eLife Assessment

The Twin Domain model proposed by Lui and Wang proposing that twin supercoiling domains of DNA emerge during transcription were first described decades ago, but direct experimental evidence has been challenging to obtain. Here, the authors make a fundamental contribution by directly measuring DNA torsion in cells using a photoactivatable intrastrand cross-linker compared to controls. They gather compelling data using this clever method, which provides direct evidence in support of the twin-supercoiled domain model, for torsional effects at transcription start and end sites, and thereby uncover novel features of higher order structure of chromatin in yeast. These data are exciting, and the tools will be of interest to anyone studying chromosome structure and gene regulation.

eLife Assessment

This useful paper uses a quantitative modeling approach to explore a putative mechanism underlying a well-studied behavioral transition in the nematode C. elegans. The premise, that what has been considered a two-state behavior can instead be described as a process whose parameters are smoothly modulated within a single state, is intriguing. However, in the paper's current state, concerns about the model and its fit to empirical data make the support for this idea inadequate.

eLife Assessment

The study presents valuable findings on the molecular mechanisms of glucose-stimulated insulin secretion from pancreatic islets, focusing on the main regulatory elements of the signaling pathway in physiological conditions. While the evidence supporting the conclusions is solid, the study can be strengthened by the use of a beta cell line or knockout mice. The work will be of interest to cell biologists and biochemists working on diabetes.

eLife Assessment

This paper presents miniML, an AI-based framework for the detection of synaptic events. Benchmark results presented in the paper are compelling, demonstrating the superiority of miniML over current state-of-the-art alternatives. The performance of miniML is demonstrated across various experimental paradigms, showing that miniML has the potential to become a valuable tool for the analysis of synaptic signals.

eLife Assessment

This manuscript describes a novel approach for assessing cognitive function in freely moving mice in their home-cage, without human involvement. The authors provide convincing evidence in support of the tasks they developed to capture a variety of complex behaviors and demonstrate the utility of a machine learning approach to expedite the acquisition of task demands. This work is important given its potential utility for other investigators interested in studying mouse cognition. However, additional information (e.g., detailed construction manual, code) is needed to allow other investigators to implement this system independently and use it widely.

eLife Assessment

The authors have undertaken a useful study to update an existing niche model of highly pathogenic avian influenza. However, there are issues regarding the conceptualisation of the ecological niche of highly pathogenic avian influenza transmission that the modelling aims to capture, raising concerns about the strength of evidence used to support the findings. There are a number of modelling assumptions that are incompletely justified. Combined with shortcomings in the communication, this dilutes the strength of the key findings of this work.

eLife Assessment

This study provides valuable findings on the effects of mating experience on sweet taste perception. The data as presented provide solid evidence that the dopaminergic signaling-mediated reward system underlies this mating state-dependent behavioral modulation. The work will interest neuroscientists, particularly those working on neuromodulation and the effects of internal states on behavior.

eLife Assessment

This useful study presents a virtual reality-based contextual fear conditioning paradigm for head-fixed mice. The approach provides a way to perform multiphoton imaging of neural circuits during behaviors that have traditionally been studied in freely moving animals. However, evidence supporting key claims is currently incomplete, particularly regarding elicitation and detection of freezing behaviors, and the impact of the study would be increased by articulating what this initial exploration of parameters offers over existing approaches.

eLife Assessment

This study presents a valuable finding regarding how partner preference formation and pair bonding behavior are related to the oxytocin receptor gene expression in the NAc and paraventricular nucleus of the hypothalamus in prairie voles. The evidence supporting this claim is solid but could benefit from clarity in the framing, approach, and results. This study will be of interest to social scientists and neuroscientists who work on pair bonding and oxytocin.

eLife Assessment

This multimodal neuroimaging study leverages fMRI, PET, and deep learning to predict memory performance. The authors introduce the brain-cognition gap to link these different imaging modalities to cognition and evaluate their results in two independent cohorts. The results are a valuable addition to the literature and will be of interest to neuroscientists working at the interface of cognition, neuroimaging, and computational modeling. However, the evidence supporting the conclusions remains incomplete.

eLife Assessment

This is a well-written important paper on the recovery of fauna and flora following the end-Permian extinction event in several continental sites in northern China. The convincing conclusion, a rapid recovery in tropical riparian ecosystems following a short phase of hostile environments and depauperate biota, is supported by an impressive amount of data from sedimentology, body fossils of animals and plants, and especially trace fossils.

eLife Assessment

The manuscript addresses the 3D chromatin architecture in monocytes from patients with alcohol-associated hepatitis and its relationship to enhanced transcription of innate immune genes. While the concept and methodological approach are appealing, the evidence is incomplete as a result of insufficient sample sizes as well as other significant analytical concerns.

eLife Assessment

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

eLife Assessment

This important study by Wong et al. addresses a longstanding question in the field of associative learning regarding how a motivationally relevant event can be inferred from prior learning based on neutral stimulus-stimulus associations. The research provides convincing behavioral and neurophysiological evidence to address this question. The manuscript will be interesting for researchers in behavioral and cognitive neuroscience.

eLife Assessment

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

eLife Assessment

This study addresses an important and longstanding question regarding the molecular mechanism of protein misfolding in Ig light chain (LC) amyloidosis (AL), a life-threatening condition. By combining advanced techniques, including small-angle X-ray scattering, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry, the authors provide convincing evidence that the "H state" distinguishes amyloidogenic from non-amyloidogenic LCs. These findings not only offer novel insights into LC structural dynamics but also hold promise for guiding therapeutic strategies in amyloidosis and will be of particular interest to structural biologists, biophysicists, and many others working on amyloid diseases.

eLife Assessment

This important work combines molecular genetics and behavioral analyses to identify inhibitory neurons in the female medial preoptic area as a neural locus that is activated following male ejaculation and whose prolonged activity plays a key role in the regulation of female sexual motivation. These experiments are rigorous and well-performed. The data are compelling and demonstrate that a subpopulation of neurons in the medial preoptic area are selectively activated following the completion of mating in females. The medial preoptic area has long been implicated as critical to sexual behavior in both sexes; however the use of a self-paced mating assay for females provides fine control over manipulating and monitoring cellular activity in this region during more naturalistic behavior. In addition, this study may act to inspire others to further explore the additional brain regions found to show upregulation of neural activity (Fos) during mating completion in females using the datasets generated here.

