**Editors Assessment: **

Irises on top of being a popular and beautiful ornamental plant, have wider commercial interest due to the many interesting secondary metabolites present in their rhizomes that have value to the fragrance and pharmaceutical industries. Many of these have large and difficult to assemble genomes, and to fill that gap the Dalmatian Iris (Iris pallida Lam.) is sequenced here. Using PacBio long-read sequencing and bionano optical mapping to produce a giant 10Gbp assembly with a scaffold N50 of 14.34 Mbp. The authors didn’t manage to handle the haplotigs separately or to study the ploidy, but as all of the data is available for reuse others can explore these questions further. This reference genome should also allow researchers to study the biosynthesis of these secondary metabolites in much greater detail, opening new avenues of investigation for drug discovery and fragrance formulations.

This evaluation refers to version 1 of the preprint

eLife assessment

One of the most promising strategies in development of drugs targeting kinases is provided by using allosteric control that allows specific regulation and study of kinase function without directly targeting the active site. This important manuscript provides a convincing review of the current repertoire of tools for regulating the activity of protein kinases with the ultimate goal of developing novel approaches in treating diseases associated with signal dysregulation.

eLife assessment

One of the most promising strategies in development of drugs targeting kinases is provided by using allosteric control that allows specific regulation and study of kinase function without directly targeting the active site. This important work reviews convincingly the current repertoire of tools for regulating the activity of protein kinases with the ultimate goal of developing novel approaches in treating diseases associated with signal dysregulation.

eLife assessment

This important study provides convincing data in support of the conclusion that weak but not strong fear memories are more easily modified using behavioural and pharmacological approaches potentially as a result of differential connectivity with the amygdala showing greater connectivity through the brain in weak compared to strong memories. The scope of the paper would be strengthened if both sexes were examined and more varied definitions of weak vs. strong memories were used. This paper is of interest to behavioural and neuroscience researchers studying learning, memory, and/or neural networks.

eLife assessment

The manuscript offers important findings on the potential influence of maternally derived extracellular vesicles on embryo metabolism. However, while the content is convincing, the title appears to overstate the study's conclusions due to its speculative nature on the DNA transmission and embryo bioenergetics connection. A more measured title would better represent the evidence presented.

eLife assessment

Birman et al. present a valuable software interface, Pinpoint, for planning anatomically precise insertions of rigid instruments (e.g., electrodes, injection needles/pipettes, fibre optic implants) into the mouse brain. The authors provide compelling evidence of the potential of this software since, it: (1) incorporates the geometrical constraints of the rig and instruments; (2) interfaces with popular manipulator systems and data acquisition software; (3) runs on any browser; and (4) allows for easy collaboration among users. Despite these exciting features, quantification of the gains in experimental efficiency and accuracy derived from Pinpoint is needed.

eLife assessment

This important paper examining the relationship between ventral tegmental area dopamine activity and the activity of lateral hypothalamic orexin neurons in the context of reward learning. However, whereas the photometry imaging data are compelling, the functional links to behavior are incomplete since the necessity for dopamine-mediated orexin neuron recruitment in the hypothalamus to the observed behavioral effects is not unambiguously demonstrated. The study expands current notions of dopaminergic function and will be of broad general interest to those interested in reward related behaviors, learning, dopamine, lateral hypothalamus, or orexin function.

eLife assessment

This study presents valuable findings on the relationship between prediction error and brain activation in response to unexpected omissions of painful electric shock. The strengths are the research question posed, as it has remained unresolved if prediction errors in the context of biologically aversive outcomes resemble reward-based prediction errors. The evidence is incomplete due to the task design, which induces a disconnect between verbal instructions and experiential learning, and the lack of analyses accounting for learning and updating of expectations, which are crucial to neural prediction error signaling. The work will be of interest to cognitive neuroscientists and psychologists studying appetitive and aversive learning.

eLife assessment

This valuable study introduces an innovative method for measuring interocular suppression depth, which implicates mechanisms underlying subconscious visual processing. The evidence supporting the effectiveness of this method would be solid after successfully addressing concerns raised by the reviewers. The novel method will be of interest not only to cognitive psychologists and neuroscientists who study sensation and perception but also to philosophers who work on theories of consciousness.

eLife assessment

This paper studies how amacrine cells influence retinal output signals. The approach taken is unusually direct and has the potential to make important contributions to our understanding of amacrine cells, and more generally interneurons, to circuit function. The contributions of the work described, however, are limited by several key concerns. Specifically, the results rely heavily on assumptions made about how signals traverse the retina; as a result, the evidence for adequate separation of signals contributed by the amacrine cells and those from other parallel retinal pathways is incomplete.

eLife assessment

This important study presented a series of results to uncover the role of C-terminal half of the Syx1 SNARE domain. The evidence supporting the conclusions is solid, although more mechanisms in the study would have strengthened the work. The paper will be of interest to biophysicists and neurobiologists.

eLife assessment

This study used fMRI in an animal that simulates a type of epilepsy to ask if the responsiveness of the brain was altered during a seizure. The results suggest that the brain responsiveness is reduced during the seizures. The significance of the findings is useful and the strength of the evidence is incomplete but could be strengthened after additional experiments.

eLife assessment

This report details convincing evidence that experience with multilingualism in general, and with larger phonological inventories specifically, is related to differences in the structure of the transverse temporal gyri. The project is notable for using a relatively large sample, and confirming the primary finding in a smaller sample. Although results are sometimes slightly counterintuitive (both increases and decreases in cortical thickness are related to experience with multilingualism), the important findings strongly point to experience-dependent plasticity related to language experience as a driver of neuroanatomy of the auditory cortex.

eLife assessment

This manuscript describes useful data on the mechanisms underlying the activation of the receptor tyrosine kinase FGFR1 and stimulation of intracellular signaling pathways in response to FGF4, FGF8, or FGF9 binding to the extracellular domain of FGFR1. Solid evidence for quantitative differences in the downstream responses induced by the three ligands is presented. This manuscript will be of interest to biochemists and cell biologists working on receptor tyrosine kinases and general cell signalling across membranes.

