eLife Assessment

This important study reports a reanalysis of one experiment of a previously-published report to characterize the dynamics of neural population codes during visual working memory in the presence of distracting information. This paper presents solid evidence that working memory representations are dynamic and distinct from sensory representations of intervening distractions. This research will be of interest to cognitive neuroscientists working on the neural bases of visual perception and memory.

eLife Assessment

This study describes an improved adaptive sampling approach, multiple-walker Supervised Molecular Dynamics (mwSuMD), and its application to G protein-coupled receptors (GPCRs), which are the most abundant membrane proteins and key targets for drug discovery. The manuscript provides solid evidence that the mwSuMD approach can assist in the sampling of complex binding processes, leading to useful findings for GPCR activity, including resolution of interactions not seen experimentally. The method has the potential to have broad applicability in structural biology and pharmacology.

eLife Assessment

In Plasmodium male gametocytes, rapid nuclear division occurs with an intact nuclear envelope, requiring precise coordination between nuclear and cytoplasmic events to ensure proper packaging of each nucleus into a developing gamete. This valuable study characterizes two proteins involved in the formation of Plasmodium berghei male gametes. By integrating live-cell imaging, ultrastructural expansion microscopy, and proteomics, this study convincingly identifies SUN1 and its interaction partner ALLAN as crucial nuclear envelope components in male gametogenesis. A role for SUN1 in membrane dynamics and lipid metabolism is less well supported. The results are of interest for general cell biologists working on unusual mitosis pathways.

[Editors' note: this paper was reviewed by Review Commons.]

eLife Assessment

In this valuable study, the authors used rats to determine the receptor for a food-related perception that has been characterized in humans. The data are solid in terms of methods and analysis: the data show that this stimulus (ornithine) has some additive effects in terms of increasing preference and taste response in rats when it is mixed with other more common taste stimuli. Therefore, the combinations of experiments generally support (but do not conclusively prove) the hypothesis that the "kokumi" taste effect elicited by this stimulus in humans may be mediated by the specific receptor examined in the study.

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 tumour microenvironment. This finding is corroborated by comparing spatially resolved transcriptomics in a small-scale study; a weakness is it being descriptive, non-mechanistic, and requires experimental validation.

eLife Assessment

Xenacoelomorpha is an enigmatic phylum, displaying various presumably simple or ancestral bilaterian features. This valuable study characterises the reproductive life history of Hofstenia miamia, a member of class Acoela in this phylum. The authors describe the morphology and development of the reproductive system, its changes upon degrowth and regeneration, and the animals' egg-laying behaviour. The evidence is convincing, with fluorescent microscopy and quantitative measurements as a considerable improvement to historical reports based mostly on histology and qualitative observations.

eLife Assessment

The study presents valuable findings on the role of Aff3ir, a gene implicated in flow-induced atherosclerosis and regulating the inflammation-associated transcription factor, IRF5. The in vivo data are solid in providing evidence on the role of Aff3ir in shear stress and formation of atheromatous plaques. The work will be of interest to clinical researchers and biologists focusing on inflammation and atherosclerosis in cardiovascular disease with a broad eLife readership.

eLife Assessment

This useful study presents a hierarchical computational model that integrates locomotion, navigation, and learning in Drosophila larvae. The evidence supporting the model is solid, as it qualitatively replicates empirical behavioral data, but the experimental data is incomplete. While some simplifications in neuromechanical representation and sensory-motor integration are limiting factors, the study could be of use to researchers interested in computational modeling of biological movement and adaptive behavior.

eLife Assessment

Shihabeddin et al utilized single-cell RNA-Seq analysis of adult P23H zebrafish animals to identify transcription factors (e2fs, Prdm1a, Sp1) expressed selectively in neural progenitors and immature rods, and validated their necessity for regeneration using morphant analysis. The finding is useful, and the evidence is convincing. The deeper mechanistic analysis could further strengthen the current work by (1) distinguishing developmental vs regenerative transcriptional factors, (2) the addition of matched scATAC-Seq data, and (3) integration with single-cell multiome data from developing retina.

eLife Assessment

The authors provide valuable insights into the candidate upstream transcriptional regulatory factors that control the spatiotemporal expression of selector genes and their targets for GABAergic vs glutamatergic neuron fate in the anterior brainstem. The computational analysis of single-cell RNA-seq and single-cell ATAC-seq datasets to predict TF binding combined with cut and tag-seq to find TF binding represents a solid approach to support the findings in the study, although the display and discussion of the datasets could be strengthened. This study will be of interest to neurobiologists who study transcriptional mechanisms of neuronal differentiation.

eLife Assessment

The study presents a valuable finding on the role of cholesterol-binding sites on GLP-1 receptors although the clinical ramifications are unclear and not eminent at this point. Based on the detailed and persuasive responses provided by authors to the concerns raised by reviewers, the revised manuscript is improved substantially and is convincing enough in its scientific merit. The study is a good addition to the scientific community working on receptor biology and drug development for GLP-1 R.

eLife Assessment

This important study dissects the mathematical and biological assumptions underlying the commonly used Activity-by-Contact model of enhancer action in transcriptional regulation. The authors provide a convincing mathematical analysis that links this (mostly phenomenological) model to concrete molecular mechanisms of enhancer function. This work provides a strong foundation from which to analyze a broad swath of genome-wide data such as that generated by CRISPRi screens.

eLife Assessment

The authors examined the evolution of hepatitis C virus (HCV) in a cohort of 14 subjects with recent HCV infections. 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 contributes to a convincing study.

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. The results are convincing and expand our understanding of gluconeogenesis regulation.