eLife Assessment

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

eLife Assessment

This valuable study presents data suggesting the critical roles of two ancient proteins, XAP5 and XAP5L, in regulating the transcriptional program of ciliogenesis during mouse spermatogenesis. The supporting data are solid, and this work will be of interest to biomedical researchers studying ciliogenesis and reproduction.

eLife Assessment

This important study employed multiple orthogonal techniques and tissue samples to investigate the interaction between the NRL transcription factor and RNA-binding proteins in the retina. The findings are convincing to support an interaction between NRL and the DHX9 helicase. The significance of the study could be enhanced with functional experiments of NRL-R-loop interactions in the developing retina and their potential role in photoreceptor health and gene regulation.

eLife Assessment

This study is a valuable contribution to the field of neuronal modeling by way of providing a method for rapidly obtaining neuronal physiology parameters from electrophysiological recordings. While the approach seems promising, in its current form it is incomplete since the generated models often diverge from the data and the comparison with existing methods has concerns.

eLife Assessment

This study presents valuable findings on the role of the small GTPase Rab3A in homeostatic plasticity. While the study demonstrates that Rab3A is required for homeostatic scaling, the evidence supporting the model put forward by the authors is incomplete. The work will be of interest to researchers in the field of synaptic transmission and plasticity.

Evaluation Statement (5 February 2025)

Pannexin (Panx) channels are a family of poorly understood large-pore channels that mediate the release of substrates like ATP from cells, yet the physiological stimuli that activate these channels remain poorly understood. The preprint by Henze et al. describes an elegant approach wherein activity-guided fractionation of mouse liver led to the discovery that lysophospholipids (LPCs) activate Panx1 and Panx2 channels expressed in cells or reconstituted into liposomes. The authors provide evidence that LPC-mediated activation of Panx1 is involved in joint pain and that Panx1 channels are required for the established effects of LPC on inflammasome activation in monocytes, suggesting that Panx channels play a role in inflammatory pathways. Overall, this important study reports a previously unanticipated mechanism wherein LPCs directly activate Panx channels.

Biophysics Colab recommends this study to scientists investigating phospholipids, Panx channels, purinergic signalling and inflammation.

Biophysics Colab has evaluated this study as one that meets the following criteria:

• Rigorous methodology
• Transparent reporting
• Appropriate interpretation

(This evaluation refers to version 3 of this preprint, which has been revised in response to peer review of versions 1 and 2.)

eLife Assessment

This study provides valuable information on a novel gene that regulates meiotic progression in both male and female meiosis. The evidence supporting the conclusions of the authors is solid. This study will be of interest to developmental and reproductive biologists.

eLife Assessment

This important study identifies a new key factor in orchestrating the process of glial wrapping of axons in Drosophila wandering larvae. The evidence supporting the claims of the authors is convincing and the EM studies are of outstanding quality. However, the quantification of the wrapping index, the role of Htl/Uif/Notch signaling in differentiation vs growth/wrapping, and the mechanism of how Uif "stabilizes" a specific membrane domain capable of interacting with specific axons might require further clarification or discussion. The work will be of interest to neuroscientists working on glial cell biology.

eLife Assessment

In this important study, the authors test the model that a type of vascular lesion caused by the inactivation of one gene in the cells that line blood vessels requires the activity of a second gene for the lesions to form. The evidence supporting the conclusions is solid.

eLife Assessment

This comprehensive scRNAseq atlas of the cranial region during neural induction, patterning, and morphogenesis provides a fundamental demonstration of how different cell fates are organized in specific spatial patterns along the anterior-posterior and medial-lateral axes within the developing neural tissue. The compelling data are analyzed with a rigorous computational approach, and the data revealed both known and novel genes differentially expressed along rostro-caudal and medio-lateral axes. This will be a helpful resource for researchers studying brain development.

eLife Assessment

This fundamental work demonstrates the importance of considering overlapping modes of functional organization (i.e. gradients) in the hippocampus, showing associations with aging, dopaminergic receptor distribution and episodic memory. The evidence supporting the conclusions is convincing, although not all analyses were performed in a replication sample. The work will be of broad interest to basic and clinical neuroscientists.

eLife Assessment

The authors present an valuable and intriguing observation challenging current views on DNA methylation dynamics, revealing earlier-than-expected de novo methylation with significant implications for gene regulation in early embryonic development. However, the study's significance is difficult to ascertain due to incomplete evidence supporting the conclusions. Moreover, the observed changes in DNA methylation across promoter regions is modest, leaving its relevance open to alternative interpretations.

eLife Assessment

This is a valuable study of the role that life history differences might play in determining population size and demography. While concerns about generation times and population structure leave the evidence for the claims in parts incomplete, the work is of considerable interest to anyone who tries to understand evolutionary consequences of life history changes.

eLife Assessment

This fundamental study further validates DNAH12 as a causative gene for asthenoteratozoospermia and male infertility in both humans and mice. Compelling evidence supports the notion that DNAH12 is essential for proper axonemal development. This work will be of interest to reproductive biologists studying spermatogenesis and sperm biology, as well as andrologists focusing on male fertility.

eLife Assessment

This work presents potentially important findings suggesting that a combination of transcranial stimulation approaches applied for a short period could improve memory performance after administration. However, the evidence supporting the conclusions is currently incomplete. The work, if replicated in larger samples and animal models or clinical populations, will have both theoretical and practical implications for non-invasive enhancement of cognitive function.

eLife Assessment

This important study reports the transcriptomic and proteomic landscapes of the oviducts at four different preimplantation stages during natural fertilization, pseudopregnancy, and superovulation. The supporting data are convincing. This work will be of interest to reproductive biologists and clinicians practicing reproductive medicine.

