many experimental contexts. The technique is supported with compelling mathematical derivations as well as analysis of both computer-generated and previously published experimental data.

eLife Assessment

This important 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 is positively correlated with glycation levels and lifespan is convincing and, although there are some limitations related to data collection, they likely make the statistically significant findings more conservative. As the first extensive comparative analysis of glycation rates, life history, and glucose levels in birds, the study has the potential to be of interest to evolutionary ecologists and the aging research community more broadly.

eLife Assessment

This important study introduces a fully differentiable variant of the Gillespie algorithm as an approximate stochastic simulation scheme for complex chemical reaction networks, allowing kinetic parameters to be inferred from empirical measurements of network outputs using gradient descent. The concept and algorithm design are convincing and innovative. While the proofs of concept are promising, some questions are left open about implications for more complex systems that cannot be addressed by existing methods. This work has the potential to be of significant interest to a broad audience of quantitative and synthetic biologists.

eLife Assessment

This study presents important insights into the regulation of left-right organ formation. By combining genetic perturbation of all three Meteorin genes in zebrafish and timelapse imaging, the authors identify an essential role for this protein family in the establishment of left-right patterning. They provide convincing evidence that Meteorins are required for the morphogenesis of dorsal forerunner cells, the precursors of the left-right organizer (also named Kupffer's vesicle) in zebrafish. In line with this, Meteorins were shown to genetically interact with integrins ItgaV and Itgb1b to regulate dorsal forerunner cell clustering.

eLife Assessment

This study maps the genotype-phenotype landscapes of three E. coli transcription factors and the topographical features of these landscapes. It shows that ruggedness and epistasis do not hinder the evolution of strong transcription factor binding sites. These convincing findings contribute valuable insights into fitness landscape theories and highlight the role of chance, contingency, and evolutionary biases in gene regulation. The authors then study the topographical features of these landscapes, especially the number and distribution of local maxima, as well as the statistical properties of evolutionary paths on these landscapes.

eLife Assessment

This important study characterizes and validates a new activity marker - fast labelling of engram neurons (FLEN) - which is transiently active and driven by cFos, allowing the monitoring of intrinsic and synaptic properties of engram neurons shortly after the learning experience. The results convincingly demonstrate the utility of this novel viral tool for studying early changes in the properties of engram cells. However, the study would benefit from exploring how accurately FLEN reflects endogenous cFos activity, how this labelling technique compares to previous versions, and from careful consideration of alternative explanations such as changes in release probability.

eLife Assessment

This study provides important evidence that the postmating behavioral switch in male mice is mediated by distinct stages of synaptic plasticity within the medial amygdala-MPOA-BSTrh pathway. The findings are convincing, supported by rigorous behavioral characterization and electrophysiological approaches that disentangle the contributions of mating, cohabitation, and parental experience to neural circuit changes. While some methodological details and statistical reporting require clarification, the study significantly advances our understanding of the neural mechanisms underlying paternal behavior.

eLife Assessment

This study provides valuable observations indicating that human pyramidal neurons propagate information as fast as rat pyramidal neurons despite their larger size. Convincing evidence demonstrates that this property is due to several biophysical properties of human neurons. This study will be of interest to neurophysiologists.

eLife Assessment

This study is valuable as it provides information about the genes regulated by sex hormone treatment in song nuclei and other brain regions and suggests candidate genes that might induce sexual dimorphism in the zebra finch brain. The analysis presented is thorough and detailed. Whereas the evidence for gene regulation by hormone treatment is well supported, the evidence for an association of those genes with song learning (as written in the title) is incompletely supported as no manipulation of song learning or song analysis was conducted.

eLife Assessment

This valuable paper introduces Heron, lightweight scientific software that is designed to streamline the implementation of complex experimental pipelines. The software is tailored for workflows that require coordinating many logical steps across interconnected hardware components with heterogeneous computing environments. The authors convincingly demonstrate Heron's utility and effectiveness in the context of behavioral experiments, addressing a growing need among experimentalists for flexible and scalable solutions that accommodate diverse and evolving hardware requirements.

eLife Assessment

This important study advances our understanding of the role of dopamine in modulating pair bonding in mandarin voles by examining dopamine signaling within the nucleus accumbens across various social stimuli using state-of-the-art causal perturbations. The evidence supporting the findings is compelling, particularly cutting-edge approaches for measuring dopamine release as well as the activity of dopamine receptor populations during social bonding. Some concerns remain about the statistical analyses.

