eLife Assessment

This study makes an important contribution by characterizing the role of the exocyst in secretory granule exocytosis in the Drosophila larval salivary gland. The results are solid and lead to the novel interpretation that the exocyst participates not only in exocytosis, but also in earlier steps of secretory granule biogenesis and maturation. However, the authors are urged to provide additional proof that the exocyst subunit knockdowns were effective and to acknowledge the possibility that inactivation of an essential exocytosis component could indirectly affect other parts of the secretory pathway.

eLife Assessment

This fundamental study substantially advances our understanding of how habitat fragmentation and climate change jointly influence bird community thermophilization in a fragmented island system. The authors provide convincing evidence using appropriate and validated methodologies to examine how island area and isolation affect the colonization of warm-adapted species and the extinction of cold-adapted species. While minor clarifications regarding the definition of fragmentation could further enhance the presentation, the study is of high interest to ecologists and conservation biologists, as it provides insight into how ecosystems and communities respond to climate change.

eLife assessment

This proof-of-concept study focuses on an A->G DNA base editing strategy that converts CAG repeats to CAA repeats in the human HTT gene, which causes Huntington's disease (HD). These studies are conducted in human HEK293 cells engineered with a 51 CAG canonical repeat and in HD knock-in mice harboring 105+ CAG repeats. The findings of this study are valuable for the HD field, applying state-of-the-art techniques. However, the key experiments have yet to be performed in neuronal systems or brains of these mice: actual disease-rectifying effects relevant to patients have yet to observed, leaving the work incomplete.

eLife assessment

This study presents a useful examination of the prevalence of interactions between amino acids from different periods of Earth's history and coenzymes. While the premise of this work is well founded, the data lend themselves to alternative interpretations, suggesting that the main conclusions might be incompletely supported by the findings. The work would benefit from the inclusion of additional supplementary data and further analysis. This manuscript would be of interest to evolutionary biologists and biophysicists.

eLife assessment

This is a valuable study of the mechanisms of microtubule organization in pancreatic islet beta cells that enable optimal insulin secretion. Using a combination of live imaging and photo-kinetic assays in an in vitro culture system, the authors provide solid evidence to demonstrate that kinesin-1-mediated microtubule sliding, which has previously been known from neurons and embryos, is essential for establishing the sub-membranous microtubule band in response to glucose levels in beta cells. The inclusion of an animal model or primary cells, as well as data on the physiological relevance of the finding, would have strengthened the study. The work will be of interest to cell biologists studying cytoskeletal dynamics and organelle trafficking and to translational biologists working on diabetes.

eLife Assessment

In this valuable paper, the authors created a reporter mouse line in which the Axon Initial Segment (AIS) is intrinsically labeled by an ankyrin-G-GFP fusion protein activated by Cre recombinase, tagging the native Ank3 gene. Using confocal, superresolution, and two-photon microscopy as well as whole-cell patch-clamp recordings in vitro, ex vivo, and in vivo, the authors convincingly document that the subcellular scaffold of the AIS and electrophysiological parameters of labeled cells remain unchanged. They further uncover rapid AIS remodeling following increased network activity in this model system, as well as highly reproducible in vivo labeling of AIS over weeks.

eLife Assessment

This in several parts valuable study confirms the roles of Dact1 and Dact2, two factors involved in Wnt signaling, during zebrafish gastrulation and demonstrates their genetic interactions with other Wnt components to modulate craniofacial morphologies. Unfortunately, there are several limitations associated with the study, making it challenging to distinguish the primary and secondary effects of each factor, and their roles in craniofacial morphogenesis. The findings of a new potential target of dact1/2-mediated Wnt signaling are potentially of value; however, experimental evidence supporting their functional significance remains incomplete due to inconsistent results and limitations inherent to the overexpression approach.

eLife Assessment

This important work presents a consolidated overview of the NeuroML2 open community standard and provides convincing evidence for its central role within a broader software ecosystem for the development of neuronal models that are open, shareable, reproducible, and interoperable. A major strength of the work is the continued development over more than two decades to establish, maintain, and adapt this standard to meet the evolving needs of the field. This work is of broad interest to the sub-cellular, cellular, computational, and systems neuroscience communities undertaking studies involving theory, modeling, and simulation.

eLife Assessment

This useful study uses an intranasal mouse infection model with Streptococcus suis, a gram-positive bacterial pathogen that causes severe losses in pigs around the world. The manuscript provides insights that the capsular polysaccharide, one of the virulence factors of this pathogen, contributes to tissue dissemination and neurotropism in the host. However, the evidence is currently incomplete, and further experiments and careful interpretation of the current results and methods used are necessary to support the conclusions of the manuscript.

eLife Assessment

A regression discontinuity analysis finds essentially no effect of 1 additional year of secondary education on brain structure in adulthood. This is a valuable finding that adds to the literature on the impact of education on brain health. The evidence presented is solid, with strengths including methodological novelty as well as principled study design; the impact is, however, limited as the manipulated variable only relates to a single additional year of education (remaining in education to 15 vs 16 years of age). The interpretation is further missing discussion of the healthy volunteer bias of the UK Biobank sample, amplified in the imaging extension.

eLife Assessment

This is an important study examining the role of conserved PCH-2 protein at different stages of C. elegans meiosis. The authors use elegant molecular genetic approaches to provide convincing evidence to support their claims. The work will be of interest to scientists studying meiosis, DNA recombination, and chromosome segregation.

eLife Assessment

The manuscript provides important new insights into the mechanisms of statistical learning in early human development, showing that statistical learning in neonates occurs robustly and is not limited to linguistic features but occurs across different domains. The evidence is convincing, although an additional experimental manipulation with conflicting linguistic and non-linguistic information as well as further discussion about the linguistic vs non-linguistic nature of the stimulus materials would have strengthened the manuscript. The findings are highly relevant for researchers working in several domains, including developmental cognitive neuroscience, developmental psychology, linguistics, and speech pathology.

eLife Assessment

This paper contains valuable ideas for methodology concerned with the identification of genes associated with disease prognosis in a broad range of cancers. However, there are concerns that the statistical properties of MEMORY are incompletely investigated and described. Further, more precise details about the implementation of the method would increase the replicability of the findings by other researchers.