eLife assessment:

This study presents valuable findings on the impact of C-natriuretic peptide (CNP) treatment in vivo on the fertility of aged mice. Solid data indicate CNP induces the cAMP-PKA pathway, causing reduced recruitment of Parkin protein to mitochondria in oocytes, resulting in reduced mitophagy, which may be significant for increased mitochondrial bioenergetics and improved cytoplasmic and nuclear maturation. The authors make additional claims regarding the mechanisms by which CNP impacts oocyte quality in vivo for which the evidence is inconclusive. This work will be of interest to reproductive biologists and clinical infertility specialists.

eLife assessment

This important study will provide evidence about a novel screen-triage-treat strategy for cervical cancer prevention. The strategy would contribute to improving access to cervical cancer prevention to vulnerable women with low access to health care, and, therefore, at the highest risk of cervical cancer. However, the current protocol description is currently incomplete and missing key information for clarity and reproducibility.

eLife assessment

This is an important study that uses chromatin accessibility as a measure to determine the impact of neuronal activity on the state of chromatin regulatory elements in striatal neurons. The authors provide convincing evidence of how Pdyn gene expression is highly dependent on a distal regulatory genomic region both at basal and upon neuronal activation in this particular system, a mechanism conserved as well in human neuronal cells. Although the basic idea of accessibility changes have been studied before, this paper ties previous findings all together in one place and uses the analysis to identify a functionally relevant and conserved enhancer for the prodynorphin gene with potential relevance for neuropsychiatric disorders beyond basic cellular neuroscience. The study will be of interest to neuroscientists studying the striatum, neuronal plasticity, or related neuropsychiatric disorders.

eLife assessment

This study is useful in identifying several gain-of-function division variants that can suppress the elongated cell division defect phenotype caused by the depletion of Age1 (or AdvA as named in other studies), a known essential cell division protein in Acinetobacter baumannii. However, characterizations of AdvA's localization patterns and its interactions with other divisome proteins are incomplete due to the lack of (1) functional characterizations of fluorescent fusion proteins, (2) considerations for membrane protein topology in the bacterial two hybrid assay, and (3) lack of high-quality fluorescence images for the co-localization studies. The results do not yet support the major claim that Age1 plays a critical role in the assembly of the A. baumannii divisome.

eLife assessment

This important study presents convincing evidence on how the sea slug Aplysia kurodai optimizes its digestion of brown algae, in a classical predator-prey 'arms race' at the molecular level. The experimental protein structures and enzyme assays provide support for the claims of how the A. kurodai avoids inhibition by algal compounds, and also hold promise for biotechnological applications.

eLife assessment

This important study presents convincing evidence on how the sea slug Aplysia kurodai optimizes its digestion of brown algae, in a classical predator-prey 'arms race' at the molecular level. The experimental protein structures and enzyme assays provide support for the claims of how A. kurodai avoids inhibition by algal compounds, and also hold promise for biotechnological applications.

eLife assessment

This valuable study investigates the environmental drivers behind termite construction, focusing, in particular, on pellet deposition behavior, with the conclusion that termites likely sense curvature indirectly through substrate evaporation. The findings reconcile discrepancies between previous studies through experimental and computational approaches. Although the strength of the evidence supporting these claims is compelling, the authors do not discuss how their results affect our understanding of insect nest construction or animal-built structures more broadly.

eLife assessment

This important study presents an exhaustive structural analysis of a complete tripartite HipBST toxin-antitoxin system of the Enteropathogenic E. coli O127:H6, which represents a fascinating variation on the well-studied HipAB toxin-antitoxin system. The convincing data show that major features of the canonical HipAB system have been rerouted to form the tripartite HipBST, revealing a new mode of inhibition of a toxin kinase.

eLife assessment

This important study demonstrates use of the mammalian Musashi-1 (MSI-1) RNA-binding protein as a tool for regulating gene expression in Escherichia coli. The system could also be used for mechanistic studies of MSI-1. The authors provide solid evidence that MSI-1 functions as an effective repressor that acts post-transcriptionally. The impact of MSI-1 as a synthetic biology tool could be strengthened by expanding the analysis of MSI-1's allosteric regulation by oleic acid. The work will be of interest to synthetic biologists.

eLife assessment

This is an important study that develops a new model of the way muscle responds to perturbations, synthesizing models of how it responds to small and large perturbations, both of which are important to predict how muscles function for stability but also how they can be injured. The evidence presented to support the model is solid, but the work is incomplete as it is particularly lacking a more detailed analysis of the trade-offs associated with using the model to simulate different types of preparations, especially single muscle fibers compared to whole muscles or whole muscles and tendons. With a clearer discussion of the limitations of the model and the situations in which it is best applied, the work will be of interest to those developing realistic models of the stability and control of movement in humans or other animals.

eLife assessment:

This important study combines molecular genetics and target validation to discover genes involved in obesity and determine their role. The reviewers unanimously agree that the work is important in terms of significance: it has conceptual and practical implications beyond metabolism, including embryonic and placental development. They also considered that the strength of evidence is convincing from the use of their forward genetic screen in mice. In some instances, reviewers considered that the work was not more than solid because although the methods, data, and analyses broadly support the claims, minor weaknesses emerge on which they suggest improvements for you to consider and selectively address.

eLife assessment

This work reports a valuable finding on glucocorticoid signaling in male and female germ cells in mice, pointing out sexual dimorphism in transcriptomic responsiveness. While the evidence supporting the claims is generally solid, additional assessments would be required to fully confirm an inert GR signaling despite the presence of GR in the female germline and GR-mediated alternative splicing in response to dexamethasone treatment in the male germline. The work may interest basic researchers and physician-scientists working on reproduction and stress-related disease conditions.

eLife assessment

This important study enhances our understanding of the effects of landscape context on grassland plant diversity and biomass. Notably, the authors use a well-designed field sampling method to separate the effects of habitat loss and fragmentation per se. Most of the data and analyses provide solid support for the findings that habitat loss weakens the positive relationship between grassland plant richness and biomass.

