eLife Assessment

This useful study examined the associations of a healthy lifestyle with comprehensive and organ-specific biological ages defined using common blood biomarkers and body measures. Its large sample size, longitudinal design, and robust statistical analysis provide solid support for the findings, which will be of interest to epidemiologists and clinicians.

eLife Assessment

This fundamental, clearly written, and timely manuscript links the timing of ART with the kinetics of total and intact proviral HIV DNA. The conclusions are interesting and novel, and the importance of the work is high because the focus is on African women and clade C virus, both of which are understudied in the HIV reservoir field. The strength of the evidence is compelling. Overall, this work will be of very high interest to scientists and clinicians in the HIV cure/persistence fields.

eLife Assessment

This important study shows that Toxoplasma gondii uses paracrine mechanisms, in addition to cell-intrinsic methods, to evade the host immune system, with MYR1 playing a key role in transporting effector molecules into host cells. The authors present convincing evidence that in vivo, MYR1-deficient parasites can be rescued by wild-type parasites, revealing a limitation in pooled CRISPR screens, where such paracrine effects may obscure the identification of key parasite pathways involved in immune evasion

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 valuable study highlights how the diversity of the malaria parasite population diminishes following the initiation of effective control interventions but quickly rebounds as control wanes. The data presented is convincing and the work shows how genetic studies could be used to monitor changes in disease transmission.

eLife Assessment

This valuable 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 solid experimental findings suggest data from other species are likely translatable to mice, bridging the abundant literature from humans and other mammals into this experimentally tractable animal model, but the data establishing the role of Cdh6 in synapses among IPANs and in cell-cell contacts with non-neuronal cells is incomplete. 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 important study reports on a basis for neurabin-mediated specification of substrate choice by protein phosphatase-1. The data from the comprehensive approach using structural, biochemical, and computational methods are compelling, but the role of the crucial tryptophan residue in the recognition motif can be further tested to strengthen the main argument. This paper is broadly relevant to those investigating various cellular signaling cascades that entail phosphorylation as the main mechanism.

eLife Assessment

This solid paper reports on the use of artificial intelligence to assess bone marrow adipose tissue in the skull. The method employing MRI is novel and that approach allows for the identification of genetic loci that regulate this trait as well as others using data from the UK biobank. Overall this is an important contribution although the authors should consider several points: 1-validation of the T1-weighted MRI signal intensity; 2-further discussion of the sex differences; and 3-cross-trait linkage disequilibrium score regression (LDSC) for osteoporosis, Parkinson's disease, and cognitive function.

eLife Assessment

The authors use a multidisciplinary approach to provide a useful link between Beta-alanine and S. Typhimurium (STM) infection and virulence. The work shows how Beta-alanine synthesis mediates zinc homeostasis regulation, possibly contributing to virulence. However, the work is incomplete and requires additional data to firmly establish the connection between Beta-alanine synthesis and zinc homeostasis. Measuring the source and zinc content of STM in vivo and examining mechanisms in human clinical strains and other serovars would be essential.

eLife Assessment

This article reports a useful set of findings on how electrophysiological response properties of neurons correlate with their position in the brain. The evidence currently remains incomplete, with reviewers making specific suggestions for how clustering needs to be redone. The manuscript would also benefit from a more focused presentation of results and the removal of incorrect claims about recording biases.

eLife Assessment

This valuable study clarifies the mechanism by which the kinesin-10 motor protein, chromosome-associated kinesin, Kid (KIF22), enables chromosome movement during mitosis, demonstrating that human and Xenopus Kid proteins function as processive, homodimeric kinesins capable of processive microtubule plus-end motility. The convincing work highlights that Kid can recruit and transport duplex DNA along microtubules via its conserved C-terminal DNA binding domain, revising our understanding of chromokinesins' role in chromosome motility during mitosis. Although the data are robust, the manuscript would benefit from some editing for clarity.

eLife Assessment

This valuable study uses the analysis of connectomic and transcriptomic datasets to survey the anatomy and connectivity of neurosecretory cells in the Drosophila brain. While the connectivity analyses are convincing, the anatomical and functional data provided to verify cell type identity and paracrine signaling is incomplete. Once these aspects are improved, this study would be of interest to neuroscientists working on hormonal signaling in Drosophila and other animals.

eLife Assessment

The study describes a valuable new technology in the field of targeted protein degradation that allows identification of E3-ubiquitin ligases that target a protein of interest. The presented data are convincing, however, additional work will be needed to optimize for high-throughput evaluation. This technology will therefore serve the community in the initial stages of developing targeted protein degraders.

eLife Assessment

This important study identifies the "H-state" as a potential conformational marker distinguishing amyloidogenic from non-amyloidogenic light chains, addressing a critical problem in protein misfolding and amyloidosis. By combining advanced techniques such as small-angle X-ray scattering, molecular dynamics simulations, and H-D exchange mass spectrometry, the authors provide convincing evidence for their novel findings. However, incomplete experimental descriptions, limitations in SAXS data interpretation, and the way HDX MS data is presented affect the strength and generalizability of the conclusions. Strengthening these aspects would enhance the impact of this work for researchers in amyloidosis and protein misfolding.

eLife Assessment

The manuscript by Guo and colleagues reports valuable findings about the inhibitory activity of caffeic acid phenethyl ester (CAPE) against TcdB, a key toxin produced by Clostridioides difficile. C. difficile infections are a major public health concern, and this manuscript provides interesting data on toxin inhibition by CAPE, a potentially promising therapeutic alternative for this disease. The strength of the evidence to support the conclusions is solid, with some concerns about the moderate effects on the mouse infection model and direct binding assays of CAPE to the toxin.

eLife Assessment

This important study uses Mendelian Randomisation to show that early life phenotypes (i.e. onset of age at menarche and age at first birth) have an influence on a multitude of health outcomes later in life. The provided empirical evidence supporting the antagonistic pleiotropy theory is solid. However, some additional analyses and a more comprehensive discussion of the findings are needed to make the study stronger.