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.

eLife Assessment

This useful study provides incomplete evidence that TANGO2 homologs, including HRG-9 and HRG-10, are not heme chaperones but play a role in cellular bioenergetics and oxidative stress homeostasis. While outstanding strengths include the use of different model systems, genetic tools, and behavioral assays, there are weaknesses in the data presented for the conclusions drawn. Due to the differences in experimental protocols between this study and the previous work reported by Sun et al., it is insufficient to rule out the role of TANGO2 as a heme chaperone, and furthermore, the authors provide only indirect evidence for the role of TANGO2 in bioenergetic and oxidative stress pathways. Nevertheless, this study paves the way for future mechanistic studies addressing the mechanisms of how TANGO2 regulates oxidative stress independent of its previously demonstrated role as a heme chaperone.

eLife Assessment

This study provides valuable findings on the role of site-specific DNA methylation changes during spermatogenesis and their contribution to paternal epigenetic inheritance. The study proposes that selective loss of DNA methylation at a subset of promoters is required for nucleosome retention and the establishment of epigenetic states that may influence embryonic gene regulation. The present study's conclusion is mostly supported by solid data.

eLife Assessment

This important study provides solid evidence for new insights into the role of Type-1 nNOS interneurons in driving neuronal network activity and controlling vascular network dynamics in awake, head-fixed mice. The authors use an original strategy based on the ablation of Type-1 nNOS interneurons with local injection of saporin conjugated to a substance P analogue into the somatosensory cortex. They show that ablation of type I nNOS neurons has surprisingly little effect on neurovascular coupling, although it alters neural activity and vascular dynamics.

eLife Assessment

This useful study presents computational analyses of over 5,000 predicted extant and ancestral nitrogenase structures. While the data and some analyses are solid, the study remains incomplete in demonstrating that the metrics used for comparing nitrogenase structures are statistically rigorous. The data generated in this study provide a vast resource that can serve as a starting point for functional studies of reconstructed and extant nitrogenases.

eLife Assessment

This valuable study uses C. elegans to provide new insights into the role of the conserved protein FLWR-1/Flower in synaptic transmission. Employing a variety of techniques, including calcium imaging, ultrastructural analysis, and electrophysiology, the paper provides evidence that challenges some previous thinking about FLWR-1 function. While most of the findings are convincing, some of the authors' conclusions about the mechanisms of FLWR-1 function remain somewhat speculative.

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 results seem improbable and need to be checked to make sure they are correct.

eLife Assessment

This important study provides a nuanced analysis of the impact of cues on cost/benefit decision-making deficits in male rats that could have translational relevance to many addictive disorders. The main findings are that cues paired with rewarded outcomes increase the proportion of risky outcomes, whereas risky choice is reduced when cues are paired with reward loss. The experimental data is convincing, but the computational analysis based on the optimisation of different Q-learning models is incomplete. The findings will be of interest to behavioural neuroscientists and clinicians with an interest in risk, decision making, and gambling disorders.

eLife Assessment

This work presents an atlas of vasopressin (AVP) and its receptor AVPR1a in mouse brains using RNAscope to map single transcript expressions of Avp and Avpr1a across various brain regions in males and females. The findings are valuable in that they identify brain regions expressing Avpr1a mRNA transcript. The impact of findings is decreased by incomplete analysis of the data due to limited description of Avpr1a mRNA distribution within brain regions and limited statistical inference.

eLife Assessment

This valuable study investigates the computational role of top-down feedback -- a property that is found in biological circuits -- in Artificial Neural Network (ANN) models of the neocortex. Using hierarchical recurrent ANNs in an audiovisual integration task, the authors show a visual bias consistent with that observed in human perception, which mildly improves learning speed. While the study offers a tool that is of value for studying top-down feedback in cortical models, with the potential to inspire other fields (e.g. machine learning), the presented evidence for a general framework of deep learning architectures that predict behavior is incomplete, and the methods section lacks sufficient detail in terms of hyperparameter choice and network structures.

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 microendoscopes used for imaging deep brain regions. By combining simulations and experiments, the authors provide convincing evidence showing that the obtained field of view is significantly increased with corrected, versus uncorrected microendoscopes. 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

This study presents potentially valuable insights into the role of climbing fibers in cerebellar learning. The main claim is that climbing fiber activity is necessary for optokinetic reflex adaptation, but is dispensable for its long-term consolidation. There is evidence to support the first part of this claim, though it requires a clearer demonstration of the penetrance and selectivity of the manipulation. However, support for the latter part of the claim is incomplete owing to methodological concerns, including the robustness of the CF marking and manipulation approach and the unclear efficacy of longer-duration climbing fiber activity suppression.

eLife Assessment

This important study investigates the influence of the cingulate cortex on the development of the social vocalizations of marmoset monkeys by making bilateral lesions of this brain area in neonatal animals. The evidence supporting the authors' claims is convincing. The work will be of broad interest to cognitive neuroscientists, speech and language researchers, and primate neuroscientists.

eLife Assessment

This study investigates how the maintenance of a spatial location in working memory affects the representation of visual information in area V4 of monkeys. As such, it is important not only for understanding vision but also for determining how working memory impacts perceptual signals and their underlying circuits. The data provide convincing evidence of a direct communication between prefrontal circuits that store spatial information and V4, which, under the current experimental conditions, manifests mainly as changes in temporal activity patterns (oscillations).

eLife Assessment

This important study investigates how AD(H)D affects attention using neural and physiological measures in a Virtual Reality (VR) environment. Solid evidence is provided that individuals diagnosed with AD(H)D differ from control participants in both the encoding of the target sound and the encoding of acoustic interference. The VR paradigm here can potentially bridge lab experiments and real-life experiments. The study is of potential interests to researchers who are interested in auditory cognition, education, and ADHD.

eLife Assessment

In this useful study, the authors perform voltage imaging of CA1 pyramidal cells in head-fixed mice running on a track while local field potentials (LFPs) are recorded. The authors conclude that synchronous ensembles of neurons are differentially associated with different types of LFP patterns, namely theta and ripples. However, evidence for the claims in the paper remains incomplete, due to caveats of the experimental approach and claims that are based on a relatively sparse data set collected with a cutting-edge but still largely untested method.

eLife Assessment

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

eLife Assessment

The submission by Gopal and colleagues reports important findings describing the structure of genetic and colour variation in its native range for the globally invasive weed Lantana camara. Whilst the importance of the research question and the scale of the sampling is appreciated, the analysis, which is currently incomplete, requires further tests to support the claims made by the authors.