eLife Assessment

The authors aim to elucidate the mechanism by which pyroptosis (through the formation of Gasdermin D (GSDMD) pores in the plasma membrane) contributes to increased release of procoagulant Tissue Factor-containing microvesicles. The data offers solid mechanistic insights as to the interplay between pyroptosis and microvesicle release with NINJ1. The study provides useful insights into the potential of targeting Ninj1 as a therapeutic strategy.

eLife Assessment

In this valuable study, the authors integrate several datasets to describe how the genome interacts with nuclear bodies across distinct cell types and in Lamin A and LBR knockout cells. They provide convincing evidence to support their claims and particularly find that specific genomic regions segregate relative to the equatorial plane of the cell when considering their interaction with various nuclear bodies. The authors are encouraged to consider citing the relevant work of other labs who have shown the presence of different types of Lamin Associated Domains (LADs).

eLife Assessment

This important study allows for a better understanding of anthelmintic drug resistance in nematodes. The authors provide a detailed analysis of the role of UBR-1 and its underlying mechanism in ivermectin resistance using convincing behavioural and genetic experiments with C. elegans. Although the authors have addressed the concerns of the reviewers, it would be prudent for the authors to disclose the Dyf phenotype in ubr-1 mutants. The authors should at the very least report the Dyf phenotype and the experiment on which they base the argument that the Dyf phenotype does not affect their conclusions.

eLife Assessment

This manuscript describes a resource detailing the econstitution of Holothuria glaberrima gut following self-evisceration in response to a potassium chloride injection, using scRNAseq and fluorescent RNA localization in situ. It provides some new findings about organ regeneration, as well as the origins of pluripotent cells, and places these findings in the context of regeneration across species. The paper's schematic model and HCR images are a valuable foundation for future work. The authors provide convincing RNA localization images to validate their data and to provide spatial context. These validation experiments are of good quality but remain challenging to connect to the complex spatial organization of complex tissues. This resource will be of interest to the field of regeneration, particularly in invertebrates, but also in comparative studies in other species, including evolutionary studies.

eLife Assessment

The authors present convincing findings on trends in hind limb morphology through the evolution of titanosaurian sauropod dinosaurs, the land animals that reached the most remarkable gigantic sizes. The important results include the use of 3D geometric morphometrics to examine the femur, tibia, and fibula to provide new information on the evolution of this clade and on evolutionary trends between morphology and allometry.

eLife Assessment

This is a valuable study that tests the functional role of food-washing behavior in removing tooth-damaging sand and grit in long-tailed macaques and whether dominance rank predicts level of investment in the behavior. The evidence that food-washing is deliberate is compelling, but the evidence for variable and adaptive investment depending on rank, including the fitness-relevance and ultimate evolutionary implications of the findings, is incomplete given limitations of the experimental design. Overall, the paper should be of interest to researchers interested in foraging behavior, cognition, and primate evolution.

eLife Assessment

This important study characterizes the molecular signatures and function of a type of enteric neuron (IPAN) in the mouse colon, identifying molecular markers (Cdh6 and Cdh8) for these cells. A battery of compelling and comprehensive experimental findings suggests data from other species are likely translatable to mice, bridging the abundant literature from humans and other mammals into this experimentally tractable animal model. This work will be of interest to scientists studying the motor control of the colon and more generally the enteric neuromuscular system.

eLife Assessment

This valuable study reports on the critical role of ANKRD5 (ANKEF1) in sperm motility and male fertility. However, the supporting data remain incomplete. This work will be of interest to biomedical researchers working in sperm biology and andrologists.

eLife Assessment

This study demonstrates the critical role of Afadin on the generation and maintenance of complex cellular layers in the mouse retina. The data are solid, which provides important insights into how cell-adhesion molecules contribute to retinal organization. However, further investigations are needed to clarify the mechanisms underlying the cellular disorganization phenotype in the retina and axonal projection to the brain.

eLife Assessment

Centromeres are specific sites on chromosomes that are essential for mitosis and genome fidelity. This valuable work extends previous studies to convincingly show that the centromere-histone core contributes to force transduction through the kinetochore. The centromere mainly strengthens one of the two paths of force transduction, influenced by the centromeric DNA sequence, the mechanism for which remains to be determined. This work will be of interest to those studying cell division and chromosome segregation.