eLife Assessment

This basic research study presents useful data concerning the menstrual fluid composition and its potential for endometriosis biomarker research. However, despite solid bioinformatics analyses, the choice of markers used to separate or identify the different cell types needs to be justified and the results better discussed in relation to current knowledge of the pathophysiology of endometriosis.

eLife Assessment

This important work combines self-report, neural and physiology data to examine the efficacy and mechanisms of counter conditioning versus extinction in reducing re-emergence of conditioned threat responses and show that this appears to rely on the nucleus accumbens rather than the ventromedial prefrontal cortex. These findings are supported by convincing evidence, though some areas could benefit from added clarity and a few targeted refinements and justifications of analytical choices. Results will be of interest to researchers across multiple subfields, including neuroscientists, cognitive theory researchers, and clinicians, particularly those with an interest in clinical applications in trauma therapies.

eLife Assessment

This valuable study examines the activity and function of dorsomedial striatal neurons in the estimation of time. The authors examine striatal activity as a function of time as well as the impact of optogenetic striatal manipulation on the animal's ability to estimate a time interval, providing solid evidence for their claims. The study could be further strengthened with a more rigorous characterization of activity and a stronger connection between their proposed model and the experimental data. The work will be of interest to neuroscientists examining how striatum contributes to behavior.

eLife Assessment

This important study presents interesting results aimed at explaining the effects of a human mutation on the mitochondrial import protein TIMM50 on mitochondrial function and neuronal excitability. While the evidence supporting the conclusions is convincing, the mechanisms driving changes in the levels of certain proteins within and outside the mitochondria (such as certain ion channels) remain unexplained. This paper will be of interest to scientists in the mitochondria field.

eLife Assessment

This important study advances our understanding of how FGF13 variants confer seizure susceptibility. By acting in a set of inhibitory interneurons, FGF13 regulates synaptic transmission and excitability. The data presented here are convincing and combine cell type-specific knockouts and electrophysiology, complemented by histology/RNA studies. Collectively, this research will be of interest to a wide audience, particularly those involved in the study of epilepsy, inhibitory neurons, and ion channels.

eLife Assessment

This useful study reports how neuronal activity in the prefrontal cortex maps time intervals during which animals wait to reach a reward, with this mapping remaining consistent across days. While most claims are supported by solid evidence, the study could have benefitted from an improved experimental design to more clearly disambiguate correlations between neuronal patterns and not only time but also stereotypical behaviors and restraint from impulsive decisions. This study will be of particular interest to neuroscientists focused on decision-making and motor control.

eLife Assessment:

This study presents valuable findings that add to our understanding of cortical astrocytes, which respond to synaptic activity with calcium release in subcellular domains that can proceed to larger calcium waves. The proposed concept of a spatial "threshold" is based on solid evidence from in vivo and ex vivo imaging data and the use of mutant mice. Details of the specific threshold must be taken with caution and are necessarily incomplete, but may be supported by additional experiments with higher resolution in space and time in the future.

eLife Assessment

This important study addresses key assumptions underlying current models of the formation of value-based decisions. The authors provide convincing evidence that the subjective values human participants assign to items change across sequences of multiple decisions. They establish methods to detect these changes in frequently used behavioral task designs.

eLife Assessment

The study describes a useful tool for assessing microglia morphology in a variety of experimental conditions. The MorphoCellSorter provides a solid platform for ranking microglia to reflect their morphology continuum and may offer new insight into changes in morphology associated with injury or disease. While the study provides an alternative approach to existing methods for measuring microglia morphology, the functional significance of measured morphological changes remains unclear.

eLife Assessment

This well-written report uses functional neuroimaging in human observers to provide convincing 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 in its present form will be valuable to those examining attention, perception, learning and prediction, but with a few additional analyses could more informatively rule out potential alternative hypotheses. Further discussion of the mechanistic implications could clarify further the broad extent of its significance.

eLife Assessment

This important work advances our understanding of CHMP5's role in regulating osteogenesis through its impact on cellular senescence. The evidence supporting the conclusion is mostly convincing, although including additional experiments and discussions would further strengthen the study. This paper holds potential interest for skeletal biologists who study the pathogenesis of age-associated skeletal disorders.

eLife Assessment

In this potentially valuable computational study, the authors conducted atomistic and coarse-grained simulations to probe the temperature-dependent phase behaviors of ELF3, a disordered component of the evening complex in plant. The results aim to highlight the role of polyQ tracts in modulating the temperature sensitivity. The level of evidence is considered incomplete, due to the lack of systematic calibration of the coarse-grained model and limited statistical uncertainty analysis, especially considering the relatively subtle nature of the differences due to temperature change.

eLife Assessment

This important study identifies species- and sex-specific neuronal cell types and gene expression in the medial preoptic area (MPOA) to help understand the evolutionary divergence of social behaviors. The evidence from single-nucleus RNA sequencing and immunostaining is convincing and suggests that cellular differences in the MPOA 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 valuable study investigates the brain representations of Braille letters in blind participants and provides evidence using EEG and fMRI that the decoding of letter identity across the reading hand takes place in the visual cortex. The evidence supporting the claims of the authors is convincing and the work will be of interest to neuroscientists working on brain plasticity.

eLife Assessment

This study presents a useful finding on the ferroptosis-mediated tumor microenvironment (TME) in triple-negative breast cancer (TNBC) using public single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data. The evidence supporting the claims of the authors is somewhat incomplete and some data are rather questionable; the authors should clarify the relations between ferroptosis-related genes in immune cells and those genes applied in a risk factor analysis in tumor cells. Moreover, the authors should provide experimental validation for the risk score model based on ferroptosis-related genes. The work will be of interest to scientists or clinical scientists working in the field of breast cancer.