eLife Assessment

The study is important - not only for its comprehensive transcriptomic analysis of the developmental trajectory of syncytiotrophoblasts (STBs), but also for its comparative evaluation of primary human placental tissues and two human trophoblast organoid models. The study highlights the utility of these organoid models in advancing research on human STB biology. The conclusions of this work are supported by compelling analyses and experimental evidence.

eLife Assessment

This valuable study uses robust time-dependent microscopy assays to show that during HIV-1 infection, the viral accessory protein Vif causes cell cycle arrest during metaphase and not G2/M as previously thought. The conclusions are convincing in the context of the immortalized cellular models used, and they serve as a starting point to determine whether Vif-dependent regulation of the cell cycle modulates HIV-1 replication and pathogenesis in more physiologically relevant primary cells or in vivo.

eLife Assessment

This important work investigates the mechanism that underlies the switch between feeding and mating behaviors in the oriental fruit fly, Bactrocera dorsalis. Using a variety of approaches, the authors show that this switch is mediated by the neuropeptide, sulfakinin, acting peripherally through the sulfakinin receptor 1 to regulate the expression of antennal odorant receptors. The evidence is solid in support of the hypothesis that sulfakinin signaling mediates changes in the periphery, although additional experimental details would strengthen these claims.

eLife Assessment

Shen et al. present a computational account of individual differences in mouse exploration when faced with a novel object in an open field from a previously published study (Akiti et al.) that relates subject-specific intrinsic exploration and caution about potential hazards to the spectrum of behaviors observed in this setting. Overall, this computational study is an important contribution that leverages a very general modeling framework (a Bayes Adaptive Markov Decision Process) to quantify and interrogate distinct drivers of exploratory behavior under potential threat. Given their assumptions, the modeling results are convincing: the authors are able to describe a substantial amount of the behavioral features and idiosyncracies in this dataset, and their model affords a normative interpretation related to inherent risk aversion and predation hazard "flexibility" of individual animals and should be of broad interest to researchers working to understand open-ended exploratory behaviors.

eLife Assessment

This useful study examines the function of the rnc gene, which encodes the RNase III ribonuclease, as it relates to virulence of Salmonella Enteritidis. The authors demonstrate that the rnc gene is markedly upregulated in strains proposed to exhibit high virulence and that the product of the rnc gene promotes the expression of SodA, which contributes to the survival of Salmonella Enteritidis in the face of oxidative stress. The study also suggests that elevated levels of rnc gene expression assist Salmonella Enteritidis in evading immune responses by diminishing the presence of accumulated double-stranded RNA (dsRNA), although the evidence substantiating this and the above assertions remains incomplete.

eLife Assessment

The authors propose that positive biodiversity-ecosystem functioning relationships found in experiments have been exaggerated because commonly used statistical analyses are flawed. To remedy this, a new type of analysis based on a concept of "partial density monoculture yield" is proposed. However, the presented concept and analysis methods are not reproducibly described, do not appear to be complete, and are inadequate for hypothesis testing. The reviewers found that the authors misinterpret current research in the field and made limited efforts to understand or address the reviewer comments on a previous version of the study.

eLife Assessment

The authors present an important theoretical framework that describes the interplay between liquid-liquid phase separation and protein aggregation within a mean-field model. This work will be of high interest to the biophysics and molecular biology communities, as it will help understand and analyse assembly within biomolecular condensates in cells or in-vitro. Major strengths of this convincing work are the consideration of aggregates with various dimensionality and the possibility for protein gelation.

eLife Assessment

This valuable study provides an experimental paradigm and state-of-the-art analysis method for studying the existence of call types and transition differences among Mongolian gerbil families in a naturalistic environment. The analyses are convincing, with a thorough treatment of the acoustic data and a demonstration of the robustness of the observed effect across days. The work will likely be of interest to the auditory neuroscience and neuroethology communities.

eLife Assessment

This valuable study investigates evolutionary aspects around a single amino acid polymorphism, known to be under long-term balancing selection, in an immune peptide of Drosophila melanogaster. Using alleles with different substitutions, the investigators demonstrate that while one allele provides better survival after systemic infections by a bacterial pathogen, the alternative allele endows its carriers with a longer lifespan under certain conditions. The authors suggest that these contrasting fitness effects of the two alleles contribute to balancing their long-term evolutionary fate. While the work is very interesting, the strength of the provided evidence is still incomplete, and the study would benefit from more rigorous approaches.

eLife Assessment

This manuscript addresses infections of the parasite Taenia solium, which causes neurocysticercosis (NCC). NCC is a common parasitic infection that leads to severe neurological problems. It is a major cause of epilepsy, but little is known about how the infection causes epilepsy. The authors used neuronal recordings, imaging of calcium transients in neurons, and glutamate-sensing fluorescent reporters. A strength of the paper is the use of both rodent and human preparations. The results provide convincing evidence that the larvae secrete glutamate and this depolarizes neurons. Although it is still uncertain exactly how epilepsy is triggered, the results suggest that glutamate release contributes. Therefore, the paper is a fundamental step towards understanding how Taenia solium infection leads to epilepsy.

eLife Assessment

This study presents a valuable new method for probing the DNA and proteins associated with targeted genomic elements in cells. The authors present solid evidence that the method can map DNA-DNA interactions for individual loci and can detect enriched proteins at repetitive DNA loci such as telomeres, but benchmarks of the method's resolution and specificity remain incomplete. The methodological details of this study will be of particular interest and utility to chromatin biologists.

eLife Assessment

This valuable paper describes the crystal structure of a complex of Sld3-Cdc45-binding domain (CBD) with Cdc45, which is essential for the assembly of an active Cdc45- MCM-GINS (CMG) double hexamers at the replication origin. Although the results shown in the paper are of interest to researchers in DNA replication and genome stability, the biochemical analysis of protein-protein interaction and DNA binding is incomplete, and the paper needs additional data and revised discussion.

eLife Assessment

The aim of this useful study is to investigate the role of semilunar granule cells on memory engrams in the dentate gyrus. Which cells get recruited during contextual memory processing is a timely and significant question. However, evidence for the study's major conclusions is currently incomplete due to caveats in study design, technical limitations, and missing controls.

eLife Assessment

This study offers a valuable genomic dataset, analyses, and functional studies on gonadal sex determination and development. The work addresses long-standing questions regarding the role of the Drosophila sex determination hierarchy, sex chromosomes, and the interaction between the sex determination hierarchy and sex chromosome composition in gonad development. Although this convincing work has been conducted rigorously, the authors missed some key opportunities in their analysis.