eLife Assessment

The manuscript presents valuable data suggesting that enalapril elevates pSmad1/5/9 signaling, reduces cellular senescence, and enhances physiological functions in aged mice. However, the in vivo evidence remains incomplete, as studies blocking pSmad1/5/9 or using NAC to negate enalapril's purported benefits are lacking, and no lifespan extension data are shown. While in vitro findings support Smad1/5/9 as a key mediator, additional experiments - including BMP receptor inhibition and comprehensive senescence markers - are necessary to validate its essential role in vivo. Overall, the study provides promising insights into enalapril's anti-senescence potential but requires further rigorous investigation to fully substantiate its mechanism and therapeutic impact.

eLife Assessment

This manuscript provides convincing evidence derived from diverse state-of-the-art approaches to suggest that non-dopaminergic projection neurons in the ventral tegmental area (VTA) make local synapses. These important findings challenge the prevailing wisdom that VTA interneurons exclusively form local synaptic contacts and instead reveal that VTA neurons expressing interneuron markers also form long-range projections to forebrain targets such as the cortex, ventral pallidum, and nucleus accumbens. Given the importance of VTA interneurons to many models of VTA-linked behavioral functions, these findings have significant implications for our understanding of the neural circuits underlying reward, motivation, and addiction.

eLife Assessment

This work uses enhanced sampling molecular dynamics methods to generate potentially useful information about a conformational change (the DFG flip) that plays a key role in regulating kinase function and inhibitor binding. The focus of the work is on the mechanism of conformational change and how mutations affect the transition. The evidence supporting the conclusions is incomplete.

eLife Assessment

This useful study provides a novel perspective on assessing the generalizability of meta-analytic findings by introducing prediction intervals (and distributions) as tools to evaluate whether future studies will likely yield non-zero effects. The methodology is generally solid, with a thorough exploration of a large set of published meta-analyses that broadens our understanding of between-study heterogeneity. However, some critical details are incomplete, requiring refinement to ensure statistical rigor.

eLife Assessment

This important study demonstrates the potential of synthetic gene circuits to detect and target aberrant RAS activity in cancer cell lines. The circuit design is novel and the evidence supporting the claims is convincing. As a proof-of-concept, this will be of broad interest. Testing the system with other KRAS mutations and clinically relevant output proteins, as well as gaining a better understanding of the underlying molecular mechanism, will both strengthen the study and help translate the technology toward clinical applications in cancer therapeutics.

eLife Assessment

This study presents a valuable nonlinear mathematical model that addresses how cell shape transitions in response to ECM stiffness. The evidence supporting the claims of the authors is solid, although additional work is required to improve the manuscript. For instance, the authors should improve the overall readability of the text and amend the experimental validation section. The work will be of interest to scientists working on a spectrum of fields including cell mechanics, cell behaviors, and cancer research.

eLife Assessment

This is an important and solid study that examines the role of TFAM, a protein that helps maintain mtDNA, in mtDNA mutator mice. The authors have demonstrated that TFAM's counteractive role in mtDNA mutator mice is tissue-specific. Minor revisions will enhance the clarity and discuss some of the findings for the broader audience.

eLife Assessment

The manuscript by Qi et al. provides valuable insights into the structural basis of RNA methylation by the METTL3-METTL14 complex, revealing a novel cryptic pocket critical for m6A recognition. The solid experimental approach, integrating crystallography, molecular simulations, and functional assays, supports a proposed two-step mechanism for enzymatic activity. Refining structural data and addressing binding kinetic inconsistencies would further enhance clarity and impact. This manuscript will interest researchers in RNA modification, cancer biology, and therapeutic drug development.

eLife Assessment

This study presents a valuable finding on the signaling mechanisms underlying Treg cell homeostasis by identifying the simultaneous requirement of diacylglycerol (DAG) kinases (DGK) alpha and zeta for Foxp3+ Treg cell function and follicular responses, with implications for the pathogenesis of some autoimmune diseases. Whereas data based on the characterization of double knock-out mice (for DGK alpha and zeta) is solid, showing the emergence of autoimmune manifestations, the study has gaps in its experimental approaches since it is not clear what can be attributed to the simultaneous DKGα and ζ deficiency, versus the individual deficiency of either one. Experiments on the pathogenic potential of the DKO Tregs in the absence of other T-cells were not presented and results on the role of CD25 downregulation and CD28-independent activation of Treg cells were not properly discussed. Nonetheless, the reported data would be of interest to immunologists working on T-cell intracellular signaling and autoimmunity.

eLife Assessment

This study proposes a useful assay to identify relative social ranks in mice incorporating the competitive drive for two basic resources - food and living space. Using this new protocol, the authors provide solid evidence of stable ranking among male and female pairs, while reporting more fluctuant hierarchies among triads of males. The evidence is, however, incomplete in providing ethologically based validation, assessment of the influence of competitor recognition, rigorous analysis of training data, and proof of concept of application to neuroscience. With these concerns addressed, this manuscript will be of interest to those interested in social behavior and related neuroscience.

eLife Assessment

Veiga et al demonstrate the importance of incorporating RNAseq and machine learning approaches for neoantigen prediction. The evidence is convincing, and these findings contribute important information towards the selection of neoantigens for personalized antitumor vaccination.

eLife Assessment

By using molecular tools, electrophysiology, and ultrastructural reconstructions, this manuscript investigates the role of the Nogo/RTN4 receptor homolog RTN4RL2 at the afferent synapses between the sensory inner hair cells and spiral ganglion neurons and proposes that this regulates key aspects of hearing. The study is important because it provides insights into potential therapeutic targets for hearing loss related to synaptic dysfunction. The experimental data, based on the use of excellent tools, is solid and could be further improved with additional experiments that strengthen the validity of the findings and their interpretation, described in detail in the reviewers' comments.

eLife Assessment

In this important study, the authors reconstruct the evolutionary history of a large and widespread group of freshwater fishes (Nemacheilidae) across Eurasia since the early Eocene, based on molecular phylogenetic analysis with very comprehensive samplings including 471 specimens belonging to 250 living species. The authors convincingly infer that range expansions of the family were facilitated by tectonic connections, favorable climatic conditions, and orogenic processes, adding to our understanding of the effects of climatic change on biodiversity during the Cenozoic. This work is of interest to evolutionary biologists, ichthyologists, paleontologists, and general readers.