eLife Assessment

In this work, the authors use a Drosophila melanogaster 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 significance of the generated cell types under homeostatic conditions and in response to injury remains to be further explored and open up new avenues of research.

eLife Assessment

This study presents valuable findings by using Fmr1 knockout mice as a model to investigate the role of Fmr1 in sleep regulation. These mice exhibited clear evidence of sleep and circadian disturbances, including abnormal retinal innervation of the SCN, which may provide a potential mechanistic explanation for the observed behavioral deficits. Interestingly, the results suggest that a scheduled feeding approach could improve sleep and circadian rhythms while enhancing social interactions and reducing repetitive behaviors in a mouse model of Fragile X syndrome. The topic is both intriguing and highly significant; however, while the evidence supporting the authors' claims is solid, several issues hinder the manuscript's clarity and impact.

eLife Assessment

This study presents an important discovery regarding the diversity and evolution of gall-forming microbial effectors. Supported by convincing computational structural predictions and analyses, the research provides insights into the unique mechanisms by which gall-forming microbes exert their pathogenicity in plants. This study also offers guidance that is of value for future studies on pathogen effector function and co-evolution with host plants.

eLife Assessment

This important study reports a detailed computational analysis of the CFTR ion channel's permeation mechanism, advancing our understanding of its structure-function relationship. The conclusions are based on extensive molecular dynamics simulations and thorough analysis, but the use of an approximate chloride ion model, known to underestimate key ion-protein interactions, leaves them incomplete without experimental or alternative computational validation. The work will be of interest to biophysicists working on CFTR and cystic fibrosis.

eLife Assessment

Rennert et al. developed a valuable thermodynamic framework to study the force response of branched actin networks from the crucial and unexplored perspective of energetic cost. They used the fact that the entropy production rate must be positive to derive inequalities that set limits on the maximum force produced by branched actin networks, and speculate that the dissipative cost beyond that required to move the load may be necessary to maintain an adaptive steady state. This work is highly innovative, but remains incomplete until the hypotheses of the model are better justified and the conclusions about the dissipative cost of the system are better established.

eLife Assessment

This study presents a potentially fundamental analysis of the original color of a fossil feather from the crest of a 125-million-year-old enantiornithine bird, using sophisticated 3D microscopic and numerical methods to conclude that the feather was iridescent and brightly colored, possibly indicating that this was a male bird that used its crest in sexual displays. At present, the strength of evidence supporting the authors' conclusions is considered incomplete based on methodological incompleteness and questions about taphonomy.

eLife Assessment

This fundamental manuscript comprehensively examines the roles of nine structural proteins in herpes simplex virus 1 (HSV-1) assembly and nuclear egress. By integrating cryo-light microscopy and soft X-ray tomography, the study presents an innovative approach to investigating viral assembly within cells. The research is thoroughly executed, yielding compelling data that explain previously unknown functions of these structural proteins. This work is of broad interest to virologists, cellular biologists, and structural biologists, offering a robust, contextually rich methodology for studying large protein complex assembly within the cellular environment, serving as an excellent starting point for high-resolution techniques.

eLife Assessment

This study provides important insights into the regulation of type-I interferon signaling and anti-tumor immunity, demonstrating that ORMDL3 promotes RIG-I degradation to suppress immune responses. The evidence is convincing, with well-executed mechanistic experiments and in vivo validation in syngeneic tumor models. These findings have significant implications for cancer immunotherapy, highlighting ORMDL3 as a potential therapeutic target.

eLife Assessment

This study addresses an important and longstanding question regarding the molecular mechanism of protein misfolding in Ig light chain (LC) amyloidosis (AL), a life-threatening condition. By combining advanced techniques, including small-angle X-ray scattering, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry, the authors provide convincing evidence that the "H state" distinguishes amyloidogenic from non-amyloidogenic LCs. These findings not only offer novel insights into LC structural dynamics but also hold promise for guiding therapeutic strategies in amyloidosis and will be of particular interest to structural biologists, biophysicists, and many others working on amyloid diseases.

eLife Assessment

This study addresses an important and longstanding question regarding the molecular mechanism of protein misfolding in Ig light chain (LC) amyloidosis (AL), a life-threatening condition. By combining advanced techniques, including small-angle X-ray scattering, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry, the authors provide convincing evidence that the "H state" distinguishes amyloidogenic from non-amyloidogenic LCs. These findings not only offer novel insights into LC structural dynamics but also hold promise for guiding therapeutic strategies in amyloidosis and will be of particular interest to structural biologists, biophysicists, and many others working on amyloid diseases.

