eLife Assessment

This important study reports a detailed computational analysis of the CFTR ion channel's permeation mechanism, advancing our understanding of its structure-function relationship. The conclusions are based on extensive molecular dynamics simulations and thorough analysis, but the use of an approximate chloride ion model, known to underestimate key ion-protein interactions, leaves them incomplete without experimental or alternative computational validation. The work will be of interest to biophysicists working on CFTR and cystic fibrosis.

eLife Assessment

Rennert et al. developed a valuable thermodynamic framework to study the force response of branched actin networks from the crucial and unexplored perspective of energetic cost. They used the fact that the entropy production rate must be positive to derive inequalities that set limits on the maximum force produced by branched actin networks, and speculate that the dissipative cost beyond that required to move the load may be necessary to maintain an adaptive steady state. This work is highly innovative, but remains incomplete until the hypotheses of the model are better justified and the conclusions about the dissipative cost of the system are better established.

eLife Assessment

This study presents a potentially fundamental analysis of the original color of a fossil feather from the crest of a 125-million-year-old enantiornithine bird, using sophisticated 3D microscopic and numerical methods to conclude that the feather was iridescent and brightly colored, possibly indicating that this was a male bird that used its crest in sexual displays. At present, the strength of evidence supporting the authors' conclusions is considered incomplete based on methodological incompleteness and questions about taphonomy.

eLife Assessment

This fundamental manuscript comprehensively examines the roles of nine structural proteins in herpes simplex virus 1 (HSV-1) assembly and nuclear egress. By integrating cryo-light microscopy and soft X-ray tomography, the study presents an innovative approach to investigating viral assembly within cells. The research is thoroughly executed, yielding compelling data that explain previously unknown functions of these structural proteins. This work is of broad interest to virologists, cellular biologists, and structural biologists, offering a robust, contextually rich methodology for studying large protein complex assembly within the cellular environment, serving as an excellent starting point for high-resolution techniques.

eLife Assessment

This study provides important insights into the regulation of type-I interferon signaling and anti-tumor immunity, demonstrating that ORMDL3 promotes RIG-I degradation to suppress immune responses. The evidence is convincing, with well-executed mechanistic experiments and in vivo validation in syngeneic tumor models. These findings have significant implications for cancer immunotherapy, highlighting ORMDL3 as a potential therapeutic target.

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 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

The authors present three transgenic models carrying three representative exon deletions of the dystrophin gene. The findings presented are valuable to the field of muscle diseases, particularly muscular dystrophies. The evidence provided in the manuscript is convincing, with rigorous biochemical assays and state-of-the-art microscopy methods.

eLife Assessment

This valuable work provides solid evidence that a neuronal metallothionein, GIF/MT-3, incorporates metal-persulfide clusters. A variety of well-designed assays support the authors' hypothesis, revealing that sulfane sulfur is released from MT-3. The biological role of the persulfidated form is not yet clearly defined. There are caveats to the findings that limit the study, but the work will nevertheless prompt major follow-up work.

eLife Assessment

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

eLife Assessment

In this valuable report, the authors investigated the effect of mitochondrial transplantation on post-cardiac arrest myocardial dysfunction (PAMD), which is associated with mitochondrial dysfunction. They convincingly demonstrated that mitochondrial transplantation enhanced cardiac function and increased survival rates after the return of spontaneous circulation (ROSC). They have also shown that myocardial tissues with transplanted mitochondria exhibited increased mitochondrial complex activity, higher ATP levels, reduced cardiomyocyte apoptosis, and lower myocardial oxidative stress post-ROSC.

eLife Assessment

These useful findings assigned a novel functional implication of histone acylation, crotonylation. Although the mechanistic insights have been provided in great detail regarding the role of the YEATS2-GCDH axis in modulating EMT in HNC, the strength of evidence for the manuscript is incomplete. The patient cohort is very small, with just 10 patients; to establish a significant result the cohort size should be increased. Furthermore, the functional implication of p300 is also to be looked into.

eLife Assessment

In this important study, the authors advance our understanding of copper uptake by chalkophores and their targeted metalloproteins in Mycobacterium tuberculosis. These convincing data demonstrate that chalkophore-acquired copper is solely incorporated into the Mtb bcc:aa3 copper-iron respiratory oxidase under low copper conditions, and that chalkophore-mediated protection of the respiratory chain is critical to Mtb virulence. These findings may be leveraged for drug discovery and will be of broad interest to those studying bacterial pathogenesis.

eLife Assessment

This manuscript reports fundamental discoveries on how necrotic cells contribute to organ regeneration through apoptotic signalling to produce cells with non-lethal apoptotic caspase activity that contribute to the regenerated tissue. These findings will be of broad interest to those who study wound repair and tissue regeneration. The strength of the evidence is solid and has been improved in the revised version.

eLife Assessment

This manuscript establishes a mathematical model to estimate the key parameters that control the repopulation of planarian stem cells after sublethal irradiation as they undergo fate-switching as part of their differentiation and self-renewal process. The findings are valuable for future investigation of stem cell division in planarians. The methods are solid, integrating modeling with perturbations of key transcription factors known to be critical for cell fate decisions, but the authors have only shown that this is the case for a small number of stem cell types.