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. This 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

Leveraging state-of-the-art experimental and analytical approaches, this important study characterizes the recruitment and activation of large populations of human motor units during slow isometric contractions in two lower limb muscles. Evidence for the main claims is solid and advances our understanding of how humans generate and control voluntary force.

eLife Assessment

This study provides valuable advances in our understanding of how inputs from multiple sources can impact the physiology of motor neurons during the process of multisensory integration. Specifically, the authors show how streams of auditory and principally visual information modulate the physiology of Mauthner neurons in goldfish, thus allowing the different senses to influence escape behavior. Supporting evidence is generally convincing, although material reporting the direct control of behavior is less representative of the data.

eLife Assessment

This important study highlights the use of siderophores as antibacterials, and the authors also discuss the consequences and efficacy of 'siderophore therapy' in more complex communities/environments. The evidence supporting the overall hypotheses ranges is largely convincing. The work will be of broad interest to people working in the fields of evolutionary ecology, microbiology and medical sciences.

eLife Assessment

This work is an important contribution to the development of a biologically plausible theory of statistical modeling of spiking activity. The authors convincingly implemented the statistical inference of input likelihood in a simple neural circuit, demonstrating the relationship between synaptic homeostasis, neural representations, and computational accuracy. This work will be of interest to neuroscientists, both theoretical and experimental, who are exploring how statistical computation is implemented in neural networks.

eLife Assessment

This study provides important findings on the modulation of cortical neuronal responses to sensory stimuli by motor-driven predictive signals. The study is methodologically sound and well-designed. Solid evidence is presented for the conclusion that audiomotor mismatch responses are observed in the auditory cortex and that these are strongly modulated by crossmodal signals, though further investigation of the effects of running speed on audiomotor coupling and of sound offset effects on the observed responses would strengthen the interpretation of the results.

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

This fundamental study advances substantially our understanding of sound encoding at synapses between single inner hair cells of the mouse cochlea and spiral ganglion neurons. Dual patch-clamp recordings-a technical tour-de force-and careful data analysis provide compelling evidence that the functional heterogeneity of these synapses contributes to the diversity of spontaneous and sound-evoked firing by the neurons. The work will be of broad interest to scientists in the field of auditory neuroscience.

eLife Assessment

This useful study employs AlphaFold2 to predict interactions among 20 nuage proteins, identifying five novel interaction candidates, three of which are validated experimentally through co-immunoprecipitation. Expanding the analysis to 430 oogenesis-related proteins and screening ~12,000 Drosophila proteins for interactions with Piwi, the study identifies 164 potential binding partners, demonstrating how computational predictions can streamline experimental validation. This study provides a solid basis for further investigations into eukaryotic protein interaction networks.

eLife Assessment

This study presents important findings on cold tolerance shared between hibernating and non-hibernating mammals, identifying a key molecule, GPX4, through multi-species genome-wide CRISPR screens. The evidence supporting these conclusions is compelling, combining multi-species CRISPR screening with rigorous pharmacological assays. This work will be of significant interest to biologists studying hibernation physiology and medical researchers interested in cold tolerance.

eLife Assessment

The presented evidence is compelling given a range of complementary and mutually supportive studies. Experiments are generally robustly conducted and well-presented, supporting the claims regarding miRNA mechanisms converging on EMC10 overexpression with 22q11 Del. This is an important study that works to establish a novel antisense oligonucleotide-based approach to treating 22q11.2 deletion syndrome; the findings are likely to advance therapeutic efforts. The authors provide evidence both in vitro in patient-derived iPSCs and in vivo in a 22q11 Del mouse supporting the knockdown (KD) of EMC10 as an effective strategy for the amelioration of neuronal and behavioral deficits.

eLife Assessment

This is an important study that aims to investigate the behavioral relevance of multisensory responses recorded in the auditory cortex. The experiments are elegant and well-designed, and are supported by appropriate analyses of the data. However, the evidence presented for learning-dependent encoding of visual information is incomplete and it is possible that the surprisingly short-latency increases in activity are actually motor-related signals. Demonstrating that they really are visual responses is necessary in order to draw definitive conclusions from this study.

eLife Assessment

This study addresses a significant question in sensory ethology and active sensing in particular. It links the production of a specific signal - electrosensory chirps - to various contexts and conditions to propose that chirps may also serve an active sensing role in addition to their more well-known role in communication. The evidence supporting the role for active sensing is strong. In particular, the evidence showing increased chirping in more cluttered environments and the relationship between chirping and movement are convincing. The study provides a lot of valuable data, and is likely to stimulate follow-up behavioral and physiological studies.

eLife Assessment

This work attempts to demonstrate an ATP-independent non-canonical role of proteasomal component PA28y in the promotion of oral squamous cell carcinoma growth, migration, and invasion. The evidence remains incomplete and the work would benefit from further experimental work. The authors have not adequately addressed the reviewers' comments.

eLife Assessment

This study provides valuable insights into our understanding of the development of the enteric nervous system. The authors use genetically engineered mice to study the behavior of stem cells in organizing the enteric nervous system and the secreted signals that regulate these cells. The study rests on a degree of incomplete evidence since the characterization of some of the mouse resources is not complete in the current version.

eLife Assessment

This fundamental study addresses the regulation of the MICAL-family of actin regulators by Rab GTPases, which play a key role in directing membrane trafficking within cells. The compelling evidence explains how Rab8 family members bind at two sites to allosterically regulate MICAL1, and relieve an auto-inhibited state unable to bind actin. This study lays the basis for further progress in understanding membrane trafficking and cytoskeleton dynamics in eukaryotic cells.

eLife Assessment

This study offers valuable insights into the molecular mechanisms by which Osx influences osteocyte function, particularly through its regulation of Cx43. However, the evidence supporting the authors' claims is incomplete, necessitating additional experimental data and further investigation to fully substantiate these findings. While this study presents a new perspective on the complex role of Osx in bone biology, it also raises significant questions about the intricacies of its regulatory network.

eLife Assessment

This work presents an important method for depleting ribosomal RNA from bacterial single-cell RNA sequencing libraries, enabling the study of cellular heterogeneity within microbial biofilms. The approach convincingly identifies a small subpopulation of cells at the biofilm's base with upregulated PdeI expression, offering invaluable insights into the biology of bacterial biofilms and the formation of persister cells. Further integrated analysis of gene interactions within these datasets could deepen our understanding of biofilm dynamics and resilience.