eLife assessment

Using an elegant and thorough experimental design, Thomazeau et al show that, in the developing mouse visual cortex, presynaptic NMDA receptors at layer 5 neocortical synapses mediate spike-timing dependent LTD via JNK2, non-ionotropic signaling. These fundamental findings shed light on how NMDA receptors can tune synaptic function without acting as coincidence detectors. The experiments are supported by compelling evidence, gathered through optogenetics and quadruple patch clamp recordings from cortical slices.

eLife Assessment

This valuable work provides a robust yet simple protocol to isolate small extracellular vesicles from small volumes of plasma. The evidence supporting the conclusions is convincing, although a more thorough statistical comparison of the different techniques and technique combinations explored in the study would have been appreciated. The work will be of broad interest to cell biologists and biochemists.

eLife Assessment

This work provides a simple, rapid and valuable protocol for the isolation of small extracellular vesicles from small volumes of plasma, using two well-known methodologies, in tandem: size exclusion chromatography (SEC) and density gradient ultracentrifugation (DGUC). The authors exhaustively test these methodologies separately and in combination, showing superior results for the SEC-DGUC in terms of purity and yield. The results obtained in this work are convincing, using multiple state-of-art methodologies for the characterization of the isolates that support their conclusions.

eLife Assessment

This important study advances our understanding of genome annotations for chiton genomes. It provides a solid estimation of syntentic relationships for the chromosomes of the four new genomes plus an analysis linking these to other available chiton genomes, and an update for how these relate to molluscan genomes.

eLife Assessment

This fundamental study explores how genotypic changes relate to phenotypic stasis or variation within chitons, a molluscan group. Chitons are significant because their ancient body plan has remained largely unchanged for millions of years, yet the paper reveals rapid and large-scale genomic changes. This convincing study is a splendid advance in approximately doubling the number of sequenced chiton genomes, providing what appears to be among the best genome annotations for chiton genomes available to date. The study's key focus is on the genomic rearrangements across five reference-quality genomes of chitons and their implications for understanding evolutionary mechanisms, particularly in comparison to other molluscan clades.

eLife Assessment

This manuscript offers important insights into how polyphosphate (polyP) influences protein phase separation differently from DNA. The authors present compelling evidence that polyP distinguishes between protein conformational states, leading to diverse condensate behaviors. However, differences in charge density between polyP and DNA complicate direct comparisons, and the extent to which polyP-driven phase transitions reveal initial protein states remains unclear. Addressing these concerns would strengthen the manuscript's impact for researchers interested in biomolecular condensates, protein dynamics, and stress response mechanisms.

eLife Assessment

This valuable study reveals the pro-locomotor effects of activating a deep brain region containing diverse range of neurons in both healthy and Parkinson's disease mouse models. While the findings are solid, mechanistic insights remain limited due to the small sample size. This research is relevant to motor control researchers and offers clinical perspectives.

eLife Assessment

This important study uses extensive comparative analysis to examine the relationship between plasma glucose levels, albumin glycation levels, and diet and life history, within the framework of the "pace of life syndrome" hypothesis. The evidence that glucose is positively correlated with glycation levels and lifespan is convincing and, although there are some limitations related to data collection, they likely make the statistically significant findings more conservative. As the first extensive comparative analysis of glycation rates, life history, and glucose levels in birds, the study has the potential to be of interest to evolutionary ecologists and the aging research community more broadly.

eLife Assessment

This valuable study by Guo and colleagues reports 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

The manuscript provides an important assessment of the number and distribution of different retrovirus env genes present in primate genomes in the form of ancient endogenous retroviruses (ERV loci) and the potential role that viral recombination played in the diversification of retrovirus env genes and their propagation in the primate germline over millions of years. The paper convincingly describes how intermixing/recombination occurs with this viruses, representing a conceptual advance with potentially broad implications.

eLife Assessment

This study provides a valuable contribution to understanding how negative affect influences food-choice decision making in bulimia nervosa, using a mechanistic approach with a drift diffusion model (DDM) to examine the weighting of tastiness and healthiness attributes. The solid evidence is supported by a robust crossover design and rigorous statistical methods, although concerns about low trial counts, possible overfitting, and the absence of temporally aligned binge-eating measures limit the strength of causal claims. Addressing modeling transparency, sample size limitations, and the specificity of mood induction effects, would enhance the study's impact and generalizability to broader populations.

eLife Assessment

This study dissects the function of 3 outputs of a specific population of modulatory neurons, dorsal raphe dopamine neurons, in social and affective behavior. It provides valuable information that both confirms prior results and provides new insights. The strength of the evidence is convincing, based on cutting-edge approaches and analysis. This study will be of interest to behavioral and systems neuroscientists, especially those interested in social and emotional behavior.

eLife Assessment

This study thoroughly assesses tactile acuity on women's breasts, for which no dependable data currently exists. The study provides two important contributions, by convincingly showing that tactile acuity on the breast is poor in comparison to other body parts, and that acuity is worst in larger breasts, indicating that the number of tactile sensors is fixed. However, further arguments concerning the role of the nipple in spatial localisation are not well supported by the current evidence. This study will be of interest to the broader community of touch, as well as those interested in breast reconstruction and sexual function.

eLife Assessment

This study proposes a valuable and interpretable approach for predicting hematoma expansion in patients with spontaneous intracerebral hemorrhage from non-contrast computed tomography. The predictive performance of the proposed method is solid through external validation using two datasets. The work will be of interest to medical biologists working on stroke and neuroimaging.

eLife Assessment

This is a valuable study that tests the functional role of food-washing behavior in removing tooth-damaging sand and grit in long-tailed macaques and whether dominance rank predicts level of investment in the behavior. The evidence that food-washing is deliberate is compelling and the evidence that individual investment in the behavior varies is solid. Overall, the paper should be of interest to researchers interested in foraging behavior, cognition, and primate evolution.