eLife assessment

This study provides useful insights into the subcellular localization, interaction with integrins, and function of the cell surface receptor Piezo1 in migrating human T-cells. The data collected is convincing but incomplete. Therefore the idea that Piezo1 is critically sensing mechano-physical cues during T-cell migration is not well supported by direct experimental evidence.

eLife assessment

This important study substantially advances our understanding of mechanisms of TRABID pathogenic patient mutations, studied in vitro and in vivo during neurodevelopment. The evidence supporting the conclusions is compelling with rigorous biochemical and state of the art imaging approaches. The work will be of interest to cell biologists, neuroscientists and clinical neurologists.

eLife assessment

This important study reports a novel measurement for the chemotactic response to potassium by Escherichia coli. The authors convincingly demonstrate that these bacteria exhibit an attractant response to potassium and connect this to changes in intracellular pH level. However, some experimental results are incomplete, with additional controls/alternate measurements required to support the conclusions. The work will be of interest to those studying bacterial signalling and response to environmental cues.

eLife assessment

This valuable study addresses the temporal patterning of a specific Drosophila CNS neuroblast lineage, focusing on its larval development. The work is solid: the authors find that a temporal cascade, involving the Imp and Syp genes, changes the fate of one daughter cell/branch from glioblast (GB) to programmed cell death (PCD), as well as gates the decommissioning of the NB at the end of neurogenesis.

eLife assessment

This fundamental work substantially advances our understanding of cell migration, especially in that of cranial neural crest. The evidence supporting the conclusion is compelling, with rigorous biochemical assays for materials used and with intensive genetic interventions. The work will be of broad interest to developmental biologists and cell biologists.

eLife assessment

This manuscript examines shared and divergent mechanisms of disruptions of five different mTOR pathway genes on embryonic mouse brain neuronal development. The significance of the manuscript is important, because it bridges several different genetic causes of focal malformations of cortical development. The strength of evidence is compelling, relying on both gain and loss of function, demonstrating differential impact on excitatory synaptic activity, conferring gene-specific mechanisms of hyperexcitability. The results have both theoretical and practical implications for the field of developmental neurobiology and clinical epilepsy.

eLife assessment

The present study offers valuable insights into the emergence of oscillations in neural networks. It underscores the importance of achieving a delicate balance between excitatory and inhibitory links and deals with the topological conditions for oscillations providing incomplete evidence for the observed features. It employs formal mathematical proofs and advanced computational simulations, providing insights for researchers in the field of neural dynamics and network behavior.

eLife assessment

The authors report that an interaction between the sodium-activated potassium channel Slack and Nav1.6 sensitizes Slack to inhibition by quinidine. This is an important finding because it contributes to our understanding of how the antiseizure drug quinidine affects epilepsy syndromes arising from mutations in the Slack-encoding gene KCNT1. The results are largely compelling, although additional data would strengthen the claims of a direct channel-channel interaction in neuronal cell membranes.

eLife assessment

This important study demonstrates that disrupting a common protein-folding system restores sensitivity to antibiotics in drug-resistant clinical bacterial pathogens. Although some additional controls would be welcome, the work is overall convincing in showing that targeting protein folding can be used to combat multi-drug resistant pathogens, both by potentiating the efficacy of existing drugs and by therapeutic use of small-molecule inhibitors. This study is significant and timely as it furnishes a new strategy that is relevant to microbiologists and clinicians interested in combating antimicrobial resistance.

eLife assessment

This fundamental study advances our understanding of nitrogen metabolism by identifying a new type of guanidine forming enzyme in eukaryotes. The evidence supporting this pioneering research is convincing, with rigorous biochemical, cellular, and in vivo experiments.

eLife assessment

This paper presents an important discovery of the molecular basis of differential apterous expression during early Drosophila wing disc development. The evidence supporting these conclusions is compelling, ranging from classical genetic approaches to state-of-the-art genetic engineering techniques. By opening new questions, this paper is expected to be of broad interest to developmental biologists and geneticists working on transcriptional regulation.

eLife assessment

This valuable study draws attention to the importance of a previously overlooked structural motif in kinase regulation. While the data presented are intriguing, the analysis is incomplete. Additional experiments are needed to support the authors' hypothesis. The work will be of interest to protein biochemists and enzymologists with an interest in kinases and allostery.

eLife assessment

This study develops an important method for dissecting out two overlapping cell signaling pathways, phosphoinositide signaling and membrane protein trafficking. The combination of two state-of-the-art techniques provides compelling evidence for a reciprocal influence between an enzyme and a channel. The work will be of interest to the broader cell biology, biophysics and biochemistry communities.

eLife assessment

This study presents a valuable finding on the key factors of T cell responses associated with durable antibody responses following COVID-19 mRNA vaccinations. The data were collected with solid methods and approaches, but the interpretation of the conclusion may be biased due to the experimental design. If confirmed, it may have a great impact on future COVID-19 vaccine design. However, some of the evidence supporting the claims of the authors is incomplete with a small size of the samples, unproven validity of using the expanded T cells, and over-interpretation on the sequence homology data.

eLife assessment

This paper is important because of its integration of movement and contextual information to control a virtual arm for individuals with upper-limb differences. The provided evidence convincingly demonstrates the approach's feasibility for manipulating a single object shape in different orientations within a virtual environment. However, additional improvements are needed for this proof-of-concept neuro-model to fulfil practical requirements.

eLife assessment

This study presents a new and valuable theoretical account of spatial representational drift in the hippocampus. The evidence supporting the claims is convincing, with a clear and accessible explanation of the phenomenon. Overall, this study will likely attract researchers exploring learning and representation in both biological and artificial neural networks.

eLife assessment

This valuable work fills a gap in the mapping of gene expression patterns in the early embryo of C. elegans. The presented data are solid and provides a resource for future analysis.