eLife Assessment

The authors present three transgenic models carrying three representative exon deletions of the dystrophin gene. The findings presented are valuable to the field of muscle diseases, particularly muscular dystrophies. The evidence provided in the manuscript is convincing, with rigorous biochemical assays and state-of-the-art microscopy methods.

eLife Assessment

This valuable work provides solid evidence that a neuronal metallothionein, GIF/MT-3, incorporates metal-persulfide clusters. A variety of well-designed assays support the authors' hypothesis, revealing that sulfane sulfur is released from MT-3. The biological role of the persulfidated form is not yet clearly defined. There are caveats to the findings that limit the study, but the work will nevertheless prompt major follow-up work.

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.

eLife Assessment

In this valuable report, the authors investigated the effect of mitochondrial transplantation on post-cardiac arrest myocardial dysfunction (PAMD), which is associated with mitochondrial dysfunction. They convincingly demonstrated that mitochondrial transplantation enhanced cardiac function and increased survival rates after the return of spontaneous circulation (ROSC). They have also shown that myocardial tissues with transplanted mitochondria exhibited increased mitochondrial complex activity, higher ATP levels, reduced cardiomyocyte apoptosis, and lower myocardial oxidative stress post-ROSC.

eLife Assessment

These useful findings assigned a novel functional implication of histone acylation, crotonylation. Although the mechanistic insights have been provided in great detail regarding the role of the YEATS2-GCDH axis in modulating EMT in HNC, the strength of evidence for the manuscript is incomplete. The patient cohort is very small, with just 10 patients; to establish a significant result the cohort size should be increased. Furthermore, the functional implication of p300 is also to be looked into.

eLife Assessment

In this important study, the authors advance our understanding of copper uptake by chalkophores and their targeted metalloproteins in Mycobacterium tuberculosis. These convincing data demonstrate that chalkophore-acquired copper is solely incorporated into the Mtb bcc:aa3 copper-iron respiratory oxidase under low copper conditions, and that chalkophore-mediated protection of the respiratory chain is critical to Mtb virulence. These findings may be leveraged for drug discovery and will be of broad interest to those studying bacterial pathogenesis.

eLife Assessment

This manuscript reports fundamental discoveries on how necrotic cells contribute to organ regeneration through apoptotic signalling to produce cells with non-lethal apoptotic caspase activity that contribute to the regenerated tissue. These findings will be of broad interest to those who study wound repair and tissue regeneration. The strength of the evidence is solid and has been improved in the revised version.

eLife Assessment

This manuscript establishes a mathematical model to estimate the key parameters that control the repopulation of planarian stem cells after sublethal irradiation as they undergo fate-switching as part of their differentiation and self-renewal process. The findings are valuable for future investigation of stem cell division in planarians. The methods are solid, integrating modeling with perturbations of key transcription factors known to be critical for cell fate decisions, but the authors have only shown that this is the case for a small number of stem cell types.

eLife Assessment

This study provides evidence that single-cell multi-omics profiling can reveal key regulators of HIV-1 persistence and early immune dysregulation, particularly implicating KLF2 and Th17 cells as major players in viral reservoir dynamics. The findings are solid, supported by rigorous integration of scRNA-seq and scATAC-seq data, but are limited by sample size and lack of validation with external datasets. Overall, this work makes a valuable contribution to understanding HIV-1 immune evasion and highlights potential therapeutic targets for reservoir eradication.

eLife Assessment

This valuable study describes a software package in R for visualizing metabolite ratio pairs. The evidence supporting the claims of the authors is solid and broadly supports the authors' conclusions. This work would be of interest to the mass spectrometry community.

eLife Assessment

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

eLife Assessment

This important study reveals that disrupting fatty acid metabolism in macrophages significantly restricts the growth of Mycobacterium tuberculosis, showing that impaired lipid processing triggers various antimicrobial responses. Overall, the approach is robust, utilizing CRISPR-Cas9 knockout of multiple genes involved in lipid metabolism which yielded convincing data. This work highlights how host lipid metabolism affects the ability of tubercle bacilli to thrive intracellularly, pointing to potential new therapeutic targets.