eLife Assessment

This study provides fundamental insights into the regulation of a retained intron in the mRNA coding for OGT, a process known to be regulated by the O-GlcNAc cycling system, and highlights the functional role of the splicing regulator SFSWAP. The evidence supporting the claims of the authors is convincing; the authors performed an elegant state-of-the-art CRISPR knockout strategy and sophisticated bioinformatic analysis to identify SFSWAP as a negative regulator of alternative splicing. The work will be of interest to researchers in the fields of splicing and glycobiology.

eLife Assessment

The role of ACVR2A is potentially of importance to both the biology of trophoblast cells and to the pathogenesis of preeclampsia. In this manuscript, the authors have taken a useful first step towards better understanding this protein using a loss of function model in trophoblast cell lines and then examining invasion, proliferation, and transcription in these cells. The study is solid and further in vivo evidence on how target factors participate in the occurrence of placental structural disorders and diseases through potential downstream pathways will be invaluable in the future.

eLife Assessment

This important study highlights the key role of the gut-liver axis mediated by LPS in causing hepatic steatosis. The authors provide solid evidence, in vivo, in vitro, and in silico, for the role of acyloxyacyl hydrolase in mediating this effect using KO mice subjected to MASD-inducing diets. The findings are significant for the liver research community and others interested in the gut-liver axis.

eLife Assessment

This valuable work investigates the social interactions of mice living together in a system of multiple connected cages. It provides solid evidence for a statistical approach capturing changes in social interactions after manipulating prefrontal cortical plasticity. This research will be of broad interest to researchers studying animal social behavior.

eLife Assessment

This manuscript provides potentially important findings examining in 2D and 3D models in MYC liver cancer cells changes in DNA repair genes and programs in response to hypoxia. The authors use convincing methodology in most cases, but there is some concern that the analysis is incomplete.

eLife Assessment

Centromeres are specific sites on chromosomes that are essential for mitosis and genome fidelity. This valuable research advance builds upon previous studies to convincingly show that the centromere-histone core contributes to force transduction through the kinetochore. The centromere mainly strengthens one of the two paths of force transduction, influenced by the centromeric DNA sequence. The mechanism underlying this phenomenon will be an exciting future avenue of research, given that centromeric DNAs are not conserved. This work will be of interest to those studying cell division and chromosome segregation.

eLife Assessment

The bacterial cell wall is crucial to maintain viability. It has previously been suggested that Gram positive bacteria have a periplasmic region between the cell membrane and peptidoglycan cell wall that this is maintained by the presence of teichoic acids. In this valuable study, Nguyen et al. make clever use of electron microscopy and metabolic labelling to interrogate the role of teichoic acids in supporting the maintenance of the periplasmic region in Streptococcus pneumoniae. The findings are solid and close some crucial knowledge gaps whilst providing novel tools to further interrogate discrepancies in the field. This work will be of broad interest to microbiologists.

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 sites of action may also contribute to these changes.

eLife Assessment

This important study reports findings that Trpγ, a type of transient receptor potential (TRP) channel expressed in Dh44-releasing neuroendocrine cells, mediates starvation-dependent lipid catabolism. Overall, the claims of the authors are supported by solid evidence. The work should be of interest to both basic and medical biologists working on lipid metabolism.

eLife Assessment

This study provides an important computational tool for analyzing and deconvoluting a pool of plasmids sequenced without barcoding using nanopore long-read sequencing. The tool, which has been convincingly validated, is readily available to scientists interested in rapid and cost-effective verification of plasmid sequences as well as in scaling up analysis by pooling samples within barcodes.

eLife Assessment

This useful study reveals that as C. elegans, a poikilothermic ("cold-blooded") animal, adapt to cold (4ºC), they display a drastic reduction in translation (assessed by polysome profiling and SUNSET). The remaining translation (by ribo-seq) correlates with mRNA levels (by RNA-seq), and the changes in gene expression at least partially require IRE-1, an established endoplasmic reticulum stress sensor. The reviewers consider the data assessing global translation and RNA expression upon cold exposure and the data demonstrating the requirement of ire-1 to be solid, but the conclusion that "transcription" is the major regulatory step and "lipid changes" can be a signal for IRE-1 activation in cold adapted worms needs substantially more evidence. Overall, this study demonstrated a good correlation between translation and RNA levels and yielded an inventory of gene changes as C. elegans adapt to cold, and will be of general interest to researchers interested in stress response and cold adaptation.

eLife Assessment

This manuscript provides important findings for understanding the mechanisms of a major gene causing the gonad of fish and other vertebrates, including mammals, to become an ovary rather than a testis. Evidence is solid, but alternative explanations for a number of the claims must be considered and discussed. The impact of the work would benefit by placing it in a richer historical context.

In summarizing the sentence, it emphasizes that “violence” is not merely a physical or historical event but also an ideological force manifest in how art is appropriated and othered. The term “violence” here is used to describe systemic injustices that have been embedded in art historical narratives, drawing on examples like Native American ledgers to show that even everyday objects carry traces of this contested history. To clarify, the sentence calls for a rethinking of global art history one that does not shy away from the difficult past, but rather uses it to understand the present complexities of global cultural exchanges.

Ananda Coomaraswamy

Key Works:

The Transformation of Nature in Art (1943)

Christian and Oriental Philosophy of Art (1922)

Background and Context: Coomaraswamy’s writings seek to recover and articulate the philosophical and aesthetic principles underlying traditional (often non-Western) art forms. In The Transformation of Nature in Art, he argues that art is a symbolic transformation of nature a process that reveals the deep, sacred orders of various cultures. Similarly, Christian and Oriental Philosophy of Art compares Western and Eastern artistic traditions, critiquing the Western tendency to impose its own values and methodologies on non-Western art. His work has been influential in questioning the dominant Western narratives that have long marginalized non-Western cultural expressions. In the context of global art history, Coomaraswamy’s ideas challenge the “provincialism” inherent in art historical narratives that fail to acknowledge the profound contributions of non-Western aesthetic systems.