eLife assessment

This is a valuable study of the molecular basis of summer-to-winter transition in the pear psyllid pest, Cacopsylla chinensis (hemiptera). The molecular and organismal experiments using current methodologies to evaluate the cold responsiveness of the target proteins are mostly convincing, but the structural and phylogenetic analyses remain inconclusive. The results of this study will be of interest to entomologists.

eLife assessment

Linker histone variants are prevalent throughout the eukaryotic lineage, but their specific roles in shaping chromatin structure are not well elucidated as antibodies did not exist to study these variant H1s. This useful study provides for a solid advance by addressing where these variants are localized in the human nucleus, finding specific enrichment that might shed light on their function. The work could benefit from a deeper functional dissection and some additional controls to independently validate the localization patterns observed. The findings will be of interest for the chromatin field.

eLife assessment

This valuable methodological development, which combines light (confocal) microscopy with high-resolution scanning EM and EM tomography, expands the level of structural detail accessible to large-volume EM studies and thus represents an approach to integrate the analyses of cellular and sub-cellular levels in biological samples. The data provide a convincing proof-of-principle. They will be of particular value to cell biologists interested in the in-depth interpretation of high-resolution ultrastructural information from sparsely distributed targets - at multiple scales and in diverse biological structures.

eLife assessment

This fundamental work substantially advances our structural understanding of S-layers in Archaea and how they are built to form formidable cell support structures able to stabilise the cytoplasmic membrane under harsh physicochemical conditions. The supporting evidence for the S-layer model is convincing, making excellent use of state-of-the-art 3D cryo-electron tomography reconstructions, although the proposed S-layer model would benefit from some additional validation.

eLife assessment

This manuscript reports important findings in the field of developmental neurobiology, particularly in our understanding of human cortical development. The methods, data, and analyses are solid yet, the lack of clonal resolution or timelapse imaging makes it hard to assess whether the inheritance of centrosomes occurs as the authors claim.

eLife assessment

This study presents a valuable finding that erythrocyte precursors could re-gain EPO responsiveness after DFP chelation therapy. In addition, the authors investigated iron trafficking in erythroblasts using the MDS mouse model. However, the evidence supporting the claims of the authors is still inadequate. The work will be of interest to medical biologists working on hematology.

eLife assessment

This study transcriptomically profiles the developing zebrafish hindbrain from gastrulation through stages of rhombomere formation. The strength is that the transcriptomic data will be a valuable resource to the field. The paper would profit from a deeper analysis of functional aspects of hindbrain development during its segmentation into rhombomeres.

eLife assessment

This manuscript posits a novel role for the anterior cingulate cortex (ACC) in coding for sequential action strategies and the prevalence of each strategy. These findings provide important insight into ACC function and will therefore be of broad interest within the field of cognitive neuroscience. The evidence supporting the primary hypothesis is currently incomplete but could be rendered convincing with some further effort to rule out potential confounding factors.

eLife assessment

This well-written and well-reasoned manuscript describes a behavioral and computational modeling study designed to understand pure exploration, where action selection is driven by pure information seeking and not rewards. Using a novel task, the authors find that a subset of people use information value to drive their selection behavior, consistent with a simple information maximization model of reinforcement learning. The rest of the participants did not exhibit this behavior. This valuable work provides intriguing, yet somewhat incomplete, insights into understanding directed exploration and its computational form.

eLife assessment

The manuscript from Richter et al. is a very thorough anatomical description of the external sensory organs in Drosophila larvae. It represents an important tool for investigating the relationship between the structure and function of sensory organs. Using improved electron microscopy analysis and digital modeling, the authors provide compelling evidence offering the basis for molecular and functional studies to decipher the sensory strategies of larvae to navigate through their environment.

eLife assessment

This work presents important findings for the field of Alzheimer's disease, especially for the electrophysiology subfield, by investigating the temporal evolution of different disease stages typically reported using M/EEG markers of resting-state brain activity. The evidence supporting the conclusions is solid and the methodology as well as the descriptions of the processes are of high quality, although a separation of individuals who are biomarker positive versus negative would have strengthened the interpretability of the results and the conclusions of the study.

eLife assessment

Lee and colleagues examined how neural representations are transformed between the olfactory tubercle (OT) and the ventral pallidum (VP) using single neuron calcium imaging in head-fixed animals trained in classical conditioning. They show that the dimensionality of neural responses is lower in the VP than in the OT. The study provides important results, and the data are overall solid although the reviewers thought some of the conclusions are not fully supported by the data and overstated, including the main conclusion that the OT neurons primarily encode odor identity but not value.

eLife assessment

This is an important study that provides detailed insights into the morphology of the lateral parietal cortex. Through this work new shallow sulci in the parietal cortex were identified and linked to function and behaviour. The evidence presented is convincing, even though some claims about the definition of highly variable sulci should be tampered down, and some important precisions about the labelling process are lacking to secure reproducibility. The present work both advances our understanding of the parietal cortex while also stimulating further debate on precise, detailed manual anatomy vs large scale automated data processing.

eLife assessment

In this study, the authors present convincing evidence to demonstrate theta cycle skipping by individual neurons of the lateral septum, which they then relate to population coding of future trajectories encapsulated by theta cycles. This valuable finding furthers our understanding of how the septum conveys navigational information downstream.

eLife assessment

This important manuscript presents the development and validation of an oral THC consumption mouse model utilizing highly palatable e-capsule gelatin. The results convincingly demonstrate suffient oral consumption to produce known THC behavioral and physiological effects, as well as brain levels. The utility of the model for chronic consumption remains to be determined. As the field of cannabinoid research moves toward modelling common routes of administration, these model systems will be important in assessing the effects of cannabinoid-based drugs.

eLife assessment

In uncertain conditions, decisions are not made in isolation but are rather biased by the recent past. This new work provides valuable insights into these history biases in human perceptual decision-making, by characterizing the neural correlates of stimulus history biases and their short-term dynamics. The study provides compelling behavioral and MEG evidence that humans adapt their history biases to the correlation structure of uncertain sensory environments.