eLife Assessment

This important study investigates the signaling pathways regulating retinal regeneration. Convincing evidence shows that the sphingosine-1-phosphate (S1P) signaling pathway is inhibited following retinal injury. Small-molecule activators and inhibitors support a model in which S1P signaling must be inhibited to generate Müller glial progenitor cells-a key step in retinal regeneration. The presented results support the major conclusions. However, whether the drug treatments directly or indirectly affect the Müller cells remains unclear.

eLife Assessment

This important study reports the developmental dynamics and molecular markers of the rete ovarii during ovarian development. The data supporting the main conclusions are convincing. This study will be of interest to developmental and reproductive biologists.

eLife Assessment

This important study focused on characterizing clonally derived MSC populations from the synovium of normal and osteoarthritis (OA) patients, demonstrating their potential to regenerate cartilage in vivo. Although the strength of evidence is solid, further work is needed to fill the gaps in the CD47Hi cell characterization and the in vivo response assessment. The study will be of interest to scientists advancing MSC based regenerative medicine approaches.

eLife Assessment

This valuable study presents a mouse gastruloid model that can be used to generate hematopoietic progenitors as well as leukemic cells. However, in its current form, the manuscript is inadequate because the primary claims are not supported. Overall, the hematopoietic progenitor cells generated in this system need to be better defined.

eLife Assessment

This important article describes a meticulously-developed improved strategy for generation of functionally null mutants in Leishmania spp. via cytosine base editing, with reduced background toxicity and enhanced efficiency relative to a previously-described method. The authors show use of the strategy in a small-scale loss-of-function screen, providing compelling evidence that large-scale screens will be possible. The newly developed tools will be of great interest to researchers working with Leishmania and beyond.

eLife Assessment

This important study uses a comprehensive observational dataset to provide solid evidence on how genetic diversity and species diversity differentially affect multiple ecosystem functions within and across multi-trophic levels in an aquatic ecosystem. The work will be of interest to ecologists working on multi-trophic relationships and biodiversity.

eLife Assessment

This study provides important observations about the role of Hebbian synapse rewiring (which predicts that correlated activity between neurons begets stronger synapses) on brain connectivity development, by examining a naturally emerging case where Hebbian predictions can be tested because neurons with differing activity undergo development under otherwise similar conditions (albino mouse lateral geniculate nucleus [LGN], where retinal ganglion cells [RGCs] from the contralateral retina form inappropriate projections alongside a majority of ipsilateral RGCs). The evidence supporting the conclusions is compelling, with combined confocal imaging and serial electron microscopy (EM) reconstructions showing complete synaptic isolation of aberrantly projecting RGCs onto LGN thalamocortical projection neurons, and mixed connectivity onto LGN local interneurons. The morphological descriptions of connectivity presented here will be of interest to researchers studying synaptic connectivity and plasticity during development.

eLife Assessment

This important paper provides an unbiased landscape for the cerebellar cortical outputs to the brainstem nuclei. By conducting anatomical and physiological analyses of the axonal terminals of Purkinje cells, the data provides convincing evidence that Purkinje cells innervate brainstem nuclei directly. The results show that in addition to previously known inputs to vestibular and parabrachial nuclei, Purkinje cells synapse onto the pontine central grey nucleus but have little effect on the locus coeruleus and mesencephalic trigeminal neurons.

eLife Assessment

This fundamental study comprehensively characterizes insulin producing cells (IPCs) resident in the Drosophila melanogaster brain. A compelling experimental tour de force, the combination of connectomics, mapping of receptors for neuromodulators, electrophysiological recordings, Calcium imaging and optogenetics demonstrates that IPCs operate as a functionally heterogeneous population, as necessary to address continuously changing metabolic demands. These findings will be of interest to both neuroscientists and physiologists seeking to study context-dependent neuroendocrine regulation.

eLife Assessment

This important study highlights the novel role of RSPO mimetic SZN-043 in the activation of hepatic WNT signaling and promoting hepatocyte regeneration. The authors provided solid evidence of SZN-043 increasing hepatocyte proliferation in various mouse models, including a humanized mouse liver model, ALD model, and CCL4 fibrosis model, although mechanistic characterization of liver pathology remains incomplete. This study will be of interest to researchers in liver regeneration and repair mechanisms.

eLife Assessment

Nold et al. examined exercise-induced pain modulation in a pharmacological within-subject fMRI study using the opioid-antagonist naloxone and different levels of aerobic exercise and pain. This study provides valuable findings showing that the intensity of exercise does not seem to impact the hypoalgesic effect; however, the evidence is incomplete for the claims relating to the overall effect of exercise on pain, since they cannot be tested with the proposed experimental design.

eLife Assessment

Lloyd et al. used an evolutionary comparative approach to study DNA damage repair associated with low sleep duration in Astyanax mexicanus, highlighting how the cavefish population has evolved a reduced DNA damage response. The results presented here have important implications. Their results are generally solid however, the evidence suggesting that sleep differences are linked to DNA damage response is missing and this hypothesis remains to be fully tested.

eLife Assessment

In this useful study, the authors perform voltage imaging of CA1 pyramidal cells in head-fixed mice running on a track while local field potentials (LFPs) are recorded. The authors conclude that synchronous ensembles of neurons are differentially associated with different types of LFP patterns, namely theta and ripples. However, evidence for the claims remains incomplete, due to caveats of the experimental approach that were not acknowledged and strong claims that are based on a sparse data set.

eLife Assessment

This important study substantially advances our understanding of the neural circuits that regulate social behavior by identifying a population of hypothalamic neurons in the preoptic area that promote social interactions following short-term isolation. The evidence supporting the authors' claims is solid, with well-designed experiments using validated activity-dependent tagging and manipulation methods, though some differences in outcomes between experiments highlight limitations of the tagging approach. The work will be of broad interest to neuroscientists studying social behavior, neural circuit function, and hypothalamic mechanisms and will represent a meaningful contribution to the field.