eLife Assessment

This useful study provides convincing evidence that Drosophila can taste cholesterol through a subset of bitter-sensing gustatory receptor neurons, and that flies avoid high-cholesterol food. However, the same receptors have been previously found to be involved in the detection of multiple seemingly unrelated chemicals, and the reported expression patterns of these receptors contradict past reports. These caveats are not mentioned in the paper, raising critical concerns about the study's conclusions.

eLife Assessment

This valuable study advances understanding of how corticotrophin releasing factor in the bed nucleus of the stria terminalis regulates sustained and phasic fear and how this differs between sexes. The evidence is convincing and based on state-of-the-art techniques. The work will be of interest to neuroscientists studying the biological basis of fear processing.

eLife Assessment

This valuable study used functional MRI experiments to identify the involvement of a left parietal area (PF) in reasoning about the physical properties of actions, objects, and events. Solid evidence was shown regarding the commonalities and differences across different types of reasoning tasks, yet the methodological and theoretical interpretations require further scrutiny. The study would be of interest to researchers studying the cognitive and neural mechanisms of reasoning and problem solving.

eLife Assessment

This important study substantially advances our understanding of the circadian clock in Antarctic krill, a key species in the Southern Ocean ecosystem. Through logistically challenging shipboard experiments conducted across seasons, the authors provide compelling evidence for their conclusions. The study will be of broad interest to marine biologists and ecologists.

eLife Assessment

This important study assessed the effects of food intake on sharp wave-ripples in the hippocampus of mice during subsequent sleep. Convincing evidence supports the conclusion that sharp wave-ripples are enhanced by food consumption. This work will likely interest researchers studying multiple functions including memory, metabolism, and brain-body physiology.

eLife Assessment

Using electrophysiological recordings in freely moving rats, this valuable study investigates the role of gamma oscillations in the development of spatial representations in the hippocampus. Specifically, solid evidence supports the claim that distinct gamma oscillatory inputs contribute to the emergence of 'theta sequences', which encode the animal's ongoing trajectory. This study will be of interest to neuroscientists working in the fields of spatial navigation and neuronal dynamics.

eLife Assessment

This important study combines genetic analysis, biochemistry, and structural modeling to reveal new insights into how changes in protein-protein structure activate signal transduction as part of the bacterial general stress response. The data, which was collected using validated and standard methods, and its interpretations are convincing; however, to fully meet the title's promise, additional experimental evidence is needed to strengthen the proposed model and its potential application to other systems. This manuscript will be of broad interest to microbiologists, structural biologists, and cell biologists.

eLife Assessment

This is a saturation mutagenesis screening of CDKN2A gene, successfully assessing the functionality of the missense variants. The work is solid and well-prosecuted. The manuscript was improved during the revision process and this work will serve as a valuable resource for diagnostic labs as well as cancer geneticists.

eLife Assessment

This study is a valuable observation that deals with the toxic effects of an intermediary in lipid degradation [trans-2-hexadecenal (t-2-hex)] in yeast through modification of mitochondrial protein import via the TOM complex. We find that the claim that the TOM complex is a main target of t-2-hex are supported by solid evidence, however the molecular mechanism remains unclear allowing multiple interpretation. Despite the shortcomings, this study is inspiring for researchers from the organellar, protein trafficking and lipid field and serves as a starting point to further precise and mechanistic analyses of the phenomenon.

eLife Assessment

In this manuscript, Lim and collaborators present a useful system for developing self-amplifying RNA that should not provoke a strong host inflammatory response. However, some of the claims are incomplete; additional experiments to investigate the effects on translation of the gene of interest and replication efficiency of the self-amplifying RNA could strengthen the manuscript.

eLife Assessment

This useful study describes a novel method for imaging NAD(P)H fluorescence lifetime and thus metabolic states in the Drosophila brain. These solid findings support recent work demonstrating the importance of energy homeostasis to sustain memory formation and maintenance. Further efforts to demonstrate the adequacy of the statistical methods and the significance of the observed differences in FLIM signals in the α/β KCs would greatly enhance the manuscript. The approach will be helpful for researchers working with systems where genetic manipulation is challenging.

eLife Assessment

This study presents an important finding on how lentiviral infection has driven the diversification of the HIV/SIV entry receptor CD4. Using a combination of molecular evolution approaches coupled with functional testing of extant and ancestral reconstructions of great ape CD4, the authors provide solid evidence to support the idea that endemic simian immunodeficiency virus infection in gorillas have selected for gorilla CD4 alleles that are more resistant to SIV infection. Expanding the study to interrogate the evolution and function of additional primate CD4 sequences could yield even stronger evidence.

eLife Assessment

This report explores the role of matrix metalloprotease MMP21 in left-right patterning in Xenopus. Based on a series of compelling experiments, the authors demonstrate that MMP21 can be secreted and acts upstream of dand5 without affecting cilia flow. The experiments are interesting and valuable; however, the claims by the authors lack consideration of other models that could also explain their findings.

eLife Assessment

This fundamental work presents two clinically relevant BMP4 mutations that contribute to vertebrate development. The compelling evidence, both from wet lab and AI generated predictions, supports that the site-specific cleavage at the BMP4 pro-domain precisely regulates its function and provides mechanistic insight how homodimers and heterodimers behave differently. The work will be of board interest to researchers working on growth factor signaling mechanisms and vertebrate development.

eLife Assessment

This fundamental article significantly advances our understanding of FGF signalling, and in particular highlights the complex modifications affecting this pathway. The evidence for the authors' claims is convincing, combining state of the art conditional gene deletion in the mouse lens with histological and molecular approaches. This work should be of great interest to molecular and developmental biologists beyond the lens community.

eLife Assessment

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. Although solid evidence is presented that is consistent with learning-dependent encoding of visual information in auditory cortex, further work is needed to establish the origin and nature of these non-auditory signals and to definitively rule out any effects of movement-related activity.