eLife Assessment

This work presents an important method for depleting ribosomal RNA from bacterial single-cell RNA sequencing libraries, enabling the study of cellular heterogeneity within microbial biofilms. The approach convincingly identifies a small subpopulation of cells at the biofilm's base with upregulated PdeI expression, offering invaluable insights into the biology of bacterial biofilms and the formation of persister cells. Further integrated analysis of gene interactions within these datasets could deepen our understanding of biofilm dynamics and resilience.

eLife Assessment

This study presents a useful theoretical model of molecular evolution and attempts to use it to resolve the paradox of rapid evolution of ribosomal RNA genes. While intuitive, the model's underlying issue is grouping many factors under "variance in reproductive success" without explicitly modeling the molecular processes. This limitation, along with insufficient consideration of technical challenges in alignment and variants calling, provides incomplete support for the authors' claim that the observed paradoxical patterns in rRNA genes can largely be explained by homogenizing processes, such as gene conversion, unequal crossover and replication slippage.

eLife Assessment

This is a valuable study on the diffusion rates of drug molecules in human-derived cells, presenting convincing data indicating that their diffusion behavior depends on their charged state. It proposes that blocking drug protonation enhances diffusion and fractional recovery, suggesting improved intracellular availability of weakly basic drugs. The findings are significant for drug design and understanding the biophysical behavior of small molecules in cells.

eLife Assessment

This is a useful revised manuscript that shows a set of data including the first cryo-EM structures of human PIEZO1 as well as structures of disease-related mutants in complex with the regulatory subunit MDFIC, which generate different inactivation phenotypes. The molecular basis of PIEZO channel inactivation is of great interest due to its association with several pathologies. This manuscript provides some structural insights that may help to ultimately build a molecular picture of PIEZO channel inactivation. While the structures are of use and clear conformational differences can be seen in the presence of the auxiliary subunit MDFIC, the strength of the evidence supporting the conclusions of the paper, especially the proposed role for pore lipids in inactivation, is incomplete.

eLife Assessment

In this manuscript, Kaplan et al. study mesenchymal Meis2 in whisker formation and the links between whisker formation and sensory innervation. These useful findings analyze the impact of the conditional deletion of Meis2 using the Wnt1 driver on whisker development and their interaction with trigeminal nerves. The evidence supporting the conclusions is incomplete lacking mechanistic links to the phenotype described and detailed information on the methods used to analyze single-cell RNA sequencing data. The work will be of interest to developmental and skin biologists.

eLife assessment

The work introduces a valuable new method for depleting the ribosomal RNA from bacterial single-cell RNA sequencing libraries and shows that this method is applicable to studying the heterogeneity in microbial biofilms. The evidence for a small subpopulation of cells at the bottom of the biofilm which upregulates PdeI expression is solid. However, more investigation into the unresolved functional relationship between PdeI and c-di-GMP levels with the help of other genes co-expressed in the same cluster would have made the conclusions more significant.

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 study investigates the impact of disrupting the interaction of RAS with the PI3K subunit p110α in macrophage function in vitro and inflammatory responses in vivo. Solid data overall supports a role for RAS-p110α signalling in regulating macrophage activity and so inflammation, however for many of the readouts presented the magnitude of the phenotype is not particularly pronounced. Further analysis would be required to substantiate the claims that RAS-p110α signalling plays a key role in macrophage function. Of note, the molecular mechanisms of how exactly p110α regulates the functions in macrophages have not yet been established.

eLife Assessment

This important study investigates the molecular mechanisms underpinning how the tumor necrosis factor alpha-induced protein (TIPE) regulates aerobic glycolysis to promote tumor growth in melanoma. Convincing data using multiple independent approaches provides new insights into the molecular mechanisms underpinning aerobic glycolysis in melanoma cells. The work will be of interest to biomedical researchers working in cancer and metabolism.

eLife Assessment

The manuscript reports on an important comparison of a range of approved clinical inhibitors for BTK used for the treatment of chronic lymphocytic leukemia (CLL). The authors provide compelling evidence for their claims, using a combination of HDX-MS and NMR spectroscopy. The novelty is that this study also seeks to evaluate resistance mutation bias. The manuscript will be of high interest to scientists working on protein drug interactions.

eLife Assessment

This useful work provides insight into agonist binding to nicotinic acetylcholine receptors, which is the stimulus for channel activation that regulates muscle contraction at the neuromuscular junction. The authors use in silico methods to explore the transient conformational change from a low to high affinity agonist-bound conformation as occurs during channel opening, but for which structural information is lacking owing to its transient nature. The simulations indicating that ligands flip ~180 degrees in the binding site as it transitions from a low to high affinity bound conformation are solid. A limitation is the approximation of binding energies using Poisson-Boltzmann Surface Area and mismatch between calculated and experimental binding energies for two of the four ligands tested. Nonetheless, this work presents an intriguing picture for the nature of a transient conformational change at the agonist binding site correlated with channel opening.

eLife Assessment

Zhang et al. present important findings that reveal a new role for TET2 in controlling glucose production in the liver, showing that both fasting and a high-fat diet increase TET2 levels, while its absence reduces glucose production. TET2 works with HNF4α to activate the FBP1 gene upon glucagon stimulation, while metformin disrupts TET2-HNF4α interaction, lowering FBP1 levels and improving glucose homeostasis. While the results are solid, more details about the mechanisms and methods are needed to strengthen the study's conclusions.

eLife Assessment

Identifying chromatin interactions with high sensitivity and resolution at the genome-wide scale continues to be technically challenging. This study introduces findings based on the improved MNase-based proximity ligation method, MChIP-C, which enables genome-wide measurement of chromatin interactions at single-nucleosome resolution. The evidence presented in this manuscript is convincing, and the technological advancements will be valuable for the study of 3D genome architecture.