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 solid, however, some of the claims are not fully supported by the data. To enhance the conclusions and readability, the writing clarity, data analysis and justification of experimental design rationale need to be worked on to enhance the study's interest among chemical biologists, biochemists, and scientists in drug discovery.

eLife Assessment

This valuable paper shows image correlation spectroscopy (ICS) as a new tool to analyze the clustering of proteins involved in DNA damage response (DDR). The solid evidence presented demonstrates that this method is more sensitive than traditional focus counting, although some of the claims require further contextualization. This new method provides an alternative tool to analyze immuno-stained focus for researchers in the fields of DDR and cell biology.

eLife Assessment

This important study provides a comprehensive analysis of how substitutions within the catalytic domain of the tyrosine kinase Met affect its sensitivity to inhibition by ATP-competitive, small molecule inhibitors and provides a mechanistic framework for understanding drug resistance. The evidence supporting the authors' claims is convincing, the data sets are comprehensive, and the analyses are rigorous. This work will be of broad interest to biochemists, structural biologists, and medicinal chemists.

eLife Assessment

This important study leverages an impressive and comprehensive longitudinal 16S microbiome dataset from baboons to provide insights regarding the use of a microbiome-based clock to predict biological age, with solid evidence for age-associated microbiome features and environmental and social variables that impact microbiome aging. This study of microbiomes as markers of host age will be relevant to a broad range of researchers, especially those interested in alternatives to measuring biological aging.

eLife Assessment

This is a valuable report of tracheal terminal cells (TTCs) in Drosophila being immune privileged. The authors demonstrated that TTCs lack the expression of membrane-associated peptidoglycan recognition receptor PGRP-LC, which protects these cells from activating immune pathway or JNK-mediated cell death to maintain TTC homeostasis. While genetic experiments using RNAi and overexpression are mostly convincing, the data on the expression of PGRP-LCx and cell death phenotypes following immune activation are currently incomplete. The work will be of interest to researchers in innate immunity across various model systems.

eLife Assessment

This useful study presents the first detailed and comprehensive description of brain sulcus anatomy of a range of carnivoran species based on a robust manual labeling model allowing species comparisons. Although the database is recognized and the method for reconstructing cortical surfaces is convincing, the evidence supporting the conclusions is incomplete due to the lack of appropriate quantitative measurements and analyses. Considering additional specimens to assess intraspecies variations, as well as exploring the functional correlates of interspecies differences would increase the scope of the study. Setting an instructive foundation for comparative anatomy, this study will be of interest to neuroscientists and neuroimaging researchers interested in that field, as well as in brain morphology and sulcal patterns, their phylogeny, and ontogeny in relation to functional development and behaviour.

eLife Assessment

This important paper by Lechler and colleagues describes the transcriptomic signature and fate of intermediate cells (ICs), a transient and poorly defined embryonic cell type in the skin. The paper convincingly shows through lineage tracing that ICs are granular and not spinous cell precursors, and through ectopic expression in vivo, that cell contractility, a mechanical feature of ICs, lies upstream of differentiation.

eLife Assessment

This valuable study shows that eliminating a large portion of the principal neurons in the mammalian olfactory bulb does not affect the initial establishment of the circuit but has an impact on its maintenance. The strength of the paper is that the anatomical changes induced by genetic ablation of neurons are clear-cut. There is solid support for the findings, with a description of the structural and behavioral effects of ablating the majority of M/T neurons.

eLife Assessment

This study presents a valuable finding on a potential signaling pathway responsible for the direct effects of nicotine on intestinal stem cell growth and tumorigenesis.  The evidence supporting the claims of the authors is solid. This research will be of interest to medical biologists specializing in intestinal tumors.

eLife Assessment

This study provides an important re-evaluation of modality-specific information processing in the thalamus of trained mice. Using an elegant task design that probes competing tactile and visual stimuli, the authors present compelling evidence that behavioral training reshapes the sensitivity of higher-order thalamic nuclei. Despite the powerful task design and the significance of the main findings, the origin of the cross-modal responses remains an open question and requires future investigation.

eLife Assessment

This paper addresses an important topic (normative trajectory modelling), seeking to provide a method aiming to accurately reflect the individual deviation of longitudinal/temporal change compared to the normal temporal change characterized based on a pre-trained population normative model. The evidence provided for the new methods is, however, incomplete, with the simulations validating the method needing to be extended.

eLife Assessment

This article presents valuable findings on the impact of climate change on odonates, integrating phenological and range shifts to broaden our understanding of biodiversity change. The study leverages extensive natural history data, offering a combined analysis of temporal trends in phenology and distribution and their potential drivers. The support for the findings is solid, though additional clarification regarding the methods and alternative sensitivity analyses could make the conclusions stronger.

eLife Assessment

This study poses an important step forward in understanding the brain-network embedding of beta oscillations. The study advances our circuit-level understanding of the pathophysiology associated with dopaminergic alterations in psychiatric or neurological disorders. The study provides compelling evidence that beta oscillations across the neocortex and basal ganglia map onto shared functional and structural networks that show significant positive correlations with dopamine receptors.

eLife Assessment

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

eLife Assessment

This important study presents a statistical framework for the analysis of photometry signals and provides an open-source implementation. The evidence supporting the benefits of the presented functional mixed-effect modeling analysis as opposed to 1) summary statistics and 2) other pointwise regression models is convincing with a thorough comparison with other methods and datasets. This work will be of great interest to researchers using not only fiber photometry, but other time-series data such as calcium imaging or electrophysiology data, and wanting to implement trial-by-trial temporal analysis, taking also into account variability within the dataset.

eLife Assessment

This valuable study is a companion to a paper introducing a theoretical framework and methodology for identifying Cancer Driving Nucleotides (CDNs). The evidence that recurrent SNVs or CDNs are common in true cancer driver genes is convincing, with more limited evidence that many more undiscovered cancer driver mutations will have CDNs, and that this approach could identify these undiscovered driver genes with about 100,000 samples.