eLife Assessment

This valuable study provides a comprehensive description of the Nematostella vectensis matrisome - the genes encoding the proteins of the extracellular matrix. The authors combine new mass spectrometry data with bioinformatic analyses of previously published genomic and single-cell RNAseq data. Although this work will be of interest to biologists working on the evolution of the matrisome, as well as more broadly those working with non-bilaterian animals, in its current state it is incomplete due to the lack of rigorous criteria for manual curation and comprehensive annotation of the predicted matrisome.

eLife Assessment

This important study utilizes single-cell RNA sequencing to reveal the heterogeneity of trans-sialidase-like superfamily gene expression in Trypanosoma cruzi populations. The approach is highly convincing, as it successfully assigns cells to specific developmental forms and highlights the variability in surface protein expression among trypomastigotes. However, while the findings are solid and contribute to the understanding of immune evasion mechanisms, the study would benefit from a more detailed exploration of the regulatory factors governing trans-sialidase expression. Strengthening this aspect would further enhance its impact on researchers studying T. cruzi pathogenesis and host-parasite interactions.

eLife Assessment

The study is useful for advancing spatial transcriptomics through its novel regression-based linear model (glmSMA) that integrates single-cell RNA-seq with spatial reference atlases, though its methodological framework remains incomplete regarding spatial communication applications and feature dependence. The approach demonstrates notable utility by enabling higher-resolution cell mapping across multiple biological systems and spatial platforms compared to existing tools.

eLife Assessment

Kwon et al. present an important paper using a novel approach to estimating rotavirus vaccine efficacy using data from a passive surveillance network in the US. They provide convincing evidence to support their conclusion that using the whole genome, rather than previous use of two surface proteins, enhances our understanding of strain-specific vaccine efficacy. These findings have implications for this vaccine specifically as well as type-specific vaccine evaluation more generally.

eLife Assessment

This study reanalyzed previously published scRNA-seq and TCR-seq data to examine the proportion and characteristics of dual-TCR-expressing Treg cells in mice, presenting some useful insights into TCR diversity and immune regulation. However, the evidence is incomplete, particularly with respect to data interpretation, statistical rigor, and the functionality of dual -TCR Treg cells. The study is potentially of interest to immunologists studying T-cell biology.

eLife Assessment

This important study shows, for the first time, the structure and snapshots of the dynamics of the full-length soluble Angiotensin-I converting enzyme dimer. The combination of structural and computational approaches elucidates with convincing evidence the conformational dynamics of the complex and key regions mediating the conformational change. This work provides an example of how conformational heterogeneity can be used to gain insights into protein function.

eLife Assessment

This study presents a useful contribution to understanding zinc regulation of sperm physiology, specifically its inhibitory effects on the sperm-specific potassium channel Slo3. However, the evidence supporting the claims is incomplete, as critical experimental controls are lacking, key mechanistic aspects remain insufficiently explored, and experimental descriptions are often inadequate, making it difficult to fully assess the findings. Strengthening the study with additional electrophysiological recordings in sperm cells, improved imaging controls, and clearer methodological descriptions would enhance its impact and rigor.

eLife Assessment

This important study addresses a topic that is frequently discussed in the literature but is under-assessed, namely correlations among genome size, repeat content, and pathogenicity in fungi. Contrary to previous assertions, the authors found that repeat content is not associated with pathogenicity. Rather, pathogenic lifestyle was found to be better explained by the number of protein-coding genes, with other genomic features associated with insect association status. While the results are considered solid, confidence in the results would be deepened if the authors were to comprehensively account for potential biases stemming from the underlying data quality of the analyzed genomes.

eLife Assessment

The IBEX Knowledge-Base is an important tool that will enhance scientific collaboration by providing a centralized, community-driven resource for immunofluorescence imaging and reagent validation. Its detailed use cases, open-source design, and transparent reporting offer compelling evidence of its broad utility and impact in the life sciences. Overall, the resource sets a high standard as a blueprint for future community initiatives in reproducibility and standardization.

eLife Assessment

This manuscript demonstrates that Oct4 overexpression synergizes with Notch inhibition (Rbpj knockout) to promote the conversion of adult murine Müller glia (MG) into bipolar cells. These findings are important as the authors used rigorous genetic lineage tracing (GLAST-CreER; Sun-GFP) to confirm that neurogenesis indeed originates from MGs, addressing a key issue in the field. The single-cell multiomic analyses are convincing, and while functional studies of MG-derived bipolar cells would strengthen the conclusions, they are beyond the scope of this study.

eLife Assessment

This manuscript presents important information as to how adolescent alcohol exposure (AIE) alters pain behavior and relevant neurocircuits, with convincing data. The manuscript focuses on how AIE alters the basolateral amygdala, to the PFC (PV-interneurons), to the periaquaductal gray circuit, resulting in feed-forward inhibition. The manuscript is a detailed study of the role of alcohol exposure in regulating the circuit and reflexive pain, however, the role of the PV interneurons in mechanistically modulating this feed-forward circuit could be more strongly supported.

eLife Assessment

This manuscript presents important information as to how adolescent alcohol exposure (AIE) alters pain behavior and relevant neurocircuits, with convincing data. The manuscript focuses on how AIE alters the basolateral amygdala, to the PFC (PV-interneurons), to the periaquaductal gray circuit, resulting in feed-forward inhibition. The manuscript is a detailed study of the role of alcohol exposure in regulating the circuit and reflexive pain, however, the role of the PV interneurons in mechanistically modulating this feed-forward circuit could be more strongly supported.

eLife Assessment

This study provides a novel and critically important insight into the long-term use of DREADDs to modulate neuronal activity in nonhuman primates. The methods are compelling, demonstrating the peak dynamics and the subsequent stability of chemogenetic effects for 1.5 years, informing experimental designs and interpretation of highly impactful chemogenetic studies in macaques. The protocols, data, and outcomes can serve as guidelines for future experiments. Therefore, the findings will be of significant interest to the field of chemogenetics and may also be of broader interest to researchers and clinicians who seek to utilize viral vectors and/or related genetic technologies.