eLife Assessment

The authors provide a thorough investigation of the interaction of megakaryocytes (MK) with their associated extracellular matrix (ECM) during maturation; they provide evidence that the existence of a dense cage-like pericellular structure containing laminin γ1 and α4 and collagen IV is key to fixing the perisinusoidal localization of MK and preventing their premature intravasation. Adhesion of MK to this ECM cage is dependent on integrin beta1 and beta3 expressed by MK. This strong and solid conclusion is based on the use of state-of-the art techniques such as the use of primary murine bone marrow MK cultures, mice lacking ECM receptors, namely integrin beta1 and beta3 null mice, as well as high-resolution 2D and 3D imaging. The study provides valuable insight into the role of cell-matrix interactions in MK maturation and provides an interesting model with practical implications for the fields of hemostasis and thrombosis.

eLife Assessment

In this valuable study, the authors used rats to determine the receptor for a food-related perception (kokumi) that has been characterized in humans. They employ a combination of behavioral, electrophysiological, and immunohistochemical results to provide solid support for their conclusion that ornithine-mediated kokumi effects are mediated by the GPRC6A receptor. They complemented the rat data with some human psychophysical data. The results are intriguing, but there are some deficiencies.

eLife Assessment

In this important study, the authors use zebrafish to examine protein absorption in the gut. Using a combination of imaging and single-cell RNA-seq, they characterize a population of lysosome-rich enterocytes that are important for protein uptake. They find that the microbiome impacts the ability of these cells to uptake protein. The RNA-seq provides a rich dataset for future functional experiments, which makes a convincing case for the importance of these cells.

eLife Assessment

This study presents fundamental findings that could redefine the specificity and mechanism of action of the well-studied Ser/Thr kinase IKK2 (a subunit of inhibitor of nuclear factor kappa-B kinase (IkB) that propagates cellular response to inflammation). Solid evidence supports the claim that IKK2 exhibits dual specificity that allows tyrosine autophosphorylation and the authors further show that auto-phosphorylated IKK2 is involved in an unanticipated relay mechanism that transfers phosphate from an IKK2 tyrosine onto the IkBa substrate. The findings are a starting point for follow-up studies to confirm the unexpected mechanism and further pursue functional significance.

Hurd, Cuthbert C., ed. Proceedings: IBM Computation Seminar December 1949. New York: Internation Buisiness Machines Corporation, 1951. http://archive.org/details/bitsavers_ibmproceedeminarDec49_14295048.

In a variety of context here the idea of "cards" could be held to be synonymous with "notes".

Collision cards (though used in a physics setting) could be a bit hilarious with the idea of "atomic notes" and the idea of "combinatorial creativity".

eLife Assessment

Understanding how the divisome is assembled in Chlamydia trachomatis, a bacterial pathogen, is crucial since this bacterium has a non-canonical cell wall and lacks the master regulator of cell division, FtsZ. This important study shows that a DNA translocase, FtsK, is an early and essential component of the Chlamydia trachomatis divisome. The evidence presented is convincing, leveraging the elegant use of genetics and fluorescence microscopy. As this role of FtsK is distinct relative to most other bacteria, these findings should be of significant interest to bacterial cell biologists.

eLife Assessment

In this study, the authors use the zebrafish to investigate how the microbiome affects a specialized gut cell called the lysosome rich enterocyte. They use a combination of functional assays for protein absorption, gnotobiotic manipulations and single-cell RNA-seq. The findings in the paper are considered important and the results are convincing.

eLife Assessment

The important manuscript presents convincing evidence of temporal correlations during specific oscillatory activity between the prefrontal cortex, thalamic nucleus reuniens, and the hippocampus, in naturally sleeping animals. Such correlations represent solid evidence to support the notion that the thalamic nucleus reuniens participates in the hippocampal and prefrontal cortex dialogue subserving memory processes.

eLife Assessment

This work presents an important mouse model for a liver-specific depletion of the Survival Motor Neuron (SMN) protein, where the liver retains 30% of functional full-length SMN protein. The authors provide a profile of phenotypic changes in liver-specific SMN depleted mice with convincing evidence supporting their claims.

eLife Assessment

This important body of work uses state-of-the-art quantitative methods to characterize and compare behaviors across five different fish species to understand which features are conserved and which ones are differentiated. The convincing results from this study will be of interest to ethologists and also have potential utility in understanding the neural mechanisms leading to these behaviors.

eLife Assessment

This study presents solid evidence for distinct neurotransmitter release modalities between two subclasses of dopaminergic neurons in the olfactory bulb, highlighting an important finding that dendritic neurotransmitter release in anaxonic neurons and axonal neurotransmitter release in axon-bearing neurons, and GABAergic self-inhibition in anaxonic neurons emphasizes the functional differences between these neuronal subtypes. However, some experiments looked incomplete with a relatively small sample size (low n). The conclusion would benefit significantly from additional validations.

eLife Assessment

The authors adapt a previously-established method that permits detection of in vivo extracellular levels of two distinct enkephalin opioid peptides in response to stressful experiences in mice. The present study highlights the potential of measuring actual peptides by microdialysis-LC-MS. They use this approach in conjunction with fiber photometric calcium imaging to correlate enkephalin neuron activity and enkephalin release in response to repeated stress, providing convincing evidence that this improved approach can provide new insights into opioid signaling in-vivo. This important study provides a means to understand various behavioral states controlled by endogenous opioids and the nucleus accumbens, including hedonic and stress responses, in health and disease. This work will be of broad interest to the neuroscientific community.

eLife Assessment

This study provides valuable observations indicating that human pyramidal neurons propagate information as fast as rat pyramidal neurons despite their larger size. Convincing evidence demonstrates that this property is due to several biophysical properties of human neurons. This study will be of interest to neurophysiologists.