eLife Assessment

This important work advances our understanding of DNA methylation and its consequences for susceptibility to DNA damage. This work presents evidence that DNA methylation can accentuate the genomic damage propagated by DNA damaging agents as well as potentially being an independent source of such damage. The experimental results reported are sound but the evidence presented to support the conclusions drawn is incomplete and other interpretations are possible. The work will be of broad interest to biochemists, cell and genome biologists.

eLife Assessment

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

eLife Assessment

This manuscript describes valuable new material of small, unusually preserved fossils from deep in the Cambrian of China and argues they represent very early bilaterian animals such as annelids or panarthropods. The authors present convincing evidence of the fossilisation of specimens as microbial pseudomorphs, however, the fossils show few details and it is difficult to assess their affinity. The broader claims made about the timing and nature of the Cambrian explosion are inadequately supported by the material, given that bilaterians were already known to exist during that period.

eLife Assessment

This important study employed multiple orthogonal techniques and tissue samples to investigate the interaction between the NRL transcription factor and RNA-binding proteins in the retina. The findings are solid to support an interaction between NRL and the DHX9 helicase. However, the evidence for an interaction between the NRL transcription factor and R-loops is less conclusive. The significance of the study could be enhanced by examining the functional role of NRL interactions with R-loops in the developing retina, which would offer new insights into the gene regulatory networks.

eLife Assessment

This study reports an important new scRNAseq atlas of the mouse cranial neural plate during neural induction, patterning, and morphogenesis. The study includes a robust analysis of scRNAseq datasets covering six distinct developmental stages, as well as data describing the global transcriptional response of neural plate cells to a key ventralizing signaling molecule, Sonic Hedgehog. The computational data and validation of gene expression patterns are convincing, making this a helpful resource for investigators studying the early development of the cranial neural plate and cranial mesoderm.

eLife Assessment

This manuscript focuses on the identification of RNA crosslinks within the HIV RNA genome under different conditions i.e. in infected cells and in virions using a new method called HiCapR. These cross-links reveal long-range interactions that can be used to determine the structural arrangement of the viral RNA, providing useful data that show differences in the genomic organization in different conditions. The data analysis, however, is incomplete and based on extensive computational analysis from a limited number of datasets, which are in need of experimental validation.

eLife Assessment

This study represents an important advance in our understanding of how certain inhibitors affect the behavior of voltage gated potassium channels. Robust molecular dynamics simulation and analysis methods lead to a new proposed inhibition mechanism with strength of support being mostly convincing, and incomplete in some aspects. This study has considerable significance for the fields of ion channel physiology and pharmacology and could aid in development of selective inhibitors for protein targets.

eLife Assessment

This is an important study demonstrating the importance of S100A4+ alveolar macrophages in the earlier stages of tumour development and suggesting a role in angiogenesis. As such this solid study is of interest to cancer biologists focused on early tumour development and those interested in the development of therapeutics that may specifically target early cancers.

eLife Assessment

This useful study partially succeeds in providing solid evidence in support of the therapeutic potential of the plant-derived compound eugenol for ameliorating symptoms associated with STZ-induced oxidative stress, identifying Nuclear factor E2-related factor (Nrf2) as a mediator of the effects induced by eugenol. Although the study provides interesting data, there remain concerns associated with the STZ model and the rather superficial mechanistic assessment.

eLife Assessment

This work is important because it elucidates how immune cells migrate across the blood brain barrier. In the revised version of this study, the authors present a convincing framework to visualize, recognize and track the movement of different immune cells across primary human and mouse brain microvascular endothelial cells without the need for fluorescence-based imaging using microfluidic devices. This work will be of interest to the cancer biology, immunology and medical therapeutics fields.

eLife Assessment

This important study describes mRNA shortening during cellular stress and interestingly observes that this shortening is dependent on localization in stress granules. Surprisingly, this mRNA shortening does not appear to require the shortening of poly A tails. These are novel, paradigm-shifting findings, using cutting-edge technologies and convincing data, that should be of broad interest to the RNA community and beyond.

eLife Assessment

This valuable study has the potential to shed mechanistic light on how attention mechanisms that influence competition between multiple visual stimuli are modulated by the relative neural similarity of these stimuli. The study provides convincing data that will also be used for future modeling efforts. The study will be of interest to researchers working on the neural basis of visual attention.

eLife Assessment

This valuable study examines how different exercise training intensities affect intestinal barrier function and gut microbiota composition over a 6-week period in mice. The evidence supporting the main claims about exercise-induced intestinal injury and microbiota changes is solid, featuring comprehensive histological analysis, molecular characterization, and metabolomic profiling, though key mechanistic insights and causal relationships remain to be established. The findings have practical implications for understanding exercise-induced gastrointestinal stress, particularly the observation that daily moderate exercise may be more damaging to intestinal integrity than vigorous exercise with rest days. Additional experimental validation would strengthen these conclusions.

eLife Assessment

This important study provides a comprehensive assessment of mitochondrial function across age and sex in mice. The strength of evidence supporting this resource is compelling, given the exhaustive number of tissues profiled and in-depth analyses performed.

eLife Assessment

This study provides important insights into postnatal lung development and the mechanisms underlying bronchopulmonary dysplasia (BPD), a condition with high morbidity and mortality in newborns. Through the use of neonatal hyperoxia, cell-type-specific inactivation of Tgfbr2, and other injury models, the research focuses on the role of TGF-β signaling in BPD pathogenesis, highlighting impaired myofibroblast proliferation as a key factor. The inactivation of Etc2 in Pdgfra-lineaged cells disrupts myofibroblast cytokinesis, leading to alveolar simplification and reduced cell numbers. The use of transgenic mice and single-cell transcriptomics offers a detailed and high-quality dataset, advancing our understanding of BPD and serving as a invaluable resource for developmental biology and neonatal pulmonary research. The study's comprehensive approach, robust data, and methodological rigor make it a compelling contribution to the field, providing both mechanistic insights and a resource for further research into BPD pathogenesis.

