eLife assessment

This study presents a potentially valuable investigation of water coordination in a specific kinase family with a focus on the regulation of osmosensing protein kinases. X-ray crystallographic approaches combined with functional assays are used to address the hypothesis that bound water participates in the osmosensing mechanism as an allosteric kinase inhibitor. Evidence for changes in kinase conformation and space group of the crystal as a function of added low molecular weight polyethylene glycol is solid, but there alternative interpretations for much of the other data cannot be excluded and the work thus remains incomplete. With stronger evidence and/or alternative explanations explored, the work would be of considerable interest to the kinase field as well as colleagues studying allosteric regulation of protein function.

eLife assessment

This paper seeks to understand how the presentation of peptides by medullary thymic epithelial cells may be regulated by the MHCII peptide loading modulator, H2-O, and how this may affect the selection of regulatory T (Treg) cells. Further work is needed to ensure that the findings are robust: currently the analysis of data is inadequate and inconsistencies in the reported findings are not placed in context with results from other groups. The current version does not provide sufficient support for the claims regarding the effects on Treg cell selection.

eLife assessment

This important study reveals ELF3 as a putative candidate driver of luminal progenitor (LP) transformation. Up-regulation of ELF3 during replicative stress conditions and in BRCA1 deficient cells may permit cell proliferation by suppressing genome instability. While the hypothesis is compelling, the experimental support is still incomplete, as it does not adequately demonstrate the role of ELF3 in LP cells per se. The mechanistic underpinnings by which ELF3 promotes cell tolerance to DNA damage were not fully explored either. With improvements, the work has the potential to enhance our understanding of how BRCA1 deficiency fuels LP transformation and thereby breast tumorigenesis.

eLife assessment

This is a fundamental study into human spinal neurulation, which substantially advances our understanding of human neural tube closure. Crucial unanswered questions in the field currently rely on model systems, not faithful to human development. The evidence provided is convincing, with a large number of specimens and the use of state-of-the-art methodology providing robustness. The work will be of broad interest to developmental biologists, embryologists, and medical professionals working on neural tube defects, and will act as a precious reference resource for future studies.

eLife assessment

The reviewers believe that this study provides valuable insights into understanding bone fragility in T2D patients through the use of human samples, laying the groundwork for future research. The employed methods were solid, demonstrating the feasibility of studying human samples. However, reviewers identified some minor weaknesses in the form of a limited number of subjects and a relatively small set of genes included in the analysis.

eLife assessment

This study investigated the regulatory role of Mecp2 in quiescence exit during cell cycle progression. The study is significant since it provided fundamental insights into the mechanism controlling the cell cycle process. The evidence is convincing since the authors have presented experimental data from in vitro cell culture and in vivo injury-induced liver regeneration to support their conclusion.

eLife assessment

The study's results offer a fundamental insight into how ACC1-mediated fatty-acid synthesis affects the survival and pathogenicity of iNKT cells in allergic asthma. The inclusion of mouse models, involving genetic adjustments and reconstitution experiments, along with the disparities found in iNKT cells between allergic asthma patients and control subjects in human studies, adds compelling evidence that substantiates these findings.

eLife assessment

The strength of this important study is that it provides compelling evidence in several biological models, including Xenopus embryos, that Wnt3a increases macropinocytosis and that PMA increases this cellular response. This novel link between Wnt, focal adhesions, lysosomes, and macropinocytosis will be very interesting for cell and tumor biologists. In future work, it will be good to identify the underlying mechanism, i.e., the molecular node whereby this interaction occurs.

eLife assessment

Drosophila is a powerful model organism for understanding the molecular and neural regulation of sleep. However, methodological limitations exist that would appear to limit the relevance of work done in the fly to our understanding of mammalian sleep. In this important work, the authors provide physiological, behavioral, and molecular evidence for the existence of two potential sleep stages in Drosophila. The experiments are generally well conducted and the authors' interpretations of their results are solid overall. Although technically innovative and conceptually provocative, there are aspects of the approaches used and results obtained that leave the central conclusions open to interpretation.

eLife assessment

This behavioral modeling study investigates how humans make decisions on the difficulty of perceptual categorization tasks. The study finds that such judgments are best described by an evidence-accumulation model that includes a dynamic comparison of difficulty-related evidence, which terminates when the difference in evidence between two tasks reaches a predetermined bound – a valuable finding for research in perceptual decision-making. The paper provides compelling behavioral evidence for the proposed model through: 1) quantitative model selection/validation procedures, and 2) qualitative analyses of the relation between the optimal model of the task and the human data (and the proposed model).