eLife Assessment

This important paper introduces a theoretical framework and methodology for identifying Cancer Driving Nucleotides (CDNs), primarily based on single nucleotide variant (SNV) frequencies. A variety of solid approaches indicate that a mutation recurring three or more times is more likely to reflect selection rather than being the consequence of a mutation hotspot. The method is rigorously quantitative, though the requirement for larger datasets to fully identify all CDNs remains a noted limitation. The work will be of broad interest to cancer geneticists and evolutionary biologists.

eLife Assessment

The authors proposed an important novel deep-learning framework to estimate posterior distributions of tissue microstructure parameters. The method shows superior performance to conventional Bayesian approaches and there is convincing evidence for generalizing the method to use data from different protocol acquisitions and work with models of varying complexity.

eLife Assessment

The manuscript reports a valuable finding on dopamine receptor-mediated regulation, the firing of striatal cholinergic interneurons in both healthy and dyskinesia states, identifying that Kv1 channels play a key role in the burst-dependent pause. The study presents solid experimental data, and provides additional mechanistic insights into how burst activity in SCINs leads to a subsequent pause, highlighting the involvement of D1/D5 receptors. This work will be of interest to researchers studying the pathological mechanisms of Parkinson's disease.

eLife Assessment

This study introduces a novel method for estimating spatial spectra from irregularly sampled intracranial EEG data, revealing cortical activity across all spatial frequencies, which supports the global and integrated nature of cortical dynamics. The study showcases important technical innovations and rigorous analyses, including tests to rule out potential confounds; however, the lack of comprehensive theoretical justification and assumptions about phase consistency across time points renders the strength of evidence incomplete. The dominance of low spatial frequencies in cortical phase dynamics continues to be of importance, and further elaboration on the interpretation and justification of the results would strengthen the link between evidence and conclusions.

eLife Assessment

The authors show MRI relaxation time changes that are claimed to originate from cell membrane potential changes. This would be very important if true because it may provide a mechanism whereby membrane potential changes could be inferred noninvasively. However, the membrane potential manipulations applied here will induce cell swelling, and cell swelling has been previously shown to affect relaxation time. Therefore, the claim that the relaxation time changes observed in this manuscript are due to cell membrane potential changes is inadequately supported.

eLife Assessment

The authors have provided a valuable addition to the literature on large-scale electrophysiological experiments across many labs. The evidence that the authors provided was incomplete - while some comparisons with analyses outside of the manuscript's approaches were provided, a more complete manuscript would have compared with alternative standardized analyses. In particular, alternative spike sorting metrics and the alternative of GLM-based analysis of data would have made the interpretation of the results clearer.

eLife Assessment

In this paper, Seon and Chung investigate changes in own risk-taking behavior, when they are being observed by a "risky" or "safe" player. Using computational modeling and model-informed fMRI, the authors present solid evidence that participants adjust their choice congruent with the other player's type (either risky or safe). The conclusions of the paper are an important contribution to the field of social decision-making as they show a differentiated adjustment of choices and not just a universally riskier choice behavior when being observed as has been claimed in previous studies.

eLife Assessment

This useful study reports on the impact of antibiotic pressure on the genomic stability of the mc2155 strain of Mycobacterium smegmatis, a model for Mycobacterium tuberculosis. The findings of the study indicate that exposure to antibiotics did not lead to the development of new adaptive mutations in controlled laboratory environments, challenging the notion that antibiotic resistance arises from drug-induced microevolution. The genomic analysis provides detailed insights into the stability of M. smegmatis following exposure to standard TB treatment antibiotics, and the evidence suggesting that antibiotic pressure does not contribute to the emergence of new adaptive mutations is solid.

eLife Assessment

Yamamoto and Matano provide convincing evidence that a G63E CD8+ T-cell escape mutation in the accessory viral protein Nef facilitates the induction of neutralizing antibody (nAb) responses in rhesus macaques infected with SIVmac239. Functional analyses support that this mutation specifically impairs Nef`s ability to stimulate PI3K/Akt/mTORC2 signalling. This important study suggests that the accessory viral Nef protein impairs B cell function and effective humoral immune responses and is of interest for researchers and physicians interested in HIV/AIDS and vaccine development.

eLife Assessment

This important study presents a significant methodological advance by leveraging previously discarded, unmapped DNA sequence reads to estimate pest infestation loads across plant accessions, and map variation in these apparent pest loads to defense genes. The bioinformatics approach is compelling, and the results should bear broad implications for phenotype-genotype prediction, especially regarding the use of unmapped reads for GWAS.

eLife Assessment

This important study examines the effects of NFKB2 mutations on pituitary gland development through hypothalamic-pituitary organoids. The evidence supporting the main conclusions is solid, although analysis of additional clones to exclude inter-clone variability would strengthen the conclusions. This is a revised study, but insight into the mechanism of action of NFKB2 during pituitary development is incomplete. This work will be of interest to endocrinologists and biologists working on pituitary gland development and disease.

eLife Assessment

This work identifies the molecular function of an orphan human transporter, SLC35G1, providing convincing evidence that this protein is involved in intestinal citrate absorption. This work provides important insight into transporter function and human physiology.

eLife Assessment

This study reports important findings on identifying sequence motifs that predict substrate specificity in a class of lipid synthesis enzymes. It sheds light on a mechanism used by bacteria to modify the lipids in their membrane to develop antibiotic resistance. The evidence is compelling, with a careful application of machine learning methods, validated by mass spectrometry-based lipid analysis experiments. This interdisciplinary study will be of interest to computational biologists and to the community working on lipids and on enzymes involved in lipid synthesis or modification.

eLife Assessment

This important study provides convincing evidence that developing neurons in the neocortex regulate glial cell development. The data demonstrates that the transcription factor FOXG1 negatively regulates gliogenesis by controlling the expression of a member of the FGF ligand family and by suppressing the receptor for this ligand in developing neurons. This study leads to a new understanding of the cascade of events regulating the timing of glial development in the neocortex.

eLife Assessment

This important work attempts to establish a causal link between neurotrophin signaling and experience-induced structural plasticity in dopaminergic circuits in the adult fly brain, a topic of broad interest to the neuroscience community. While the authors provide solid evidence for the role of this signaling in regulating the structure and synapses of dopaminergic circuits, the evidence for a direct link between neurotrophin signaling and experience-induced structural plasticity remains incomplete.