eLife Assessment

This manuscript establishes a mathematical model to estimate the key parameters that control the repopulation of planarian stem cells after sublethal irradiation as they undergo fate-switching as part of their differentiation and self-renewal process. The findings are important for future investigation of stem cell division in planarians and have implications for analyzing stem cell biology in other systems. The methods are convincing, integrating modeling with perturbations of key transcription factors known to be critical for cell fate decisions, but the authors have only shown that this is the case for a small number of stem cell types.

eLife Assessment

This important and well-written study uses functional neuroimaging in human observers to provide compelling evidence that activity in the early visual cortex is suppressed at locations that are frequently occupied by a task-irrelevant but salient item. This suppression appears to be general to any kind of stimulus and also occurs in advance of any item actually appearing. The work will be of great interest to psychologists and neuroscientists examining attention, perception, learning and prediction.

eLife Assessment

This valuable work presents how PRDM16 plays a critical role during colloid plexus development, through regulating BMP signaling. Solid evidence supports the context-dependent gene regulatory mechanisms both in vivo and in vitro. The work will be of broad interest to researchers working on growth factor signaling mechanisms and vertebrate development.

eLife Assessment

The authors utilize a valuable computational approach to exploring the mechanisms of memory-dependent klinotaxis, with a hypothesis that is both plausible and testable. Although they provide a solid hypothesis of circuit function based on an established model, the model's lack of integration of newer experimental findings, its reliance on predefined synaptic states, and oversimplified sensory dynamics, make the investigation incomplete for both memory and internal-state modulation of taxis.

eLife Assessment

This important study examines the role of pericytes in patterning the zebrafish blood-brain barrier (BBB) and controlling its permeability. Using pdgfrb mutant zebrafish models lacking brain pericytes, the authors report that pericyte-deficient cerebrovasculatures are ill-patterned, yet display unaltered restrictive BBB permeability properties at larval and juvenile stages. More severe phenotypes are detected in adults, with focal leakage sites associated with hemorrhages and aneurysms. Using solid and beautifully documented imaging, the authors suggest that, contrary to the situation described in rodent models, pdgfrb-dependent pericytes are not required to maintain the BBB in the zebrafish brain; these unexpected and intriguing findings reshape our understanding of BBB permeability regulation in vertebrates.

eLife Assessment

This important manuscript proposes a new strategy for the identification of new mechanisms of drug resistance based on SAturated Transposon Analysis in Yeast (SATAY), a powerful transposon sequencing method in Saccharomyces cerevisiae. This method allows us to uncover loss- and gain-of-function mutations conferring resistance to 20 different antifungal compounds. The method is convincing, allowing the authors to identify a novel interaction of chitosan with the cell wall mannosylphosphate, and show that the transporter Hol1 concentrates the novel antifungal ATI-2307 within yeast.

eLife Assessment

This important study seeks to examine the relationship between pupil size and information gain, showing opposite effects dependent upon whether the average uncertainty increases or decreases across trials. Given the broad implications for learning and perception, the findings will be of broad interest to researchers in cognitive neuroscience, decision-making, and computational modelling. Nevertheless, the evidence in support of the particular conclusion is at present incomplete - the conclusions would be strengthened if the authors could both clarify the differences between model-updating and prediction error in their account and clarify the patterns in the data.

eLife Assessment

This important study analyzes a large dataset of Salmonella gallinarum whole-genome sequences and provides findings regarding the population structure of this avian-specific pathogen. The convincing results indicate regional adaptation of the mobilome-driven resistome and a role in the evolutionary trajectory of this pathogen that will interest microbiologists and researchers working on genomics, evolution, and antimicrobial resistance.

eLife Assessment

In this valuable study, Tutak and colleagues set out to identify factors that mediate Repeat Associated Non-AUG (RAN) translation of CGG repeats in the FMR1 mRNA which are implicated in toxic protein accumulation that underpins ensuing neurological pathologies. The authors provide solid evidence that RPS26 may be implicated in mediating the RAN translation of FMR1 mRNA. This article should be of broad interest to researchers in the variety of disciplines including post-transcriptional regulation of gene expression and neurobiology.

eLife Assessment

This valuable study uses a massive and long-term experimental data set to provide solid evidence on how tree diversity affects host-parasitoid communities of insects in forests. The work will be of interest to ecologists working on biodiversity conservation, community ecology, and food webs.