eLife assessment

This study provides valuable insights into the role of two under-researched sperm-specific proteins (Cylicin 1 and Cylicin 2). The authors provide convincing evidence that they have an essential role in sperm head structure during spermatogenesis, and that their loss leads to subfertility or infertility, with a dose-dependent phenotype. Importantly, the authors identify infertile males with mutations in both Cylicin1 and Cylicin2. Thus, the findings from the mouse models might be applicable to understanding human male infertility with similar structural defects.

eLife assessment

This work presents H3-OPT, a deep learning method that effectively combines existing techniques for the prediction of antibody structure. This work is important because the method can aid the design of antibodies, which are key tools in many research and industrial applications. The experiments for validation are solid, although several points remain partially unclear, such as (1) which examples constitute proper validation, (2) what the relevance of the molecular dynamics calculations as performed is, (3) the statistics for some of the comparisons, and (4) the lack of comparison with other existing methods.

eLife assessment

This important study provides an example of integrating computational and experimental approaches that lead to new insights into the energy landscape of a model kinase. Compelling use of molecular dynamics simulations and NMR spectroscopy provide a conformational description of active and excited states of the kinase; one of which has not been captured in previously solved crystal structures. Overall, this comprehensive study expands our understanding of the architecture and allosteric features of the conserved bilobal kinase domain structure.

eLife assessment

Tissue phenotyping is central to nearly all areas of biology. In this study, the authors use an advanced form of micro-CT (X-ray histotomography) in zebrafish to phenotype blood cells in the intact animal. These approaches build upon prior work from this group and others showing this is a scalable imaging method that could readily be applied to other cell types, and provide an excellent complement to histological analysis of tissues. This is important work, as it demonstrates that the method can provide an approach that is orthogonal to conventional histology. The strength of the presented data is compelling, with description of both the hardware and software needed to implement the protocol, which will make it accessible to other researchers in the field.

eLife assessment

This paper will be of significant interest to the research community working on cytoplasmic transport and microtubule motors, offering important insights into the structural arrangement of autoinhibited Kinesin-1. The paper reports a structural model of full-length kinesin-1 describing its autoinhibitory mechanism using cryo-EM, Alphafold structural predictions, cross-linking, and mass spectrometry. The data are of high quality and together offer a compelling model for how Kinesin-1 is autoinhibited, indicating that auto-inhibition does not rely on the IAK motif alone but on a more extensive intramolecular interface.

eLife assessment

This is a valuable contribution to our understanding of how some bacteria can transport sterols from the cytoplasm to the outer membrane. Though much remains to be tested and explored, the data and analyses presented here provide solid evidence for the genetic and physical interaction of BstA/B/C with bacterially-produced sterols. The manuscript will be of interest to scientists focusing on the characterization of novel bacterial proteins and those studying lipid transport and acquisition in bacterial pathogens.

eLife assessment

This valuable study informs whether diminishing BDNF expression or alterations in the activity of BDNF-containing neurons in the paraventricular nucleus of the hypothalamus contributes to metabolic alterations in individuals with reduced RAI1 function, including those afflicted with Smith-Magenis syndrome (SMS). The evidence supporting the conclusions is compelling in that RAI1 deficits in BDNF-containing neurons partly contribute, with prominent effects on glycemic control and modest effects on feeding and body weight regulation. This study would be of interest to neuroscientists and medical biologists working on metabolic disorders such as obesity and diabetes, as the findings in this study further links SMS-associated obesity with reduced Bdnf gene expression in the PVH and shed light on the role of the Rai1 gene in the PVH Bdnf neurons and offer a basis for future therapeutic strategies for managing obesity in SMS.

eLife assessment

This useful study reports an investigation of ZC3H11A as a cause of high myopia through the analysis of human data and experiments with genetic knockout of Zc3h11a in mice, providing a model of myopia. The evidence supporting the conclusions is currently incomplete. It could be strengthened by a more thorough genetic analysis, fuller presentation of human phenotypic data, and more explanation for the reasons why there was no increased axial length in mice with myopia. The work will be of interest to ophthalmologists and researchers working on myopia.

eLife assessment

This paper addresses a fundamental issue in the field of autophagy: How is a protein responsible for autophagosome-lysosome fusion recruited to mature autophagosomes but not immature ones? The work succeeds in its ambition to provide a new conceptual advance. The evidence supporting the conclusions is convincing, with solid fluorescence microscopy, biochemical assays, and molecular dynamics simulations. This work will be of broad interest not only to cell biologists and biochemists studying autophagy but also those focusing on lipid/membrane biology.