eLife Assessment

This study presents important findings that will allow for a better understanding of the role of mitochondria in behaviours of C. elegans. There is convincing evidence that mutants in a subunit of the mitochondrial calcium uniporter (MCU-1) show defects in olfactory adaptation and this gene regulates neuropeptide secretion and allows for behavioural modulation in C. elegans. However, the evidence that mitochondrial calcium modulates odour-based behaviour in C. elegans is incomplete. This claim would require support from calcium imaging in conditioned WT and mcu-1 animals. This work would be of interest to labs working on behaviours across phyla.

eLife Assessment

This manuscript presents a valuable minimal model of habituation which is quantified by information theoretic measures. The results here could be of use in interpreting habituation behavior in a range of biological systems. However, the evidence presented is incomplete and would benefit from more rigorous approaches and a fuller accounting of the hallmarks of habituation.

eLife Assessment

The paper describes a novel approach for inferring features of synaptic networks from recordings of individual cells within the network. The paper will be a valuable contribution to those studying central pattern generators, including those involved in respiration. However, the theoretical approach to drawing inferences regarding the underlying synaptic currents is incomplete as it relies on unsupported simplifying assumptions.

eLife Assessment

The study by Power and colleagues is important as elucidating the dynamic immune responses to photoreceptor damage in vivo potentiates future work in the field to better understand the disease process. However the evidence supporting the authors' claims is incomplete. The current manuscript would further benefit from validating their conclusion with additional supporting data from earlier time points (6 to 12 hours), additional markers to characterize neutrophils, more n numbers to strengthen the analysis, and evaluation of immune responses in mice with a stronger laser ablation, as well as further evidence to distinguish resident microglia vs. infiltrating macrophages due to the BRB breakdown. The authors should reorganize the article to make it easier and more straightforward to follow.

eLife Assessment

This useful study combines multiplexed RNA-FISH with downstream analyses and modelling to describe novel dendritic mRNA distribution and behavioural features. Although the downstream analysis pipeline is novel, the results from this study are as of yet incomplete. Further inclusion of key missing controls, further work to better assess the physiological relevance, or additional modelling to expand their conclusions would make this work of greater interest to RNA biologists.

eLife Assessment

The study is useful for advancing understanding of spinal cord injuries, but it presents inadequate evidence due to the use of multiple datasets. Data were collected from different models of spinal cord injury, various regions of the spinal cord, and an iPSC model, with the differences between these models making it difficult to draw reliable conclusions.

eLife Assessment

Barzó et al. assessed the electrophysiological and anatomical properties of a large number of layer 2/3 pyramidal neurons in brain slices of human neocortex across a wide range of ages, from infancy to elderly individuals, using whole-cell patch clamp recordings and anatomical reconstructions. This large data set represents a valuable contribution to our understanding of how these properties change across the human lifespan, and although the results presented are convincing, analyzing the data by absolute age rather than age ranges as well as clarifying the methods used and some of the statistical approaches applied would strengthen the conclusions. The analysis of spine density requires additional biological replicates to support the conclusions stated. These data strengthen our understanding of how these properties change with age and will contribute to building more realistic models of human cortical function.

eLife Assessment

Oor and colleagues report the potentially independent effects of the spatial and feature-based selection history on visuomotor choices. They outline compelling evidence, tracking the dynamic history effects based on their extremely clever experimental design (urgent version of the search task). Their finding is of fundamental significance, broadening the framework to identify variables contributing to choice behavior and their neural correlates in future studies.

eLife Assessment

This study investigates a dietary intervention that employs a smartphone app to promote meal regularity, which may be useful. Despite no self-reported changes in caloric intake, the authors report significant weight loss for the relatively short duration of only 6 weeks. While the concept is very interesting and deserves to be studied due to its potential clinical relevance, the study's rigor needs to be improved upon and is currently considered incomplete, notably the reliance on self-reported food intake, a highly unreliable way to assess food intake. Additionally, the study theorizes that the intervention resets the circadian clock, but the study needs more reliable methods for assessing circadian rhythms, such as actigraphy. Further, if this restrictive dietary intervention has any more promise in achieving long-term weight loss than the myriad other restrictive diets, it remains to be tested.

eLife Assessment

This important revised report describes the control of the activity of the RNA-activated protein kinase, PKR, by the Vaccinia virus K3 protein. A strength of the manuscript is the powerful combination of a classic yeast-based assay with high-throughput sequencing and its convincing experimental use to characterize large numbers of PKR variants, now with improved controls for potential biases. A minor current limitation that the authors may address in the future is the scope of the screen in terms of the segments of PKR included.

eLife Assessment

This study retrospectively analyzed clinical data to develop a risk prediction model for pulmonary hypertension in high-altitude populations. The evidence is solid, and the findings are useful and hold clinical significance as the model can be used for intuitive and individualized prediction of pulmonary hypertension risk in these populations.

eLife Assessment

The authors analyze a comprehensive cohort of human plasma samples to identify an extracellular vesicles protein signature for early diagnosis of pancreatic cancer. The application of liquid biopsies is valuable, and the work addresses a key clinical problem as pancreas cancer is often diagnosed in late stages. The strength of evidence is solid. Altogether, this work supports the potential use of extracellular vesicles in clinical settings, with promising value to scientists and clinicians.

eLife Assessment

This fundamental work by Mäkelä et al. presents compelling experimental evidence supported by a theoretical model that the amount of chromosomal DNA can become limiting for the total rate of mRNA transcription and consequently protein production in the model bacterium Escherichia coli. The work is based on a mutant that allows inhibition of DNA replication while following growth at the single-cell level due to cell filamentation. The work significantly advances our understanding of growth and of the central dogma, and will be of considerable interest within both systems biology and microbial physiology.

eLife Assessment

This fundamental study generated a single cell atlas of mouse periosteal cells under both steady-state and fracture healing conditions to address the knowledge gap regarding cellular composition of the periosteum and their responses to injury. Based on convincing transcriptome analyses and experimental validation, the authors identified the injury induced fibrogenic cell (IIFC) as a characteristic cell type appearing in the bone regeneration process and proposed that the IIFC is a progenitor undergoing osteochondrogenic differentiation. This study will provide a significant publicly accessible dataset to reexamine the expression of the reported periosteal stem and progenitor cell markers.