eLife Assessment

This study reveals that the malaria parasite protein PfHO, although lacking typical heme oxygenase activity, is essential for the survival of Plasmodium falciparum. Structural and localization analyses demonstrated that PfHO plays a critical role in maintaining the apicoplast, specifically in gene expression and biogenesis, suggesting an adaptive function for this protein in parasite biology. While the findings convincingly support the authors' claims, further investigation into apicoplast gene expression and the specific function of PfHO remains a future challenge. The topic and results are important and will be of interest to researchers studying various aspects of malaria, Plasmodium physiology, host-pathogen interactions, and heme metabolism.

eLife Assessment

The authors present a critique of current usage of principal component analysis in geometric morphometrics, making a compelling case with benchmark data that standard techniques perform poorly. The work is an important contribution to the field and will hopefully lead to a reassessment of the methodology most scientists in morphometrics currently use. This work challenges a very commonly used analytical approach and is bound to raise some controversy in the community, but the authors' critique is based on a well-founded and well-thought out analysis.

eLife Assessment

The authors examined the evolution of hepatitis C virus (HCV) in a cohort of 14 subjects with recent HCV infections. By using computational methods, they showed that viral fitness declines as the virus mutates to escape the immune response and can rebound later in infection as HCV accumulates additional mutations. The study contributes to an important aspect of viral evolution. The combination of approaches is highly compelling; however, some aspects of the manuscript are incomplete and would greatly benefit from additional revision, mainly to increase their clarity.

eLife Assessment

This manuscript offers an exploration of the immune cells in the oyster Crassostrea gigas, by correlating distinct hemocyte morphotypes with specific single-cell transcriptional profiles. The evidence supporting the conclusion is convincing, deriving from the comprehensive dataset that not only captures unicellular diversity but also associates these cells with distinct immune roles, making it an important resource for the broader research community. There are some concerns on the data presentation that leave some questions.

eLife Assessment

This important study provides evidence for the role of neutrophil extracellular traps in chronic kidney damage (CKD) induced by chemotherapy and suggests a therapeutic approach to mitigate the kidney pathology caused by the NETs. The study utilizes a sound murine in vivo model of CKD with low-dose administration cisplatin and a genetic model for impairment of NET formation by deletion of the enzyme Pad4. In its current form, the study was seen as incomplete as there is not yet formal demonstration of NET production by neutrophils in the model of CKD used. Additionally, the accuracy and clarity of data presentation could be improved.

eLife Assessment

This important study substantially advances our understanding of noncoding somatic mutations by identifying a novel class of mutations that affect 3'UTR polyadenylation signals enriched in tumor suppressor genes in cancer. The evidence supporting the conclusions is convincing, with rigorous statistical analyses. The work will be of broad interest to cancer researchers.

eLife Assessment

This paper presents valuable findings on how autophagosomes are positioned along microtubules for their efficient fusion with lysosomes, providing significant insights into the mechanism. The evidence supporting the conclusions is solid, with high-quality fluorescence microscopy combined with Drosophila genetics. This work will be of broad interest to cell biologists interested in autophagy and related cell biology fields.

eLife Assessment

This study provides valuable evidence indicating that SynGap1 regulates the synaptic drive and membrane excitability of parvalbumin- and somatostatin-positive interneurons in the auditory cortex. Since haplo-insufficiency of SynGap1 has been linked to intellectual disabilities without a well-defined underlying cause, the central question of this study is timely. While in their revision the authors successfully addressed questions related to changes in thalamocortical presynaptic excitability, the support for the authors' conclusions is incomplete as concerns around the interpretability of the spontaneous/mini EPSCs, interpretation of results related to excitability, restriction of anatomical analysis of excitatory synapses to the somatic region, and technical problems regarding phase plots remain unresolved.

eLife assessment

In this valuable study, the authors analyze droplet size distributions of multiple protein condensates and their fit to a scaling ansatz, highlighting that they exhibit features of first- and second-order phase transitions. The experimental evidence is solid, and it prompts further research into the nature of the link between percolation and phase separation.

eLife Assessment

This important work advances our understanding of how memories interact to facilitate or interfere with one another, also informing our understanding of how humans build knowledge. The study provides compelling evidence that semantic relatedness proactively benefits memory using clean experimental design, rigorous statistics, large N samples, and well-characterized stimuli. The study also demonstrates the boundaries of these proactive benefits, showing that when studied items have weaker semantic relationships, proactive interference may be observed. This research will be of interest to memory researchers as well as cognitive psychologists, neuroscientists, and educators more broadly.

eLife Assessment

This study presents a valuable finding about the role of Perk (Protein kinase RNA-like endoplasmic reticulum kinase) and Atf4 (Activating Transcription Factor-4) in the integrated neurodegenerative and regenerative responses following the optic nerve injury. The authors present solid evidence, combining newly generated transcriptomic data with publicly available datasets to strengthen their findings. Despite some limitations in data quality and interpretation, the study is likely to be of interest to researchers studying optic neuropathies and axonal regeneration.

eLife Assessment

The authors are interested in the developmental origin of the neurons of the cerebellar nuclei. In this study, they identify a population of neurons with a specific complement of markers that originate in a distinct location from where cerebellar nuclear precursor cells have been thought to originate that show distinct developmental properties. The discovery of a new germinal zone giving rise to a new population of neurons is an exciting finding, and it enriches our understanding of cerebellar development. The important claims, better explained in the current version, are well supported by solid evidence with the authors using a wide range of technical approaches, including transgenic mice that allow them to disentangle the influence of distinct developmental organizers

eLife Assessment

This study reports a valuable finding for the treatment of colorectal cancer (CRC), as the authors demonstrated that the enzyme CPT1A plays an significant role in the response to radiotherapy in CRC patients. However, the reviewers found that the results presented are still incomplete.

eLife Assessment

This is a valuable study of the physiological mechanisms promoting network activity during fever in the mouse neocortex. Most of the supporting evidence is solid, however, there is incomplete support for the conclusion that the E/I balance is unchanged with temperature.