eLife assessment

This valuable study employs advanced imaging techniques to directly visualize molecular dynamics and presents valuable findings on the regulation of the immune receptor kinase FLS2 organization in specific microenvironments. The evidence supporting the ligand-induced association with remorin and the requirement of a previously reported phosphosite is solid, although it remains unknown whether this phosphorylation is induced by the ligand. The manuscript would be improved with a more adequate description of plant immune signaling, and better presentation of the data in the context of previous work with appropriate references. The work will be of interest to plant biologists working on cell surface receptors.

eLife assessment

This study uses specific and robust genetic approaches to assess mechanisms of kainic acid-induced neurogenesis. This is a fundamental study that bridges several complementary methods and is a convincing use of existing approaches to explore roles for sonic hedgehog in activity-dependent and aging-associated hippocampal neurogenesis.

eLife assessment

This useful manuscript challenges the utility of current paradigms for estimating brain-age with magnetic resonance imaging measures, but presents inadequate evidence to support the suggestion that an alternative approach focused on predicting cognition is more useful. The paper would benefit from a clearer explication of the methods and a more critical evaluation of the conceptual basis of the different models. This work will be of interest to researchers working on brain-age and related models.

eLife assessment

The authors aim to elucidate the mechanism by which pyroptosis contributes to the increased release of procoagulant tissue factor-containing microvesicles. The data are intriguing and attempt to shed light on the mechanism by which GSDMD plays a role in releasing tissue factor-containing microvesicles, albeit incomplete. The manuscript offers valuable information to unveil new therapeutic targets in human diseases such as sepsis, which can be further strengthened by consulting the reviewers' suggestions.

eLife assessment

This study presents a valuable finding on the relationship between a high protein diet and resistance exercise on fat accumulation and glucose homeostasis. The evidence supporting the claims of the authors is solid, although the inclusion of mechanistic insight would have strengthened the study. The work will be of interest to dieticians, diabetologists, and exercise biologists working to understand the link between dietary protein, insulin resistance, and physical activity.

eLife assessment

The manuscript analyses the mechanism of action of small compounds that target the WDR5 chromatin protein for tumor therapy. They study a class of compounds termed WIN site inhibitors and show that they affect the expression of ribosome protein genes (RPGs) and cause ribosomal stress, ultimately activating the TP53 tumor suppressor protein. The manuscript provides important insight into the mode of action of these interesting compounds. The evidence is convincing, with a few exceptions detailed in the reviewers' comments.

eLife assessment

This study presents an important finding that implicates a rhodopsin gene duplication in the progression of autosomal dominant retinitis pigmentosa in patients. The authors utilize a retinal organoid model to demonstrate a similar disease phenotype and suggest defects can be ameliorated by using photoregulin. However, the data are incomplete and require additional controls and analyses to support their conclusions. If validated the work will be of broad interest to vision researchers.

eLife assessment

Bladder dysfunction following spinal cord injury (SCI) represents a severe and disabling complication and we lack effective therapies. Following evidence that AMPA receptors play a key role in bladder function the authors show convincingly that AMPA allosteric activators can ameliorate many of the subacute defects in bladder and sphincter function following SCI, including prolonged voiding intervals and high bladder pressure thresholds for voiding. These valuable results in rodents may help in the development of these agents as therapeutics for humans with SCI-induced bladder dysfunction.

eLife assessment

This valuable study used a modified PyMT model to investigate whether increased rRNA synthesis provides a therapeutic opportunity to target chemoresistance. The evidence supporting the claims of the authors is solid, although the use of a more rigorous approach to capture all the relevant events during the EMT process would have strengthened the study. The work will be of interest to clinicians or cancer biologists.

eLife assessment

The authors report the cryo-EM structure of human vesicular monoamine transporter 2 (VMAT2) bound to the noncompetitive inhibitor tetrabenazine (in an occluded state). This important achievement captures the structure of an major facilitator superfamily (MFS) transporter that is critical for human neurotransmission. The evidence for the structure is solid, but there are several concerns regarding the mechanistic insights into the transport mechanism, which make the study more descriptive than explanatory.

eLife assessment

The manuscript by Bull et al provides valuable information on the relationship between metabolic features, in particular different lipoproteins and fatty acids, and colorectal cancer. They use solid methods and combine different data sources to analyze forward and reverse Mendelian Randomizations that support their claims.