eLife assessment

This valuable study identifies an Ephrin type-B Receptor 2 (EPHB2) interactor, MYCBP2, as a potential regulator of EPHB2 stability and function. In contrast to expectations, based on MYCBP2 function in the ubiquitin pathway, loss of function of MYCBP2 resulted in less EPHB2 receptor and defective EPHB2 function. The paper is supported by a largely convincing set of biochemical, cell culture and in vivo experiments.

eLife assessment

This is an important study that characterises the involvement of condensin complexes in the segregation of telomeres in fission yeast. The authors present convincing evidence to support their claims, employing a diverse range of complementary techniques. This research will be of interest to cell biologists working on chromosome biology and cell division.

eLife assessment

This manuscript is a useful contribution to the field of complex trait genomics. The study does have some real strengths, such as focusing on cancer age-of-onset, developing methods for this unusual trait and using two cohorts. However, the significance of findings is difficult to evaluate without further comparisons and validations, leaving the work in its current form incomplete.

eLife assessment

This study presents valuable data on the antigenic properties of neuraminidase proteins of human A/H3N2 influenza viruses sampled between 2009 and 2017. The antigenic properties are found to be generally concordant with genetic groups. However, the evidence for claims concerning the molecular basis of the antigenic differences remains incomplete, as the computational methods have been insufficiently validated.

eLife assessment

For decades it has been accepted that only the growth-arrested "stumpy" form of Trypanosoma brucei can infect the arthropod vector, the Tsetse fly, but this was recently challenged by a demonstration that - under artificial conditions that are known to enhance infectivity - the proliferative "slender" form can also establish Tsetse infections. The infectiousness of the two forms is a fundamental question in trypanosome biology and epidemiology, concerning both infection dynamics and parasite differentiation. The authors of the current study provide independently compelling evidence that without artificial enhancement, the "stumpy" form is indeed much more infective for Tsetse than the slender form. The authors suggest that this is probably also true in the wild, but the precise reason for the discrepancy in results between the two laboratories remains unclear.

eLife assessment

This paper presents valuable insights into the implication of PI3Ka in heterotopic ossification (HO), and illustrates a potential therapeutic efficacy of BYL719 in suppressing HO within a murine model of Fibrodysplasia Ossificans Progressiva. While certain data are novel and compelling, others exhibit redundancies with prior publications and are inadequate in terms of methodology and presentation. Additionally, elucidating the precise molecular mechanisms of BYL719's action is imperative for a comprehensive understanding.

eLife assessment

This paper provides valuable information regarding visuospatial working memory performance in patients with MS compared to healthy controls, using a relatively novel continuous measure of visual working memory. There are some weaknesses with the way the clinical groups were matched, but those limitations are acknowledged and the strength of evidence for the claims is otherwise convincing. The paper will be of interest to those working in the field of clinical neuroscience.

eLife assessment

The manuscript describes the synergy among PI3Kβ activators, providing compelling results concerning the mechanism of their activation. The particular strengths of the work arise to a great extent from the reconstitution system better mimicking the natural environment of the plasma membrane than previous setups have. The study will be a landmark contribution to the signaling field.

eLife assessment

The fundamental findings reported here provide insight into how the viscoelasticity of the fingertip skin influences the activity of mechanoreceptive afferents and thus the neural coding of force in humans. The basic principle studied was whether and to what extent the previous applied force directions impact the firing of FA-1, SA-1 and SA-2 neurons during the current applied force directions. The data and analyses are compelling and will be helpful for modeling the neural representations of force in the context of object grasping and manipulation.

eLife assessment

This valuable study addresses the long-term effect of warming and altered precipitation on microbial growth, as a proxy for understanding the impact of global warming. While the methods are compelling and the evidence supporting the claims is solid, additional analysis of the data would strengthen the study, which should be of broad interest to microbial ecologists and microbiologists.

eLife assessment

This study presents valuable findings that examine both how Down syndrome (DS)-related physiological, behavioral, and phenotypic traits track across time, as well as how chronic treatment with green tea extracts 25 enriched in epigallocatechin-3-gallate (GTE-EGCG), administered in drinking water spanning prenatal through 5 months of age, impacts these measures in wild-type and Ts65Dn mice. However, the strength of the evidence is incomplete, due to high variability across measures, perhaps attributable to a failure to include sex as a factor for measures known to be sexually dimorphic. This study is of interest to scientists interested in Down Syndrome and its' treatment, as well as scientists who study disorders that impact multiple organ systems.

eLife assessment

This is an important study that revealed a new noncoding RNA regulatory circuit involved in T cell function. The authors provide compelling evidence, that is more rigorous than the state-of-the-art, using genetically engineered mice and cell-based experiments. The interpretation of the results should be tempered due to the small effect size observed.

eLife assessment

This paper presents a series of experiments investigating the role of cadherin-11 mediated interactions between cancer cells and fibroblasts in metastasis using updated 3D cell co-invasion assays. The primarily descriptive data are a valuable contribution to our understanding of the nature of cross cell-type interactions in metastasis, but are incomplete with respect to the far-reaching conclusions about the central role cadherin-11, especially given the complex nature of the phenotype and the need to better contextualize these observations in a complete picture of metastasis.

eLife assessment

The manuscript tackles a significant problem in addiction science: how interdependent are measures of "addiction-like" behavioral phenotypes? The manuscript provides evidence that escalation of intake, punishment-resistant responding, and breakpoints during a progressive ratio test may reflect a single underlying construct rather than reflect distinct unrelated measures. The exceptionally large sample size and incorporation of multiple behavioral endpoints add strength to this paper, and make it a useful resource for the field. However, in some ways the evidence presented in the manuscript is inadequate to support the broader conclusions, and the significance of the study is limited by statistical concerns and incomplete analysis of sex differences.

eLife assessment

This useful paper reports on two simple methods for improving the efficiency of prime editing, a prominent gene editing technique. In combination with published modifications, the strategies described in this study may lead to significant improvements in editing efficiencies. The data are solid, and the methods will be of broad interest to anyone using gene editing.