eLife Assessment

This important study describes a computational tool termed FliSimBA (Fluorescence Lifetime Simulation for Biological Applications), which uses simulations to rigorously assess experimental limitations in fluorescence lifetime imaging microscopy (FLIM), including diverse noise factors, hardware effects, and sensor expression levels. The evidence from simulation and experimental measurements supporting the usefulness of FlimSimBA is solid. The authors may improve the application of the tool to a wide range of biological samples by providing the simulation package, currently in MATLB, in other common languages such as Python, and having better descriptions of the fitting algorithm and model assumptions. The work will interest scientists who wish to perform quantitative FLIM imaging for cells and tissues.

eLife Assessment

In this manuscript, Wang et al describe the identification, and provide initial mechanistic characterization, of a potent probiotic strain with activity against Salmonella enterica infection. The evidence provided is compelling, with multiple and varied methodologies used to support the claims made by the authors. The findings reported are valuable to the probiotic and enteric infection subfields.

eLife Assessment

Huson & Regehr characterize the spiking responses of UBCs to various patterns of synaptic stimulation and dissect the contributions of relevant glutamate receptors to their transformations. This study presents valuable findings describing how trains of mossy fiber stimulation control cerebellar unipolar brush cell discharges. The evidence that UBCs transform signals in diverse ways depending on their complement of AMPA, mGluR1, and mGluR2 receptors is solid.

eLife Assessment

This study provides important morphological observations related to the potential roles of Hebbian plasticity in establishing brain connectivity, by examining synapses formed by functionally distinct groups of retinal ganglion cell (RGC) axons in albino mouse dorsolateral geniculate nucleus (dLGN). Here, inappropriately projecting contralateral RGCs undergo developmental rewiring alongside ipsilateral RGCs, such that Hebbian theory would predict them to have separate synaptic targets. The authors provide compelling support for some presence of Hebbian rewiring, using combined confocal imaging and serial electron microscopy (EM) reconstructions to show that contralateral RGCs form completely segregated synaptic inputs onto islands of dLGN thalamocortical neurons, as well as somewhat segregated synaptic input onto local inhibitory interneurons. These findings will be of interest to researchers studying synaptic connectivity and plasticity during development.

eLife Assessment

This valuable study compares ChIP-seq and ChEC-seq2 techniques to investigate RNA polymerase II (RNAPII) binding patterns in yeast, revealing that ChEC-seq2 captures distinct regulatory events associated with active transcription missed by ChIP-seq. The authors use ChEC-seq2 data to build a stochastic model of RNAPII kinetics, providing convincing new insights into transcription regulation and the role of the nuclear pore complex. The paper highlights the importance of careful methodological comparisons in understanding RNAPII dynamics.

eLife Assessment

This study presents convincing evidence of the role of an intestine-released neuropeptide, FLP-2, in the oxidative stress response of C. elegans, as well as for the neural circuit pathway that regulates its release in response to sensing reactive oxygen species (i.e., H2O2). These valuable results advance the understanding of gut-brain signaling and the neural circuit basis of behavioral responses to stress.

eLife Assessment

This important manuscript describes a creative approach using dual-component gRNAs to create a new class of molecular proximity sensors for genome editing. The authors demonstrate that this tool can be coupled with several different gene editing effectors, showing convincingly that the tool functions as intended. This study not only introduces a first-of-its kind approach, but through careful measurements also enables future further development of the technology.

eLife Assessment

This study is part of an ongoing effort to clarify the effects of cochlear neural degeneration on auditory processing in listeners with normal audiograms. Here the authors provide important new data demonstrating associations between cochlear neural degeneration, non-invasive assays of auditory processing, and speech perception. Based on a cross-species comparison, these findings pose compelling evidence that cochlear synaptopathy is associated with a significant part of hearing difficulties in complex environments for some listeners with normal hearing thresholds, such as older individuals.

eLife Assessment

Although others have proposed that OHC electromotility subserves cochlear amplification by acting as a "fluid pump", and evidence for this has been found using electrical stimulation of excised cochleae, this important study substantially advances our understanding of cochlear homeostasis. This is the first report to test the pumping effect in vivo and consider its implications for cochlear homeostasis and drug delivery. The manuscript provides convincing evidence for OHC-based fluid flow within the cochlea.

eLife Assessment

This study presents valuable findings related to seasonal brain size plasticity in the Eurasian common shrew (Sorex araneus), which is an excellent model system for these studies. The evidence supporting the authors' claims is convincing. However, the authors should be careful when applying the term adaptive to the gene expression changes they observe; it would be challenging to demonstrate the differential fitness effects of these gene expression changes. The work will be of interest to biologists working on neuroscience, plasticity, and evolution.

eLife Assessment

This study used a novel continuous dot motion decision-making task to measure participants' perception and uncertainty/confidence in a social context. The social element is that participants can see another player's responses as well as their own. The study is a useful contribution to social decision-making primarily by introducing a new task and offering solid evidence on how participants are impacted by others' decisions during continuous perceptual choices. The manuscript could be improved through streamlining, more consistent use of terms such as "dyadic" and clarification about the differences between primary uncertainty and metacognitive confidence.

eLife Assessment

This valuable study uses consensus-independent component analysis to highlight transcriptional components (TC) in high-grade serous ovarian cancers (HGSOC). The study presents a convincing preliminary finding by identifying a TC linked to synaptic signaling that is associated with shorter overall survival in HGSOC patients, highlighting the potential role of neuronal interactions in the tumor microenvironment. This finding is corroborated by comparing spatially resolved transcriptomics in a small-scale study; a weakness is in being descriptive, non-mechanistic, and requiring experimental validation.