eLife Assessment

This manuscript describes an important study of a new lipid-mediated regulation mechanism of adenylyl cyclases. The biochemical evidence provided is convincing and will trigger more research in this mechanism. This manuscript will be of interest to all scientists working on lipid regulation and adenylyl cyclases.

eLife Assessment

The neurotrophic factor Neuritin can moderate T-cell tolerance and immunity through both regulatory T (Treg) and effector T cells, promoting Treg cell expansion and suppression while dampening effector T cells to mediate the inflammatory response. Neuritin expression influences the membrane potential, ion channels, and nutrient transporter expression patterns of CD4+ T cells, contributing to differential metabolic states in Treg and effector T cells. These findings are solid and important for understanding immune regulation involving Treg cells and effector T cells.

eLife Assessment

This important work presents data showing that all non-proneural phenotypes of the Inhibitor of DNA binding (Id) protein Emc are mediated through inappropriate nonapoptotic caspase activity. Using the developing Drosophila retina as a model the authors show that Emc acts by transcriptionally regulating the Death-Associated Inhibitor of Apoptosis 1 (diap1) gene, which impacts on Notch signaling by caspase-dependent increase of Delta protein. These are compelling findings, interesting for the caspase/apoptosis field as they add more non-apoptotic functions of caspases to the list, as well as for the Id field, which examines how Id proteins inhibit cell differentiation.

eLife Assessment

This important study, which will be of interest to those studying the evolution and maintenance of antibiotic resistance, addresses the hypothesis that antibiotic resistance arising de novo during treatment will carry a higher fitness cost and will revert to susceptibility more readily than resistance that has been transmitted between hosts. There are, however, concerns that the 'putatively transmitted isolates' in this study do not necessarily represent resistant isolates that have been transmitted between hosts. The support for the central claim of different patterns of reversion between isolates with de novo resistance and putatively transmitted resistant isolates is currently incomplete.

eLife Assessment

This study presents valuable data on the increase in individual differences in functional connectivity with the auditory cortex in individuals with congenital/early-onset hearing loss compared to individuals with normal hearing. The evidence supporting the study's claims is convincing, although additional work using resting-state functional connectivity and further links to how the results align with the underlying biology could have further strengthened the study. The work will be of interest to neuroscientists working on brain plasticity and may have implications for the design of interventions and compensatory strategies.

eLife Assessment

So et al. present an optimized protocol for single-nuclei RNA sequencing of adipose tissue in mice, ensuring better RNA quality and nuclei integrity. The authors use this protocol to explore the cellular landscape in both lean and diet-induced obese mice, identifying a dysfunctional hypertrophic adipocyte subpopulation linked to obesity. The data analyses are solid, and the findings are supported by the evidence presented. This study provides valuable information for the field of adipose tissue biology and will be particularly helpful for researchers using single-nuclei transcriptomics in various tissues.

eLife Assessment

The specific questions taken up for study by the authors-in mice of HDAC and Polycomb function in the context of vascular endothelial cell (EC) gene expression relevant to the blood-brain barrier, (BBB)-are potentially useful in the context of vascular diversification in understanding and remedying situations where BBB function is compromised. The strength of the evidence presented is incomplete, and to elaborate, it is known that the culturing of endothelial cells can have a strong effect on gene expression.

eLife Assessment

This study investigates the role of the Cadherin Flamingo (Fmi) in cell competition in developing tissues in Drosophila melanogaster. The findings are valuable in that they show that Fmi is required in winning cells in several competitive contexts. The evidence supporting the conclusions is solid, as the authors identify Fmi as a potential new regulator of cell competition, however, they don't delve into a mechanistic understanding of how this occurs.

eLife Assessment

The authors have reported an important study in which they use a double-blind design to explore pharmacological manipulations in the context of a behavioral task. While the sample size is small, the use of varied methodology, including electrophysiology, behavior, and pharmacology, makes this manuscript particularly notable. Overall, the findings are solid and motivate future explanations into the relationships between acetylcholine and motivation.

eLife Assessment

The paper reports the important discovery that the mouse dorsal inferior colliculus, an auditory midbrain area, encodes sound location. The evidence supporting the claims is solid, being supported by both optical and electrophysiological recordings. The observations described should be of interest to auditory researchers studying the neural mechanisms of sound localization and the role of noise correlations in population coding.

eLife Assessment

This useful work reveals differential activity to food and shock outcomes in central amygdala GABAergic neurons. Solid evidence supports claims of unconditioned stimulus activity that changes with learning. However, the evidence regarding claims related to valence or salience signaling in these neurons is inadequate. This work will be of interest to neuroscientists studying sensory processing and learning in the amygdala.

eLife Assessment

This important study reveals that Excitatory Amino Acid Transporters play a role in chromatic information processing in the retina. The combination of (double) mutants, behavioral assays, immunohistochemistry, and electroretinograms provides solid evidence supporting the appropriately conservative conclusions. The work will be of interest to neurobiologists working on color vision or retinal processing.

eLife Assessment

This important study explores the neural basis for a well known auditory illusion, often utilized in movie soundtracks, in which a sequence of two complex tones can be perceived as either rising or falling in pitch depending on the context in which they are presented. Convincing single-neuron data and analyses are presented to show that correlates of these pitch-direction changes are found in the ferret primary auditory cortex. While these findings provide an interesting link between cortical activity and perception, the manuscript could be clearer on the wider implications of the failure of traditional decoding models to account for these results.

eLife Assessment

This revised version of the study is important, showing that age-related gut microbiota modulate uric acid metabolism through the NLRP3 inflammasome pathway and thereby regulate susceptibility to age-related gout. Several experimental approaches (mechanistic insights) and methods (data quality) are still incomplete. If strengthened, this paper would be of broad interest to researchers working on gout and the microbiota.

eLife Assessment

This article describes a novel mechanism allows Drosophila to combat enteric pathogens while also preserving the beneficial indigenous microbiota. The authors provide compelling evidence that oral infection of Drosophila larvae by pathogenic bacteria activate a valve that traps the intruders in the anterior midgut, allowing them to be killed by antimicrobial peptides. This is an important finding revealing a new mechanism of host defense in the gut of insects.