eLife assessment

This valuable study reports on the packing of molecules in cellular compartments, such as actin-based protrusions. The study provides solid evidence for parameters that enable the building of a biophysical model of filopodia, which is required to gain a complete understanding of these actin-based structures. Some areas of the manuscript require further clarification.

eLife assessment

This paper builds on a method, previously conceptualized and validated, of genetic control for insect populations. The method, called pgSIT, uses integrated CRISPR-Cas9 based constructs to generate, in certain combinations of genotypes, mutations that cause both male sterility and female inviability. Release of such genotypes in sufficiently large numbers can lead to an inundation of a local insect population with sterile males and this can lead to localised population suppression, which represents an important method of control for problematic insect populations. The data are convincing and will be of interest to anyone working on vector control strategies.

eLife assessment

This work suggests that behavior outcome information in the inferior colliculus persists in absence of top-down feedback from the auditory cortex. The results are valuable for researchers interested in how behavior impacts neural coding, as they urge us to focus the spotlight on non-cortical mechanisms of high-level activity in early auditory pathways. The topic and direct experimental methodology are compelling; however, the demonstration remains largely incomplete, as key information is missing to evaluate if a potential confound between sensory information and behavior outcome information is introduced in the analyses. This confound would strongly challenge the conclusion and more precise analyses of the sensory responses in IC and how they relate to behavioral outcomes would also be necessary to make the study more conclusive.

eLife assessment

This valuable study examines the evolution of the pillars in the shell architecture of organo-phosphatic brachiopods. The phylogenetic implications of this shell structure in relation to other early Cambrian brachiopod families are interpreted based on solid evidence. As such, this paper contributes to our understanding of the ecology and evolution of brachiopods as a whole.

eLife assessment

The work introduces two valuable concepts in antimicrobial resistance: "variant vulnerability" and "drug applicability", which can broaden our ways of thinking about microbial infections through evolution-based metrics. While the authors present a compelling analysis of a published dataset to illustrate how informative these metrics can be, the study is still incomplete as only a subset of a single dataset on a single class of antibiotics was analyzed. Analyzing more datasets, with other antibiotic classes and resistance mutations, and performing additional theoretical simulations could demonstrate the general applicability of the new concepts.

eLife assessment

The authors establish a Drosophila model to assess the severity of disease-linked alleles of Uba5 to study DEE44, a neurodevelopmental disease caused by UBA5 gene mutations. Using in vivo and in vitro experiments, this valuable study demonstrates that alleles fall into mild, intermediate, and severe classes, with convincing evidence to support their conclusion, which includes well-conserved relationships between UBA5 structure and function across humans and flies. This study establishes a model for further characterization of Uba5-related phenotypes in a powerful model system and will be used in the future to study the functional effects of these mutations on nervous system development.

eLife assessment

This study used ChatGPT to assess certain linguistic characteristics (sentiment and politeness) of 500 peer reviews for 200 neuroscience papers published in Nature Communications. The vast majority of reviews were polite, but papers with female first authors received less polite reviews than papers with male first authors, whereas papers with a female senior author received more favourable reviews than papers with a male senior author. Overall, the study is an important contribution to work on gender bias, but the evidence that generative AI programs like ChatGPT have the potential to be applied in meta-research is incomplete, especially given the lack of a comparison to the many existing and already-validated tools for sentiment analysis based on natural language processing.

eLife assessment

Satake and colleagues' important study elucidates somatic mutation processes in plants, demonstrating that in two tropical trees, mutation rates correlate with age, not growth rates. Their convincing evidence shows that many mutations do not align with cell divisions, suggesting many somatic mutations are generated in a replication-independent manner. This study represents a significant step towards advancing our understanding of plant development and the patterns and inheritance of mutations. This significant research is poised to engage a diverse array of scholars in plant evolution and development.

eLife assessment

This important study brings together a clear application of the digital twin approach to make predictions using patient specific models with different genotypes. The data are compelling and go beyond the current state-of-the-art to support proof-of-principle evidence. Given the low subject numbers, further studies will be required going forward to support the veracity of the data and its translational utility.

eLife assessment

This research is a potentially important contribution to the field of protein biosynthesis pathways and their link to aging, especially regarding the thorough analysis of variation in measures expected to correlate with elongation rate in old and new daughter cells derived from old and new mother cells. However, the imaging results, analysis, and methodologies are incomplete, as in its current form several key questions remain unanswered.

eLife assessment

P-glycoprotein (Pgp) is a major ABC-transporter that couples ATP hydrolysis with the export of xenobiotics and drugs, influencing their pharmacokinetics. The authors provide convincing cryo-EM Pgp structures of drug complexes in previously unforeseen outward-facing conformations. These structures reveal important mechanistic insights that could be of broader impact, but because these transient-like states were captured by cysteine cross-linking the substrate to Pgp, support for the conclusions is incomplete, and further validation is required.

eLife assessment

This paper investigates the potential role of extracellular vesicles in providing extracellular matrix signals for migration of vascular smooth muscle cells. The findings could be useful for researchers interested in cell migration, but the evidence supporting the conclusions is presently incomplete.

eLife assessment

In this important study, the authors apply a residue-resolution protein coarse-grained model to investigate the differences in molecule dimensions and phase behaviour of three HP1 paralogs, HP1 paralog mixtures, and HP1/DNA mixtures. The simulations are well designed to investigate the impact of HP1 sequence on its phase behaviour. Solid evidence reveals that electrostatic interactions are a key determinant of HP1 paralog phase behaviour, thereby advancing our understanding of the molecular mechanisms driving the phase separation behaviour of HP1 paralogs.

eLife assessment

This valuable paper examines the Bithorax complex in several butterfly species, in which the complex is contiguous and not split, as it is in the well-studied fruit fly Drosophila. Based on genetic screens and genetic manipulations of a boundary element involved in segment-specific regulation of Ubx, the authors provide solid evidence for their conclusions, which could be further strengthened by additional data and analyses. The data presented are relevant for those interested in the evolution and function of Hox genes and of gene regulation in general.