eLife Assessment

This study presents a valuable finding on the molecular mechanisms that govern GABAergic inhibitory synapse function. The authors propose that Endophilin A1 serves as a novel regulator of GABAergic synapses by acting as a component of the inhibitory postsynaptic density. Although the study employs a variety of approaches to address this question, the current analysis is incomplete and requires further experiments to substantiate the claims fully. The findings are likely to interest a broad audience of scientists focusing on inhibitory synaptic transmission, the excitation-inhibition balance, and its disruption in disorders such as epilepsy.

eLife Assessment

Computational simulation of neuron function depends on a collection of morphological properties and ion channel biophysics. This manuscript introduces DendroTweaks, a useful web application and Python library that, compared to existing modeling tools, eases interactive graphical exploration, development, and validation of single-neuron models. The authors provide a convincing demonstration that their software aids with building intuition and rapid prototyping of biophysical models of neurons, which improves the accessibility of dendritic simulation.

eLife Assessment

This important study addresses the question of how large-scale events such as the COVID-19 pandemic can change peoples' beliefs and their updates. Using a well-validated task, the authors find that belief updating becomes less optimistically biased during COVID-19, compared to prior to it. While they have solid evidence for specific changes of positive learning rates in their RL model and should be commended for more extensive modeling of the task than many previous studies, comprehensive model confusion and recovery analyses could further strengthen their claims by clarifying the specificity of their findings. As with many manipulations outside the experimenters' control, it remains unclear which psychological factor impacted by the pandemic drives the group differences, and sample sizes are by necessity on the smaller side as data cannot readily be acquired.

eLife Assessment

The study presents important findings on inositol-requiring enzyme (IRE1α) inhibition on diet-induced obesity (overnutrition) and insulin resistance where IRE1α inhibition enhances thermogenesis and reduces the metabolically active and M1-like macrophages in adipose tissue. The evidence supporting the conclusions is convincing but can be enhanced with information/data on the validity, specificity, selectivity, and toxicity of the IRE1α inhibitor and supported with more detail on the mechanisms by which adipose tissue macrophages influence adipocyte metabolism. The work will be of interest to cell biologists and biochemists working in metabolism, insulin resistance, and inflammation.

eLife Assessment

This study provides important insights into the question of how interacting brain areas produce behaviour during the execution of a skilled multi-directional reaching task. Using a combination of single neuron and neural population analysis, as well as optogenetic stimulation and computational models, the authors provide solid evidence of an asymmetrical influence between mouse premotor and motor cortex during the execution of a well-practiced behaviour. This asymmetry can only be captured by some but not all population analysis methods, which is a key lesson to the field in and of itself. Analyzing how activity that is shared and private to these areas relates to different aspects of movements, and linking the model predictions to the actual data, would further strengthen this work.

eLife Assessment

This study presents an important finding that ant nest structure and digging behavior depend on ant age demographics for a ground-dwelling ant species (Camponotus fellah). By asking whether ants employ age-polyethism in excavation, the authors address a long-standing question about how individuals in collectives determine the overall state of the task they must perform, and their results may prove to be a key consideration for interpreting results from other studies in the field of social insect behavior. While the experimental evidence that the age of the ants and the group composition affect the digging of tunnels is solid, some of the analyses and modeling are seem superfluous, as they do not further support the results or contribute to a deeper understanding of the system.

eLife Assessment

This important paper takes a novel approach to the problem of automatically reconstructing long-range axonal projections from stacks of images. The key innovation is to separate the identification of sections of an axon from the statistical rules used to constrain global structure. The authors provide convincing evidence that their method is a significant improvement over existing measures in circumstances where the labelling of axons and dendrites is relatively dense, but the robustness to image noise remains to be tested.

eLife Assessment

This study presents a valuable finding that altruistic tendency during moral decision-making is context-dependent (present in the gain domain but absent in the loss domain) and its absence in the loss domain can be restored by the neuropeptide oxytocin. However, the evidence supporting this claim is somewhat incomplete and would benefit from better overall framing and clarity on its approaches. Overall, this study will be of interest to social scientists and neuroscientists who work on moral decision-making and oxytocin.

eLife Assessment

This valuable contribution combines high-resolution histology with magnetic resonance imaging in a novel way to study the organisation of the human amygdala. The main findings convincingly show the axes of microstructural organisation within the amygdala and how they map onto the functional organisation. Overall, the approach taken in this paper showcases the utility of combining multiple modalities at different spatial scales to help understand brain organisation.

eLife Assessment

The focus of this study is the development of a compelling method for analyzing network communication in the brain through an exhaustive computational analysis of virtual lesions. Using human neuroimaging data, the authors identified brain regions that exert the greatest influence over others. These important results revealed the characteristic connectivity profile of such brain regions and provided a network analysis method that will find applicability beyond the datasets used.

eLife Assessment

This valuable study combined whole-head magnetoencephalography (MEG) and subthalamic (STN) local field potential (LFP) recordings in patients with Parkinson's disease undergoing deep brain stimulation surgery. The paper provides solid evidence that cortical and STN beta oscillations are sensitive to movement context and may play a role in the coordination of movement redirection.

eLife Assessment

The central claim in this valuable manuscript is that microglia in the PVH sculpt the density of AgRP inputs to the PVH in a spatially restricted manner. The anatomical results are solid but the analysis of how microglia activity affects body weight when lactating dams are fed a high-fat diet is incomplete.

eLife Assessment

This study provides useful information on the potential role of ERbB4 expression in parvalbumin-positive cells on olfactory behaviour and circuit dynamics in the olfactory bulb. The question is timely and novel, and findings could shed light on the critical role that ErbB4 may play in modulating olfactory bulb cell function and olfactory perception. Although the authors use a comprehensive set of experiments for their analysis, the evidence is incomplete as many of the experiments are underpowered and the model for selective knockout of ErbB4 in olfactory parvalbumin cells is not validated.

eLife Assessment

This is a valuable work that convincingly reveals that place cells in the hippocampus that exhibit repeated firing fields incorporate information about non-positional variables in each firing field. They reveal that individual firing fields of a single place cell can exhibit tuning to different head orientations, suggesting hippocampal neurons are flexible in terms of how they incorporate non-positional inputs.