eLife Assessment

This important study provides compelling insights into the differential impact of intrinsic and synaptic conductances on circuit robustness using computational models of the pyloric network from the crustacean stomatogastric ganglion. The results demonstrate that model networks are more sensitive to perturbations in intrinsic conductances than in synaptic conductances, highlighting the critical role of intrinsic plasticity in stabilizing neuronal networks. These findings underscore the importance of intrinsic plasticity, a crucial yet often overlooked factor in neuronal dynamics. The generality of these conclusions should be tested across diverse networks and functions.

eLife Assessment

This observational study from the UK Biobank provides an important investigation into the associations between menopausal hormone therapy and brain health in a large, population-based cohort of females in the UK. A convincing model of brain aging using an open source algorithm is used. While some modest adverse brain health characteristics were associated with current mHT use and older age at last use, the findings do not support a general neuroprotective effect of mHT nor severe adverse effects on the female brain. This work addresses a topic that is of grave importance since menopausal hormone therapy and its effect on the brain should be better understood in order to provide individualized effective medical support to women going through menopause.

eLife Assessment

This valuable study uses dynamic metabolic models to compare perturbation responses in a bacterial system, analyzing whether they return to their steady state or amplify beyond the initial perturbation. The evidence supporting the emergent properties of perturbed metabolic systems to network topology and sensitivity to specific metabolites is solid.

eLife Assessment

This important study includes convincing evidence to show that behavioral measures and hippocampal representations when animals use task-relevant information and ignore irrelevant information do not depend on the medial prefrontal cortex. The results are expected to be of interest to those studying neural mechanisms of cognitive control and functions of associational brain regions.

eLife Assessment

The authors provide a useful summary of ten years of Brain Initiative funding including the historical development, the specific funding mechanisms, and examples of grants funded and work produced. The authors also conduct analyses of the impact on overall funding in Systems and Computational Neuroscience, the raw and field normalized bibliographic impact of the work, the social media impact of the funded work, and the popularity of some tools developed. The evidence for impact is incomplete due to the omission of a comparison group of funded grants.

eLife Assessment

The manuscript presents some useful accounts of experiences funding team projects within the BRAIN Initiative. These would be more appropriate to add to the companion manuscript since the present manuscript contains some overlapping analyses and does not stand well on its own. Therefore the evidence supporting the conclusions is incomplete.

eLife Assessment

This important computational study investigates homeostatic plasticity mechanisms that neurons may employ to achieve and maintain stable target activity patterns. The work extends previous analyses of calcium-dependent homeostatic mechanisms based on ion channel density by considering activity-dependent shifts in channel activation and inactivation properties that operate on faster and potentially variable timescales. The model simulations demonstrate the potential functional importance of these mechanisms, but the evidence is incomplete and would be strengthened by more in-depth analyses and explicit exposition.

eLife Assessment

This fundamental study concerns a model for transgenerational epigenetic inheritance, the learned avoidance by C. elegans of the PA14 pathogenic strain of Pseudomonas aeruginosa. The authors test the impact of procedural alterations made in another study, by Gainey et al., which claimed that transgenerational inheritance in this paradigm lacks robustness, despite this observation having been reported in multiple papers from the Murphy lab. The authors of the present study show that by following a non-standard avoidance protocol, Gainey et al. likely biased their measurements in a way that made it hard to observe learned avoidance. The authors also highlight the importance of bacterial growth conditions, showing that expression of the trigger molecule, the bacterial P11 RNA, which is necessary and sufficient to drive the transgenerational inheritance of the avoidance phenotype, is influenced by temperature. As expression of P11 was not verified by Gainey et al., this provides another explanation for the inability to observe transgenerational epigenetic inheritance. Together, the authors provide compelling and powerful arguments that the original phenomenon is robust and that it can be reproduced in the Murphy lab by following their original protocol precisely, including the use of azide to immobilize the worms at the food source. Overall, this study not only provides guidance for investigators in this experimental paradigm, but it also provides additional understanding of the differences between naïve preference, learned preference, and transgenerational epigenetic inheritance. The present study is therefore of broad interest to anyone studying genetics, epigenetics, or learned behavior.

eLife Assessment

This valuable study combines real-time keypoint tracking with transdermal activation of sensory neurons to investigate sensory neuron recruitment in freely moving mice, and builds on the authors' prior work in stationary mice. The evidence supporting the utility of the system is solid, although a more thorough classification of the behavioral responses to nociceptor stimulation would strengthen the work. Importantly, future analyses could include other cutaneous sensory neuron subtypes, and could also be adapted for studying more complex behaviors. The work will be of interest to sensory biologists and pain researchers.

eLife Assessment

This important study conducted experiments to quantify how neural activity independent changes in fluorescence might affect two-photon recordings when using diverse sensors. The researchers found a widespread presence of neural-activity-independent artifacts in two-photon imaging and provide convincing evidence that these artifacts are most likely caused by hemodynamic occlusion. Their findings underscore the importance of accounting for these artifacts when interpreting functional two-photon recordings.

eLife Assessment

This important study combines convincing evolution experiments with molecular and genetic techniques to study how a genetic lesion in MreB that causes rod-shaped cells to become spherical, with concomitant deleterious fitness effects, can be rescued by natural selection. The detailed mechanistic investigation increases our understanding of how mreB contributes to cell wall synthesis and shows how compensatory mutations may reestablish its homogeneity.

eLife Assessment

The authors provide important insights into a system of insect camouflage where a coating of self-made nano-particles (brochosomes) reduces the reflection of UV-light leading to lower predation by spiders. Compelling evidence is provided by micro-UV-Vis spectroscopy, electron microscopy, transcriptome and proteome analysis, histology, in-vivo predation assays and gene knock-downs. The phylogenetic analyses provide evidence that the genes coding for the brochosome proteins are clade-specific and have diversified by gene duplication.

eLife Assessment

This timely and important study used functional near-infrared spectroscopy hyperscanning to examine the neural correlates of how group identification influences collective behavior. The work provides incomplete evidence to indicate that the synchronization of brain activity between different people underlies collective performance and that changes in brain activity patterns within individuals may, in turn, underlie this between-person synchrony. This study will be of interest to researchers investigating the neuroscience of social behaviour.