eLife assessment

Erbacher et al. have used new techniques to explore the neuro-cutaneous structures of human epidermis, which is a valuable goal given the lack of in-depth studies in human skin. Human skin is less studied than rodent skin because it presents challenges in obtaining samples and finding excellent immunohistological labels. They have employed expansion microscopy and super-resolution array tomography for histological studies and have developed a human keratinocyte and human iPSC-derived sensory neuron co-culture

eLife assessment:

Interoceptive signals from internal organs activate neurons in the nucleus tractus solitarius (NTS) to help maintain homeostasis. The authors of this paper use gain-of-function and loss-of-function experiments to examine three distinct NTS neuronal populations, individually and in combination, and find that activating (or inhibiting) combinations of these neurons have more robust effects on food intake and body weight than activating (or inhibiting) them individually. The results of this paper are convincing and solid but do not provide mechanistic insights.

eLife assessment

Retinal ganglion cells which are intrinsically photosensitive play important and emerging physiological roles. The mechanisms of phototransduction are still not well known and there exists a controversy regarding the ion channels responsible for the photocurrent. The authors of this manuscript present data that can contribute to understanding the actual ionic mechanisms in two of these cell types. This manuscript will be of general interest to biologists and neuroscientists and should help resolve a major issue in retinal physiology.

eLife assessment

This prospective study advances our understanding of the predictive role of circulating tumor DNA (ctDNA) in the prognosis and of patients with mTNBC as well as other cancers. The evidence supporting the conclusions is convincing with rigorous analysis of the association between ctDNA (ctDNA-positive or not) with the progression-free survival (PFS) of patients. However, there are a few areas in which the article may be improved through further analysis of the clinical outcome and elaboration of the prospective study (i.e., the inclusion and exclusion criteria of the patients). The work will be of broad interest to clinicians, medical researchers and scientists working in cancers.

eLife assessment

This important study demonstrates that the orbitofrontal cortex is causally involved in the detection of local auditory prediction errors. The methods and procedures are convincing, although the precise functional meaning of the reported effects remains to be specified. This work is of interest to neuropsychologists and cognitive neuroscientists working on the prefrontal cortex, predictive processing, auditory perception, and electrophysiology.

eLife assessment

This paper is of interest to cell biologists studying the mechanisms of protein posttranslational modifications. The study investigates Cullin-RING ubiquitin E3 ligases (CRLs) that regulate cyclin D1 protein stability in cells by utilizing siRNA screening and ectopic expression approaches. By screening a siRNA library containing different E3 ligases, the authors identified a previously uncharacterized combination of Cullin 1-7 and associated E3 ligases (Keap1-CUL3, DDB2-CUL4A/4B, WSB2-CUL2/5, and RBX1-CUL1-7) that are important for cyclin D1 ubiquitination and proteasome-mediated degradation.

eLife assessment

This study presents a valuable finding of a novel combinatory regimen which integrate immunotherapy, radiotherapy and chemotherapy in the current refractory triple negative breast cancer. The evidence supporting the claims of the authors is solid, although inclusion of a larger number of patient samples would have strengthened the study. The work will be of interest to Clinicians working on breast cancer.

eLife assessment

This valuable study provides solid evidence implicating two transcription factors in the development of the actin cytoskeleton that shapes the mechanosensory hair bundles of the inner ear's hair cells. The work will be of interest to biologists interested in the development and maintenance of the hair bundle, both normal or impaired. Its impact would be improved by providing a mechanistic model for the observed effects.

eLife assessment

This study examines the expression of HDAC3 within DC compartment. Taking advantage of tamoxifen inducible ERT2-cre mouse model they observe the dependency of pDCs but not cDCs on HDAC3. The requirement of this histone modifier appears to occur during development around the CLP stage. Tamoxifen treated mice lack almost all pDC besides lymphoid progenitors. RNA seq studies identify multiple DC specific target genes within the remaining pDC - using Cut and Tag technology they validate some of the identified targets of HDAC3. Taken together, this study shows the requirement of HDAC3 on pDC but not cDC, congruent with the recent findings of a lymphoid origin of pDC.

eLife assessment

These authors present a powerful tool to unbiasedly identify lysosome-associated proteins in C. elegans, and they provide a compelling, in-depth assessment of how this method can be used to understand longevity pathways and identify novel proteins. Understanding lysosomal differences in specific tissues or in response to different longevity conditions are exciting as it provides new insight into how organelles could control specific homeostasis responses. This valuable tool and proteomics datasets also represent a great resource for the C. elegans community and should pry open new studies on the regulation and role of the lysosome at the organismal level.

**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.