eLife assessment

This study employs multiscale simulations to show that PIP2 lipids bind to the DIV S4-S5 linker within the inactivated state of a voltage-gated sodium channel, affecting the coupling of voltage sensors to the ion-conducting pore. The authors report the valuable finding that PIP2 prolongs inactivation by binding to the same site that binds the C-terminal tail during recovery from inactivation, suggesting binding to gating charges in the resting state that may impede activation. The coarse-grained and atomistic molecular dynamics simulations are solid, supporting the claims, although they do lack validation through experiment or simulation, such as studies of linker mutants to confirm PIP2 binding sites, a resting state Nav1.4 model to confirm voltage sensor binding, as well as tests using flexible linkers to probe interactions with PIP2 without backbone restraints.

eLife assessment

This important study advances our understanding of the biological significance of the DNA sequence adjacent to telomeres. The data presented convincingly demonstrates that subtelomeric repeats are non-essential and have a minimal, if any, role in maintaining telomere integrity of budding yeast. The work will be of interest to telomere community specifically and the genome integrity community more broadly.

eLife assessment

ZMYM2 is a transcriptional corepressor but little was known about how it is recruited to chromatin. This important study reveals that ZMYM2 homes to distinct classes of retrotransposons bound by the TRIM28 and ChAHP complexes in human cells, which is broadly relevant for the field of transcriptional regulation. Much of the evidence supporting the claims of the authors is convincing. Since widespread ZMYM2-mediated control of transposon activity is not apparent in RNA-seq data, further experiments are needed to demonstrate a more general role beyond the retrotransposons analysed in this study.

eLife assessment

This study provides valuable findings showing the production of IL-22 from intestinal ILC3 during intermittent fasting promotes beigeing of white adipose tissue. However, the study is incomplete because of the lack of mechanistic insight. In particular, the authors should clearly show the mechanism by which IL-22-derived from ILC3 directly induces beigeing.

eLife assessment

Little is known about the role of the microbiome alterations in epithelial ovarian cancer. This important and rigorous study carefully examined the microbiome composition of 1001 samples from close to 200 ovarian cancer cases and controls, and presents compelling evidence that the fallopian tube microbiota are perturbed in ovarian cancer patients. These insights are expected to fuel further exploration into translational opportunities stemming from these findings.

eLife assessment

The presence or absence of a surrounding envelope, previously a clear distinguishing feature of different viruses, has been blurred by the recent recognition that many so-called 'nonenveloped' viruses are released from cells as quasi-enveloped virions cloaked in host cell membranes. This mechanism of viral egress allows for non-lytic infection, and has potentially important implications for pathogenesis. In this manuscript, Jassey and colleagues provide solid evidence that the protein deacetylase SIRT-1 is required for the non-lytic release of enteroviruses in extracellular vesicles.

eLife assessment

This study provides important information on the biogenesis of eccDNAs during spermatogenesis. The data presented are solid and supportive of the concussion that eccDNAs in spermatogenic cells are not derived from miotic recombination hotspots but rather represent oligonucleosomal DNA fragments from apoptotic male germ cells, whose ends are ligated through microhomology-mediated end-joining. This work is of interest to researchers working on germ cell biology and cancer biology.

eLife assessment

Despite the importance of T follicular helper cells (Tfh cells) in vaccine-induced humoral responses, it is still unclear which type of Tfh cells (Tfh1, Tfh2, and Tfh17) is critical for generating protective humoral immunity. By using the rhesus macaques model (most similar to human), the authors have addressed this potentially important question and obtained suggestive data that Tfh1 is critical. Although being suggestive, the evidence for the importance of Tfh1 is incomplete.

eLife assessment

This study presents a valuable finding on the function of the gene Cst7 in sex-divergent pathological changes in microglia in a mouse model of AB-driven Alzheimer's disease. The evidence supporting the claims of the authors is solid, although the study would be strengthened by validation of some of the key differentially expressed genes identified in RNA-sequencing experiments, and the inclusion of key controls and additional timepoints to address whether Cst7 drives disease progression or is simply upregulated as a result. The work will be of interest to neuroimmunologists and neuroscientists working on microglia and neurodegenerative disease.

eLife assessment

This study provides important insights into the structural biology and molecular mechanism of the sensory proteins ToxR/S that are associated with survival and virulence of the cholera pathogen. The structural studies are solid and supported by a series of biophysical experiments revealing a split, periplasmic protein binding interface for bile acid. The results are of interest to both protein biochemistry and pharmacology, potentially opening new routes for intervention in cholera disease.

eLife assessment

This study presents a valuable methodology with increased efficiency and precision of gene editing in human primary hematopoietic stem and progenitor cells. The evidence supporting the claims is solid, although a more extensive assessment of functional hematopoietic stem cell impacts and potential off-target effects would be helpful to further strengthen the conclusions. The work will be of interest to biologists studying hematopoietic stem and progenitor cells and gene targeting for potential clinical applications.

eLife assessment

This study used ChatGPT to assess certain linguistic characteristics (sentiment and politeness) of 500 peer reviews for 200 neuroscience papers published in Nature Communications. The vast majority of reviews were polite, but papers with female first authors received less polite reviews than papers with male first authors, whereas papers with a female senior author received more favourable reviews than papers with a male senior author. Overall, the study is an important contribution to work on gender bias, and the evidence for the potential utility of generative AI programs like ChatGPT in meta-research is solid.

eLife assessment

The work by O'Reilly and Delis is important to extend the synergy ideas using methods from signal processing and information theory to cluster muscles and task parameters, thereby advancing our understanding of the modular architecture of motor control. The method is innovative, and the findings are compelling from theoretical and practical perspectives. The work will be of broad interest to motor control and neural engineering researchers.

eLife assessment

Picard et al. propose a Facial Expression Pain Signature (FEPS) as a distinctive marker of pain processing in the brain. In this valuable study, they attempt to use functional magnetic resonance imaging (fMRI) data to predict facial expressions associated with painful heat stimulation. The crucial aspect of the claim is whether the proposed biomarker is distinctive, i.e., it is specific enough to distinguish facial expressions in response to pain from similar facial expressions of non-painful origin. The experimental setup does not control for that condition, so the evidence is incomplete to support their main claims.