eLife Assessment

This study unveils important data describing cell states of olfactory ensheathing cells, and how these cell states may relate to repair after spinal cord injury. The framework used for characterizing these cells is solid. This work will be of interest to stem cell biologists and spinal cord injury researchers.

eLife Assessment

This study reports important findings about pre-saccadic foveal prediction and the extent to which it is influenced by the visibility of the saccade target relative to its background. The research methodology and results make a convincing case that foveal congruency effects develop when salient local contrast variations at the saccade target location can be used to direct the eye movement. This work should be of broad interest to visual neuroscientists, as well as those interested in understanding perception in the context of eye movements and in modeling visually guided actions.

eLife Assessment

This important study reveals that the nucleolar protein Treacle undergoes liquid-liquid phase separation in vitro and in vivo. It provides convincing evidence that the ability of Treacle to form phase-separated condensates is necessary for the proper formation of the fibrillar center of the nucleolus, rRNA transcription, and rDNA repair. These findings will be of interest to the communities studying biomolecular condensates, nucleolar organization, and ribosome biogenesis.

eLife Assessment

This is important work and provides a significant advance in our understanding of mechanosensation in the epidermis. The evidence presented is convincing and, barring a few minor weaknesses, strongly implicates activation of epidermal cells and store-operated calcium entry in the activation of nociceptive neurons innervating that tissue. This work will be of broad interest to neurobiologists, epithelial cell biologists, and mechanobiologists.

eLife Assessment

This valuable study proposes using a rigorous computational model to assess memory deficits in Alzheimer's Disease with the goal of developing an early diagnosis tool for the disease. Using an established mouse model of the disease, the authors studied multiple behavioral tasks and ages with the goal of showing similarities in behavioral deficits across tasks. Using the model, the authors indicate specific deficits in memory (overgeneralization and overdifferentiation) in mice with the transgene for the disease. However, the evidence presented is incomplete as certain concerns remain regarding the interpretation of the behavioral results and the validation of the model fit.

eLife Assessment

This useful study reports datasets on gene expression and chromatin accessibility profiles of spermatogonia at different postnatal ages in mice. Overall, the technical aspects of the sequencing analyses and computational/bioinformatics are solid. This study may be of interest to biomedical researchers working on male germline stem cells and male fertility.

eLife Assessment

Huang and colleagues examined neural responses in mouse anterior cingulate cortex (ACC) during a discrimination-avoidance task. The authors present useful findings that ACC neurons encode primarily post-action variables over extended periods rather than the outcomes or values of those actions. Though the methodological approach was sound, the evidence ruling out alternative explanations is incomplete and requires substantial control analyses.

eLife Assessment

This manuscript by Kaur et al. identifies differential gene expression observed in distinct mouse lung cell populations, namely myeloid and lymphoid cells, upon short-term exposure to e-cig aerosols with various flavors. Their findings are potentially useful because the single-cell sequencing data provides a reference for future studies of genes and cellular pathways that are most affected by e-cig aerosols and their components. However, the evidence is incomplete due to limited statistical analyses and few biological replicates, as well as a lack of experimental validation.

eLife Assessment

This important study suggests that adolescent mice exhibit less accuracy than adult mice in a sound discrimination task when the sound frequencies are very similar. While the evidence supporting this observation is solid, demonstrating that this effect arises from cognitive differences between adolescent and adult mice requires more thorough documentation of task performance, as well as control of impulsivity and baseline licking. The authors should also clarify how difficult and easy trials are interleaved in the task and provide a more comprehensive discussion of the cortical inactivation results in relation to the overall task difficulty.

eLife Assessment

This study presents important information about the role of mu opioid receptors in synaptic communication between the medial habenula and the interpeduncular nucleus. The authors provide solid evidence that mu opioid receptor activation has differential effects on glutamate release from substance P neurons and cholinergic neurons, with a canonical reduction in release from the former but a novel increase in release from the latter. They also show that blocking potassium channels can unmask a nicotinic cholinergic synaptic response that is also facilitated by mu opioid receptor activation. This work will be of interest to those studying the interpeduncular nucleus, as well as the larger neuroscience community studying opioids and motivated behavior.

eLife Assessment

This study provides proof-of-principle data for the use of trained immunity to modulate macrophage interactions with tumours. The study makes a valuable contribution to the field of trained immunity. However, the study is incomplete without vivo data, which would have made the claims in the paper stronger by providing meaningful context for the in vitro experiments that were conducted.

eLife Assessment

Using fMRI-based pRF mapping, this important study presents a novel method to estimate visual field (VF) and VF loss/or potential restoration, through analysis of contrast sensitivity patterns in the early visual cortex. While the approach is very interesting and the evidence supporting the claims of the authors is solid, some methodological concerns need to be addressed. The work will be of interest to researchers in vision/clinical vision, neuroscience, and brain imaging.

eLife Assessment

The medicinal leech preparation is an amenable system in which to understand the neural basis of locomotion. Here a previously identified non-spiking neuron was studied in leech and found to alter the mean firing frequency of a crawl-related motoneuron, which fires during the contraction phase of crawling. The findings are valuable and the experiments were diligently done and generally solid; however, the presentation could improve. The work could be taken to the next level by further experiments, and by providing more overall context for the study.

eLife assessment

The work is interesting in its characterization of a large number of antibiotic persisters from a wild-type strain. Previous work was typically limited to directly observe either high persister strains or a smaller number of wt persisters. Therefore, it sheds new light on the elusive non-dormant persisters present in exponentially growing cultures and should help resolve previous conflicting observations.

eLife Assessment

This important study compares the cortical projections to primary motor and sensory areas originating from the ipsilateral and contralateral hemispheres. Results show that, while there is substantial symmetry between the two hemispheres regarding the areas sending projections to these primary cortical areas, contra-hemispheric projections had more inputs from layer 6 neurons than ipsi-projecting ones. The evidence is compelling and the conclusions are supported by rigorous analyses.