eLife Assessment

This study presents valuable findings to the field interested in inattentional blindness (IB), the phenomenon that participants fail to notice salient stimuli when their attention is directed elsewhere. This study reveals that participants who indicate no awareness of unexpected stimuli through yes/no questions ("did you notice anything unusual?"), may still show above-chance sensitivity to specific properties of these stimuli through follow-up forced-choice questions (e.g., regarding its location or color). By introducing absent trials where no IB stimulus is presented, the authors show that this is because participants are generally conservative and biased to report not noticing in inattentional blindness experiments. The evidence supporting these conclusions is convincing, the samples sizes are large and the analysis protocol is novel.

eLife Assessment

This work provides an important framework for understanding the primary causes of disease. While the theoretical results rely on strong assumptions about the underlying causal mechanisms, the authors provide solid empirical evidence that the framework is robust to modest violations of these assumptions.

eLife Assessment

This valuable study investigates how inter-organ communication between the tracheal stem cells and the fat body plays a key role in the directed migration of tracheal stem cells in Drosophila. The evidence supporting the claims of the authors is solid. The work would be of interest to researchers in the fields of developmental biology and cancer biology.

eLife Assessment

This important work demonstrates the application of Pro-PRIME, a large language model, to engineer VHH antibodies with enhanced stability for extreme industrial environments. The evidence is convincing, showing through two rounds of design and experimental validation that AI-guided approaches can outperform traditional rational design methods. The solid methodology and results establish a foundation for further exploration of LLM-assisted protein engineering.

eLife Assessment

The preliminary data presented in this manuscript seem valuable. The data are currently incomplete and there are numerous technical concerns, some of which may arise from insufficient description of methodologies used.

eLife Assessment

This study reports an approach for restoring sperm motility in mice. The strength lies in in the novelty of the methodology being developed, but the evidence for the success of the method or its mechanism is inadequate. Additional experimental support would be required to support the conclusions of the authors.

eLife Assessment

This valuable work presents an interpretable protein-DNA Energy Associative (IDEA) model for predicting binding sites and affinities of DNA-binding proteins. The study provides a detailed description of the method, making it reproducible. However, the generalizability of the prediction model presents certain concerns, and the supporting evidence appears incomplete. Nonetheless, with a thorough re-examination of the training and testing procedures, this model can be widely applicable for predicting genome-wide protein-DNA binding sites.

eLife Assessment

This important study measures the functional specialization of distinct subregions within the mouse posterior parietal cortex (PPC) using mesoscopic two-photon calcium imaging during visual discrimination and choice history-dependent tasks. It presents compelling evidence supporting the existence of functional specialized subregions within the PPC. The work will be of interest to system and computational neuroscientists interested in decision-making, working memory, and multisensory integration.

eLife Assessment

This study is important as it highlighted how IL-4 regulates the reactive state of a specific microglial population by increasing the proportion of CD11c+ microglial cells and ultimately suppressing neuropathic pain. It provided convincing evidence on the pain-resolving roles of microglia. However, the authors are encouraged to clarify data interpretation and integrate the study's findings into the existing knowledge about microglia, monocytes, and macrophages.

eLife Assessment

This important study shows that the activity of hypothalamic hypocretin/orexin neurons (HONs) correlates with body movement over multiple behaviors. Sophisticated techniques and analyses showcase this link which appears to be unique to HONs. Evidence for this correlation is, however, incomplete as the confound of arousal with movement needs to be resolved since orexin also plays a key role in arousal. This work should be of interest to scientists studying peptidergic neurons, movement, energy regulation, and brain-body coordination.

eLife Assessment

This study presents a valuable finding that C238 in vimentin regulates long non-coding RNA XIST to suppress EMT and thereby Xist may be a therapeutic target in breast cancer. The evidence supporting the claims of the authors is solid, although the improvement of data visibility and presentation would have strengthened the study. The work will be of interest to scientists working in the field of BCs.

eLife Assessment

This is an important study that provides CCR7-APEX2 proximity labelling mass spectrometry data that is expected to provide new insights into CCR7 signaling partners and pathways. The study is technically easy to follow and the data is convincing. It will be interesting in the future to have complementary studies in lymphocytes/dendritic cells that endogenously express CCR7. This is of value to the community, and there are likely multiple opportunities to use the APEX2 data set to extend these findings, strengthen some claims, and even explore a new pathway identified in the APEX2 data set.

eLife Assessment

Working with a diverse panel of rice accessions grown in field conditions, this valuable study measures changes in transcript abundance, tests for patterns of selection on gene expression, and maps the genetic basic of variation in gene expression in normal and elevated salinity treatments. The manuscript provides solid evidence that mean gene expression levels are further from the optimum abundance for more genes under the elevated salinity treatment compared to normal treatment, and that a relatively small number of genes are hotspots that harbor genetic variants which affect broader genome-wide patterns of natural variation in gene expression under high salinity conditions. However, the design, clarity, and interpretation of several statistical analyses can be improved, some opportunities for integration among datasets and analyses could yet be realized, and genetic manipulation is required to confirm functional involvement of any specific genes in regulatory networks or organismal traits that confer adaptation to higher salinity conditions. The manuscript will be of interest to evolutionary biologists studying the genetics of complex traits and a resource for plant biologists studying mechanisms of abiotic stress tolerance.

eLife Assessment

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

eLife Assessment

This valuable study unravels the mechanisms underlying mammalian sperm-oocyte recognition and penetration, shedding light on cross-species interactions. It provides solid evidence that exposure of sperm to oviductal fluid or OVGP1 proteins from bovine, murine, or human sources imparts species-specific zona pellucida (ZP) recognition, ensuring that only sperm from the corresponding species can penetrate the ZP, regardless of its origin. These findings hold significant potential for reproductive biology, offering insights to enhance porcine in vitro fertilization (IVF), which frequently suffers from polyspermy, as well as advancing human IVF through improved intrinsic sperm selection.

eLife Assessment

This study presents an important finding on the molecular mechanism for transduction of environmentally induced polyphenism. The evidence supporting the claims of the author is solid. This paper would be of interest to those studying aphids wing dimorphism.