eLife assessment

This important study in Drosophila identifies neuronal mechanisms influenced by altered activity during a critical period (CP) of larval locomotor circuit development. Increasing activity during the CP causes permanent network changes indicating that a setpoint of network excitability is determined during the CP. Most importantly, for excitability setpoint determination during the CP excitatory and inhibitory inputs are integrated such that the effect of CP hyperexcitation can be rescued by the stimulation of endogenous inhibitory inputs to the motoneurons. Solid experimental evidence supports their novel insight into how developing neural network excitability is tuned and how it can be entrained during the CP.

eLife assessment

In this manuscript, Jain and colleagues explore whether increasing adult neurogenesis is protective against status epilepticus and the development of spontaneous recurrent seizures (chronic epilepsy) in a mouse pilocarpine model of temporal lobe epilepsy. This is an important work that provides solid data, contradicting previous studies on suppressing chronic seizures by reduced neurogenesis. To ensure the validity and robustness of the results, there is a need for additional controls and validations.

eLife assessment

This study presents a valuable insight into a computational mechanism of pain perception. The evidence supporting the authors' claims is solid, although the inclusion of 1) more diverse candidate computational models, 2) more systematic analysis of the temporal regularity effects on the model fit, and 3) tests on clinical samples would have strengthened the study. The work will be of interest to pain researchers working on computational models and cognitive mechanisms of pain in a Bayesian framework.

eLife assessment

The findings described in this manuscript are important and have theoretical or practical implications beyond a single subfield. Both reviewers comment on the strength of the paper because of the use of multiple approaches (optical imaging, physiology, rapid freeze EM, modeling, double mutant analysis). The methods, data, and analyses provide convincing support for the distinct roles of the two proteins, Doc2a and Syt7 in regulating SV release.

eLife assessment

Gain-of-function mutations and amplifications of PPM1D are found across several human cancers and are associated with advanced tumor stage, worse prognosis, and increased lymph node metastasis. Unfortunately, clinical translation has so far not been possible due to the lack of PPM1D inhibitors with favorable pharmacokinetic properties. This useful study leveraged CRISPR/Cas9 screening to identify that SOD1 inhibition is synthetic lethal with PPM1D mutation in leukemia, although the mechanistic analyses were incomplete.

eLife assessment

This study presents compelling observations of the ability of Ym1 crystals to promote type 2 immunity in vivo, in mice, that advances our knowledge of how the abundantly expressed chitinase-like protein family may function, with new methodology, new crystal structures that are more rigorous than what is currently known and very convincing immunological data. The significance of the study is important, providing an exciting opportunity to mechanistically study the impact of protein crystals in vivo in relation to human disease. This work will be of broad interest to immunologists and researchers working on type 2 inflammatory disease, in the lung.

eLife assessment

This important work by Aballay et al. advances our understanding of how G protein-coupled receptors (GPCRs) regulate immunity and pathogen avoidance. The authors provide convincing evidence for the GPCR NPR-15 to mediate immunity by altering the activity of several key transcription factors. Nevertheless, both reviewers have raised questions to be addressed, at which time this work will be of broad interest to immunologists specifically, and biologists in general.

Evaluation statement (1 September 2023)

Flores-Aldama and colleagues set out to identify molecular determinants of fast inactivation in the TRPV6 ion channel, a mechanism not observed in the closely related TRPV5 channel. The work focuses on a helix-loop-helix (HLH) motif, located at the interface between several important regions for channel gating. Using molecular dynamics simulations and analysis of mutations, the authors identify pairs of amino acid residues in a structural triad formed by the HLH, S2-S3 linker, and transmembrane domains, which show different conformations in the available TRPV5 and TRPV6 cryo-EM structures. An important aspect of the study is that some of the structural hypotheses were derived from an evolutionary analysis of sequences from orthologues of both channels, demonstrating the value of this type of analysis.

Biophysics Colab considers this to be a convincing study and recommends it to scientists interested in the molecular determinants of ion channel gating.

(This evaluation by Biophysics Colab refers to the version of record for this work, which is linked to and has been revised from the original preprint following peer review.)

eLife assessment

This valuable manuscript investigates the role of a subpopulation of glutamatergic neurons in the suprammamillary nucleus that projects to the pre-optic hypothalamus area in active coping but not locomotor activity. It provides solid evidence from experiments using fibre photometry or photostimulation during threatening tasks that these neurons allow animals to produce flexible behaviours in response to stress. However, the evidence is incomplete in several ways, including validation and quantification of anatomical tracing data that serve as a basis for the behavioral testing, the use of statistics, sex as a biological variable, genotype differences between experimental and control groups in behavioral tests, limiting its broad interest to neuroscientists across sub-fields.

eLife assessment

This article provides important findings on how bacteria use small RNAs to regulate flagellar expression with implications for multiple fields. The data supporting the conclusions are convincing with a large amount of data that include results from phenotypic analyses, genomics approaches as well as in-vitro and in-vivo target identification and validation methods. This study on the varied effects of three sRNAs (UhpU, FliX and MotR) is of broad interest to RNA biochemists and microbiologists.

eLife assessment

This study based on the use of Cancer Drug Resistance Accelerator (CDRA) chip is valuable as a platform technology to assess chemoresistance mechanisms. The strength is convincing from the technological point of view. However, the use of a single cell line model and the lack of mechanistic insights could be improved.

eLife assessment

The findings in this study are important and have a practical implication for early cancer diagnosis. Furthermore, we found the ML approach and data analysis compelling. However, significant concerns regarding the quality of the source materials used for the analysis have been raised and need to be addressed.

eLife assessment

This article brings to bear a useful, extensive set of behavioral methods and neural data to report that activity in numerous cortical regions robustly covaries with the complexity of tone sequences encoded in memory. In its current state, the findings are solid but deserve further analysis to arrive at more convincing conclusions.