eLife Assessment

This useful study presents a novel microscopy technique called "Expansion Tiling Light Sheet Microscopy" and an accompanying computational pipeline for the faster collection and analysis of 3D volumetric images in animals like planarians. This approach produces beautiful 3D microscropy images and is solid on a technical level. However, due to the use of antibody reagents that visualize many – but not all – neurons and muscle subtypes, the evidence for the biological conclusions in this study remains incomplete. With the claims appropriately contextualized, this paper will be of interest to cell biologists working on imaging and analyzing whole animals.

eLife Assessment

This study provides a valuable perspective on visual cortex architecture by identifying two cortical gradients that change across the lifespan and have distinct functional and structural features. The first gradient captures well-mapped variations in cortical thickness and myelination markers from early sensory to higher-order cortex, while the second gradient shows divergence in these measures with a more localized structure, notably predicting a previously unknown cluster of visual field maps in the anterior temporal lobe. The large-scale lifespan data are compelling, but the evidence overall is incomplete with key questions around methodical checks and implementation, the standard of evidence for the new visual maps, and how the gradient model relates to sharp tissue boundaries parcellating the cortex.

eLife Assessment

The authors present three valuable transgenic models carrying three representative exon deletions of the dystrophin gene. The findings are supported by rigorous biochemical assays and state-of-the-art microscopy methods, although the evidence, while overall solid, is only partially developed, and some points could be improved.

eLife Assessment

This study analyzes a cohort of small intestine neuroendocrine tumors, and the description of tumor-intrinsic programs that govern such rare cancers is felt to be valuable. The methods are for the most part felt to be solid, however, some broad concerns were raised that the possible separation of samples by a program may be impacted by fresh versus frozen sequencing. Similarly, the heterogeneity of the SiNET tumor microenvironment is unclear given a mixing of subtypes and the proliferation of NE and immune cells in SiNET could be influenced by technical factors. Recommendations were made to extend these data with other published datasets of SiNET tumors, expanding technical clarity and details, and validating findings using cell lines/PDX if available.

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 solid experimental data, although some conclusions regarding the functional role of specific RNA granules remain uncertain. Nevertheless, this study offers valuable insights into RNA regulation and developmental biology, with broader implications for understanding small RNA pathways in other systems.

eLife Assessment

This study presents valuable findings on changes in neuronal alpha activity elicited by prolonged pain in healthy human participants. The evidence supporting the claims of the authors, however, is incomplete and would benefit from clarifications of analytical strategies, additional statistical analyses, and shaping of the interpretations. With the methodological and interpretative parts strengthened, the work will be of interest to neuroscientists investigating the brain mechanisms of pain to identify new approaches to pain treatment

eLife Assessment

The study is a valuable addition to the field, showing how particulate matter may be acting via nociceptor neurons towards neutrophilic asthma exacerbations. The solid evidence for the role of a nociceptive pathway in model systems is relevant to human asthma in its current form but would be further strengthened by mechanistic insights. This would be particularly relevant to further translational research towards blocking the exacerbating effect of air pollution on asthma.

eLife Assessment

This important study presents the first identification of the odorant receptor for the trail pheromone in termites. The evidence supporting the conclusions is compelling, with state-of-the-art neurophysiological and genetic methods. The work will be of broad interest in multiple disciplines, such as entomology, chemical ecology, and sensory physiology.

eLife Assessment

This valuable study builds on previous work by the authors by presenting a potentially key method for correcting optical aberrations in GRIN lens-based micro endoscopes used for imaging deep brain regions. By combining simulations and experiments, the authors show that the obtained field of view is significantly increased with corrected, versus uncorrected microendoscopes. The evidence supporting the claims of the authors is solid, although some aspects of the manuscript should be clarified and missing information provided. Because the approach described in this paper does not require any microscope or software modifications, it can be readily adopted by neuroscientists who wish to image neuronal activity deep in the brain.

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 evidence is solid, it is obscured by a lack of clarity about the objectives of the analyses and in the overall writing of the article. The study will be impactful to the researchers in the field but will benefit from improved presentation.

eLife Assessment

This important paper employs multiple experimental approaches and presents evidence that changes in membrane voltage directly affect ERK signaling to regulate cell division. This result is relevant because it supports an ion channel-independent pathway by which changes in membrane voltage can affect cell growth. The reviewers point out that some experimental results and interpretations are compelling, but the strength of evidence is incomplete and additional experiments are needed to rule out other possible interpretations of the data.

Editors Assessment:

This paper reports the establishment of the International Cannabis Genomics Research Consortium (ICGRC) web portal leveraging the open source Tripal platform to enhance data accessibility and integration for Cannabis sativa (Cannabis) multi-omics research. With the aim of bringing together the wealth of publicly available genomic, transcriptomic, proteomic, and metabolomic data sets to improve cannabis for food, fiber and medicinal traits. Tripal is a content management system for genomics data, presenting a ready-to-use specialized ‘omics modules for loading, visualization, and analysis, and is GMOD (Generic Model Organism Database) standards-compliant. The paper explaining how this was put together, what data and features are available, and providing a case study for other communities wanting to create their own Tripal platform. Covering their setup and customizations of the Tripal platform, and how they re-engineered modules for multi-omics data integration, and addition of many other custom features that can be reused. Peer review fixed a few minor bugs and added clarifications on how the platform will be updated.

*This evaluation refers to version 1 of the preprint *

eLife Assessment

This study presents a valuable finding on the identification of a complex consisting of NHE1, hERG1, β1/integrin and NaV1.5 on the membrane of breast cancer cells. The evidence supporting the claims of the authors is somewhat incomplete. The inclusion of clarification of some experimental design and the amendment of cropping Western blot data would have strengthened the study. The work will be of interest to scientists working on breast cancer.

eLife Assessment

SGLT2 inhibitors (SGLT2i) have assumed important roles in reducing cardiovascular risk, particularly in those with diabetes. It has become appreciated that its protective effects are likely beyond their ability to lower blood sugar levels. This research presents a novel approach to studying the SGLT2i mechanism of action which is yet to be fully elucidated.

eLife Assessment

This study provides a valuable new perspective on how motor learning occurring in one state generalizes to new states (for example, a different limb posture). The proposed model improves upon previous theories in its ability to predict patterns of generalization, but evidence supporting this specific proposed model over possible alternatives is incomplete. The newly proposed theory appears promising but would be more convincing if its conceptual and theoretical basis were clearer and more rigorously derived.

eLife Assessment

This important work advances our understanding of factors influencing early childhood development. The large sample size and methodology applied make the findings of this study convincing; however, support for some of the claims made by the authors is incomplete. The work will be of interest to researchers in developmental science and early childhood pediatrics.

eLife Assessment

This important work addresses the role of Marcks/Markcksl during spinal cord development and regeneration. The study is exceptional in combining molecular approaches to understand the mechanisms of tissue regeneration with behavioural assays, which is not commonly employed in the field. The data presented is convincing and comprehensive, using many complementary methodologies.