eLife Assessment

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

eLife Assessment

This work presents valuable data demonstrating that a camelid single-domain antibody can selectively inhibit a key glycolytic enzyme in trypanosomes via an allosteric mechanism. The claim that this information can be exploited for the design of novel chemotherapeutics is solid but limited by the modest effects on parasite growth, as well as the lack of evidence for cellular target engagement in vivo.

eLife Assessment

This important study investigates the propensity of the intravacuolar pathogen, Leishmania, to scavenge lipids which it utilizes for its accelerated growth within macrophages. Although some of the data compellingly links increased lipid acquisition to parasite growth, data to support the underlying mechanism to describe the proposed model is incomplete. The study adds to other work that has implicated pathogen-derived processes in the selective recruitment of vesicles to the pathogen-containing vacuole, based on the content of the cargo.

eLife Assessment

The authors present a useful agent-based model to study the tensile force generated by myosin mini-filaments in actin systems (bundles and networks); by numerically solving a mechanical model of myosin-II filaments, the authors provide insights into how the geometry of the molecular components and their elastic responses determine the force production. This work is of interest to biophysicists (in particular theoreticians) investigating force generation of motor molecules from a biomechanical engineering and physics perspective. The authors convincingly show that cooperative effects between multiple myosin filaments can enhance the total force generated, but not the efficiency of force generation (force per myosin) if passive cross-linkers are present. This work would benefit from a more extensive discussion of the relevance of the results in view of the existing experimental literature.

eLife Assessment

This useful study uses the MMTV-Neu-YD5 mouse model for HER2-dependent breast cancer to generate transcriptomic and proteomic datasets from extracted primary tumour samples. The data sets generated appear to be solid and will be of interest to the community. However, mechanistic studies to support the conclusion that mitochondrial function is increased in the tumours remain incomplete and would benefit from experiments that would directly interrogate aspects such as cellular heterogeneity, and signalling.

eLife Assessment

This important study combines compelling experiments with optogenetic actuation and convincing theory to understand how signalling proteins control the switch between cell protrusion and retraction, two essential processes in single cell migration. The authors examine the importance of the basal concentration and recruitment dynamics of a guanine exchange factor (GEF) on the activity of the downstream effectors RhoA and Cdc42, which control retraction and protrusion. The experimental and theoretical evidence provides a model of RhoA's involvement in both protrusion and retraction and shows that these complex processes are highly dependent on the concentration and activity dynamics of the components.

eLife Assessment

Using experiments in the white fly, this manuscript provides evidence that the bacterial symbiont Wolbachia can be transmitted from parasitoid wasps to their insect hosts. Characterizing the transfer of Wolbachia between insect species is a valuable attempt to explain the widespread of this intracellular bacterium. This paper is incomplete as it does not furnish sufficient data to support several of its claims for which additional methods and data are necessary.

eLife Assessment

This study provides a convincing explanation for why HIV-1 Vif causes a qualitatively different cell cycle arrest to its accessory gene counterpart Vpr. The authors use elegant time-dependent microscopy reporter assays in immortalized tumor cell models to show that HIV-1 Vif causes a pseudo-metaphase arrest rather than a G2 arrest. The metaphase arrest correlates with dysregulation of the kinetochore that could be explained by the loss of phosphatase functions that determine chromosome-microtubule interactions. These valuable findings lay the groundwork for additional studies examining the mechanisms and consequences of this Vif-dependent phenotype in the viral life cycle and in primary cells more relevant to HIV-1 pathogenesis.

eLife Assessment

This study reports important findings about pre-saccadic foveal prediction and the extent to which it is influenced by the visibility of the saccade target relative to its background. The results and research methodology are solid, although the neural substrates of oscillatory pre-saccadic enhancement for high-opacity targets remain unclear. This work should be of broad interest to visual neuroscientists, as well as those aiming to understand perception in the context of eye movements and modeling of visually guided actions.

eLife Assessment

This is an interesting and important paper that grew from a careful clinical assessment of an unusual patient with hypoparathyroidism whose parathyroid glands synthesize and secrete a mutant form of PTH made. This mutant PTH (R25C-PTH), when studied in mice and in vivo, has interesting properties. It can homodimerize and can raise blood calcium and lower blood phosphate levels: the opposite to the human phenotype in the index patient. These investigators perform a careful and convincing comparison of native PTH (1-34), an anabolic drug for osteoporosis treatment, and this R25C-mutant of PTH for their effects on bone mass, strength, microarchitecture, and metabolic activity. This dimeric mutant of PTH has anabolic properties raising the possibility that such forms of PTH could be developed as potent therapies for low bone mass states.

eLife Assessment

In this manuscript the authors established a novel three-dimensional culture system for stratified epithelia that allows epithelial cells to undergo epithelial-to-mesenchymal transition (EMT) and subsequent mesenchymal-to-epithelial transition (MET) while migrating through a membrane with 3.0-µm micropores, and, thus, provides a valuable tool to study EMT and possibly wound regeneration or metastasis. Furthermore, a set of experiments provides solid data suggesting that TGF beta signaling and actin polymerization promote movement of epithelial cells into the pores, while Piezo1 and Keratin 6 prevent keratinocyte migration and EMT.

eLife Assessment

This work represents an important contribution to our understanding of how membrane energetics influence protein conformation and function in mechano-sensitive channels. Through extensive molecular dynamics simulations and energetic analysis, the study demonstrates how the channel structure is shaped by a balance of protein and membrane-induced forces, effectively reconciling experimental data from different membrane environments. However, while much of the computational data is convincing, some aspects of the energetic analysis and models employed remain incomplete.

eLife Assessment

This important work substantially advances our understanding of the interaction among gut microbiota, lipid metabolism, and the host in type 2 diabetes. However, some evidence is incomplete, particularly in the mouse experiments with FMT. Additional experiments will be required to strengthen the authors' interesting findings.

eLife Assessment

The study presents important findings on inositol-requiring enzyme (IRE1α) inhibition on diet-induced obesity (overnutrition) and insulin resistance where IRE1α inhibition enhances thermogenesis and reduces the metabolically active and M1-like macrophages in adipose tissue. The evidence supporting the conclusions is convincing and the work will be of interest to cell biologists and biochemists working in metabolism, insulin resistance, and inflammation.

eLife Assessment

This study describes the impact of mycobacterial genetic diversity on host-infection phenotypes by assessing the effect of different M. tuberculosis lineages on granulomatous inflammation using a 3D in vitro granuloma model. Despite being descriptive and showing mostly correlative relationships, the useful findings and data provide some solid support regarding the functional impact of M. tuberculosis natural diversity on host-pathogen interactions. The study will interest researchers working on mycobacteria and how genetic diversity influences virulence and immunity outcomes.

eLife Assessment

This manuscript describes the impact of modulating signaling by a key regulatory enzyme, Dual Leucine Zipper Kinase (DLK), on hippocampal neurons. The results are interesting and will be important for scientists interested in synapse formation, axon specification, and cell death. The authors have carefully addressed the comments made by the reviewers and the findings are convincing in large part due to the use of extensive mouse genetics, detailed gene expression of enriched genes, and recognition of neuron vulnerability.

eLife Assessment

This study presents important findings on the function of enteric glia expressing proteolipid protein 1 (PLP1+ glia). The evidence supporting the claims of the authors is solid, although the inclusion of additional data showing the mechanisms by which PLP1+ enteric glia acts on Paneth cells would have strengthened the study. The work will be of interest to colleagues studying intestinal biology.

eLife Assessment

This study on mouse Ly49 receptors expressed on natural killer (NK) cells shows that Ly49A, in the presence of the corresponding MHC Class I allele, can lead to NK cell licensing, thereby providing valuable insights into the mechanisms of NK cell modulation by Ly49 receptors. The work may have significant implications for studies of human Killer-cell immunoglobulin-like receptors (KIR) expressing and other NK cells. Overall, the study was well-developed with convincing evidence.

eLife Assessment

Zanetti et al use convincing biophysical and cellular assays to investigate the interaction of the birnavirus VP3 protein with the early endosome lipid PI3P. The study provides valuable insights and will be of interest to virologists. In future studies, it would be interesting to demonstrate that VP3-PIP3P is a specific interaction and not a general interaction with other PIPs.

eLife assessment

These important findings stand out from other similar studies via some convincing demonstration of behavioural and neural relationships between two helping tasks – one focusing more on social perception, one more on its influence on social behaviour – that were performed more than 300 days apart. The claims however would be stronger with a larger sample size.

eLife Assessment

This study presents a useful finding that targeting amino acid metabolism can overcome Trastuzumab resistance in HER2+ breast cancer. The evidence supporting the claims of the authors is solid and the authors may want to validate their results in additional cell lines to strengthen their conclusions. Moreover, the authors should clarify the source of patient samples and why the manuscript focused on epigenetic regulations instead of major transcription factors. The work will be of interest to scientists working in the field of breast cancer.

eLife Assessment

This is an important study reporting that activation of the presynaptic GPR55 receptor suppresses synaptic transmission by modulating GABA release through the reduction of the readily releasable pool without affecting the presynaptic AP waveform and calcium influx. The evidence supporting this claim is compelling and based on an impressive array of techniques including patch-clamp recordings from the axon terminals of cerebellar Purkinje cells and fluorescent imaging of vesicular exocytosis. However, a few technical issues leave some questions open, these include uncertainty regarding the specificity of pharmacological agents and the nature of the endogenous process that would activate this pathway in vivo. In the current form, the evidence indicating that synaptic vesicles become insensitive to VGCC activation in the presence of GPR55 is weak and would need to be supported with additional experimental data.

eLife Assessment

Overall, this is an important work: the new methodology of hamFISH is a key additional tool for the assessment of the expression of multiple genes simultaneously. The authors provide convincing evidence of the utility of this approach on Medial Amygdala (MeA) tissue leveraging previous a transcriptomic dataset for gene selection. The authors also present a deeper dive into putative relationships between the on-tissue expression of subsets of genes and connectivity and behavioral regulation. The putative biological insights are intriguing, although preliminary, but notably they set up questions for future studies.

eLife Assessment

In this valuable contribution, the authors present an approach based on a complex systems theoretical framework to characterize diet-host-microbe interactions and to develop targeted bacteriotherapies using a three-phase workflow. Overall, the solid results provide a reference for microbial community research and insights to guide future studies. However, the theoretical systems approach would benefit from further description, and some claims regarding oxalate bacterial metabolism in complex microbial communities could be strengthened. This study will interest researchers working on gut microbiomes specifically those seeking to modulate host-microbial interactions.

eLife Assessment

This important study investigates the function of a critical regulator of human early cardiac development. The convincing examination of GATA6 function is thorough and well-executed. The study will be of interest to scientists working on how the human heart acquires its identity.

eLife Assessment

The study by Pudlowski et al. shows that a previously-identified protein complex, composed of delta- and epsilon-tubulin together with TEDC1 and TEDC2, functions in generating centriolar triplet microtubules, and that this is crucial for the proper formation of centriolar subdomains and the stability of centrioles throughout the cell cycle. This is an important study that advances our understanding of centriole biogenesis and structure and is supported by convincing evidence based on knockout cell lines, immunoprecipitation, and ultrastructure expansion microscopy. The work is of interest to cell biologists, in particular researchers with interest in centrosome biology.

eLife Assessment

This manuscript describes an important finding of the transcriptional control of a chimeric gene transfer agents (GTA) cluster in Bartonella by a processive anti-termination factor (BrrG). The evidence provided is solid. This manuscript will interest researchers working on transcriptional regulation, horizontal gene transfer, and phages.

eLife Assessment

This valuable study presents findings on DNA methylation as an efficient epigenetic transcriptional regulating strategy in bacteria. The authors utilized single-molecule real-time sequencing to profile the DNA methylation landscape across three model pathovars of Pseudomonas syringae, identifying significant epigenetic mechanisms through the Type-I restriction-modification system, which includes a conserved sequence motif associated with N6-methyladenine. The evidence presented is solid and the study provides novel insights into the epigenetic mechanisms of P. syringae, expanding the understanding of bacterial pathogenicity and adaptation.