Editors Assessment:

PhysiCell is an open source multicellular systems simulator for studying many interacting cells in dynamic tissue microenvironments. As part of the PhysiCell ecosystem of tools and modules this paper presents a PhysiCell addon, PhysiMeSS (MicroEnvironment Structures Simulation) which allows the user to accurately represent the extracellular matrix (ECM) as a network of fibres. This can specify rod-shaped microenvironment elements such as the matrix fibres (e.g. collagen) of the ECM, allowing the PhysiCell user the ability to investigate physical interactions with cells and other fibres. Reviewers asked for additional clarification on a number of features. And the paper now clear future releases will provide full 3D compatibility and include working on fibrogenesis, i.e. the creation of new ECM fibres by cells.

This evaluation refers to version 1 of the preprint

eLife Assessment

This important paper demonstrates that different PKA subtypes exhibit distinct subcellular localization at rest in CA1 neurons. The authors provide compelling evidence that when all tested PKA subtypes are activated by norepinephrine, catalytic subunits translocate to dendritic spines but regulatory subunits remain unmoved. Furthermore, PKA-dependent regulation of synaptic plasticity and transmission can be supported only by wildtype, dissociable PKA, but not by inseparable PKA.

eLife Assessment

In this potentially important study, the authors conducted atomistic simulations to probe the salt-dependent phase separation of the low-complexity domain of hnRN-PA1 (A1-LCD). The authors have identified both direct and indirect mechanisms of salt modulation, provided explanations for four distinct classes of salt dependence, and proposed a model for predicting protein properties from amino acid composition. There is a range of opinions regarding the strength of evidence, with some considering the evidence as incomplete due to the limitations in the length and statistical errors of the computationally intense atomistic MD simulations.

eLife Assessment

This manuscript presents a valuable new quantitative crosslinking mass spectrometry approach using novel isobaric crosslinkers. The data are solid and the method has potential for a broad application in structural biology if more isobaric crosslinking channels are available and the quantitative information of the approach is exploited in more depth.

eLife Assessment

This useful study by Nandy and colleagues examined relationships between behavioral state, neural activity in cortical area V4, and trial-by-trial variability in the ability to detect weak visual stimuli. They present solid evidence indicating that certain changes in arousal and eye-position stability, along with patterns of synchrony in the activity of neurons in different layers of V4, can show modest correspondences to changes in the ability to correctly detect a stimulus. These findings are likely to be of interest to those who seek a deeper understanding of circuit mechanisms that underlie perception.

eLife Assessment

This useful manuscript addresses some key molecular mechanisms on the neuroprotective roles of soluble TREM2 in neurodegenerative diseases. Thw study will advance our understanding of TREM2 mutations, particularly on the damaging effect of known TREM2 mutations, and also explain why soluble TREM2 can antagonize Aβ aggregation. However, the primary experimental method, MD simulations, suffers from limited sampling, rendering the results incomplete for definite conclusions.

eLife Assessment

The study provides a valuable showcase of a workflow to perform large-scale characterization of drug mechanisms of action using proteomics in which on-target and off-targets of 166 compounds using proteome solubility analysis in living cells and cell lysates were determined. The evidence supporting the claims of the authors is solid, however, the inclusion of more replicate experiments and more statistical rigor would have strengthened the study. This will be of broad interest to medicinal chemists, toxicologists, computational biologists and biochemists.

eLife Assessment

This landmark study elucidates the intricate structural mechanisms by which both covalent and non-covalent synthetic ligands can co-occupy the binding pocket of the nuclear receptor transcription factor PPARγ. Through a compelling integration of structural, biochemical, and biophysical evidence, the authors challenge the reliability of two commonly used covalent inhibitors. These findings have far-reaching implications for the broader field of nuclear receptor research. This work will be of high interest to structural biologists and biochemists exploring ligand interactions within the nuclear receptor superfamily.

eLife Assessment

The manuscript presents an important model for the field of endosome maturation, providing perspective on the role of the deubiquitinating enzyme UPS-50/USP8 in the process. The evidence presented in the paper is clear, incorporating well-designed experiments that suggest the dual actions of UPS-50 and USP8 in the conversion of early endosomes into late endosomes. Overall, the work is convincing and centers on an intriguing subject.

eLife Assessment

This study demonstrates mRNA-specific regulation of translation by subunits of the eukaryotic initiation factor complex 3 (eIF3) using convincing methods, data, and analyses. The investigations have generated important information that will be of interest to biologists studying translation regulation. However, the physiological significance of the gene expression changes that were observed is not clear.

eLife Assessment

The study is considered important with solid evidence that demonstrates the impact of plasma membrane nano-domains and protein interactions in the plant defence response to viruses. It includes a molecular understanding of the role of a calcium dependent kinase (CPK3) and a remorin protein in the cell-to-cell spread of viruses and cytoskeletal dynamics demonstrating, conclusively, the role of CPK3 with multiple lines of evidence. The work opens avenues to investigate different viruses and other plasma membrane proteins to gain a fuller picture of the involvement of plasmodesmata and other nanodomains in virus spreading.

eLife Assessment

This valuable work describes results from a set of simulation and empirical studies of a set-up assessing exploratory behavior in a potentially rewarding environment that contains danger. The core idea is that an instrumental agent can be helped to be both effective and safe, thus avoiding excessive danger, during exploratory behavior, if its influence is flexibly gated by an independent Pavlovian fear learning system. The conclusion that safe, but effective exploration can be achieved based on a flexibly weighted combination of a Pavlovian and an instrumental agent is solid.