eLife Assessment

This study provides evidence that single-cell multi-omics profiling can reveal key regulators of HIV-1 persistence and early immune dysregulation, particularly implicating KLF2 and Th17 cells as major players in viral reservoir dynamics. The findings are solid, supported by rigorous integration of scRNA-seq and scATAC-seq data, but are limited by sample size and lack of validation with external datasets. Overall, this work makes a valuable contribution to understanding HIV-1 immune evasion and highlights potential therapeutic targets for reservoir eradication.

eLife Assessment

This valuable study describes a software package in R for visualizing metabolite ratio pairs. The evidence supporting the claims of the authors is solid and broadly supports the authors' conclusions. This work would be of interest to the mass spectrometry community.

eLife Assessment

This study provides valuable information on the single nucleus RNA sequencing transcriptome, pathways, and cell types in pig skeletal muscle in response to conjugated linoleic acid (CLA) supplementation. Based on the comprehensive data analyses, the data are considered compelling and provide new insight into the mechanisms underlying intramuscular fat deposition and muscle fiber remodeling. The study contributes significantly to the understanding of nutritional strategies for fat infiltration in pig muscle.

eLife Assessment

This important study reveals that disrupting fatty acid metabolism in macrophages significantly restricts the growth of Mycobacterium tuberculosis, showing that impaired lipid processing triggers various antimicrobial responses. Overall, the approach is robust, utilizing CRISPR-Cas9 knockout of multiple genes involved in lipid metabolism which yielded convincing data. This work highlights how host lipid metabolism affects the ability of tubercle bacilli to thrive intracellularly, pointing to potential new therapeutic targets.

eLife Assessment

This manuscript establishes a mathematical model to estimate the key parameters that control the repopulation of planarian stem cells after sublethal irradiation as they undergo fate-switching as part of their differentiation and self-renewal process. The findings are important for future investigation of stem cell division in planarians and have implications for analyzing stem cell biology in other systems. The methods are convincing, integrating modeling with perturbations of key transcription factors known to be critical for cell fate decisions, but the authors have only shown that this is the case for a small number of stem cell types.

eLife Assessment

This important and well-written study uses functional neuroimaging in human observers to provide compelling evidence that activity in the early visual cortex is suppressed at locations that are frequently occupied by a task-irrelevant but salient item. This suppression appears to be general to any kind of stimulus and also occurs in advance of any item actually appearing. The work will be of great interest to psychologists and neuroscientists examining attention, perception, learning and prediction.

eLife Assessment

This valuable work presents how PRDM16 plays a critical role during colloid plexus development, through regulating BMP signaling. Solid evidence supports the context-dependent gene regulatory mechanisms both in vivo and in vitro. The work will be of broad interest to researchers working on growth factor signaling mechanisms and vertebrate development.

eLife Assessment

The authors utilize a valuable computational approach to exploring the mechanisms of memory-dependent klinotaxis, with a hypothesis that is both plausible and testable. Although they provide a solid hypothesis of circuit function based on an established model, the model's lack of integration of newer experimental findings, its reliance on predefined synaptic states, and oversimplified sensory dynamics, make the investigation incomplete for both memory and internal-state modulation of taxis.

eLife Assessment

This important study examines the role of pericytes in patterning the zebrafish blood-brain barrier (BBB) and controlling its permeability. Using pdgfrb mutant zebrafish models lacking brain pericytes, the authors report that pericyte-deficient cerebrovasculatures are ill-patterned, yet display unaltered restrictive BBB permeability properties at larval and juvenile stages. More severe phenotypes are detected in adults, with focal leakage sites associated with hemorrhages and aneurysms. Using solid and beautifully documented imaging, the authors suggest that, contrary to the situation described in rodent models, pdgfrb-dependent pericytes are not required to maintain the BBB in the zebrafish brain; these unexpected and intriguing findings reshape our understanding of BBB permeability regulation in vertebrates.

eLife Assessment

This important manuscript proposes a new strategy for the identification of new mechanisms of drug resistance based on SAturated Transposon Analysis in Yeast (SATAY), a powerful transposon sequencing method in Saccharomyces cerevisiae. This method allows us to uncover loss- and gain-of-function mutations conferring resistance to 20 different antifungal compounds. The method is convincing, allowing the authors to identify a novel interaction of chitosan with the cell wall mannosylphosphate, and show that the transporter Hol1 concentrates the novel antifungal ATI-2307 within yeast.

eLife Assessment

This important study seeks to examine the relationship between pupil size and information gain, showing opposite effects dependent upon whether the average uncertainty increases or decreases across trials. Given the broad implications for learning and perception, the findings will be of broad interest to researchers in cognitive neuroscience, decision-making, and computational modelling. Nevertheless, the evidence in support of the particular conclusion is at present incomplete - the conclusions would be strengthened if the authors could both clarify the differences between model-updating and prediction error in their account and clarify the patterns in the data.

eLife Assessment

This important study analyzes a large dataset of Salmonella gallinarum whole-genome sequences and provides findings regarding the population structure of this avian-specific pathogen. The convincing results indicate regional adaptation of the mobilome-driven resistome and a role in the evolutionary trajectory of this pathogen that will interest microbiologists and researchers working on genomics, evolution, and antimicrobial resistance.

eLife Assessment

In this valuable study, Tutak and colleagues set out to identify factors that mediate Repeat Associated Non-AUG (RAN) translation of CGG repeats in the FMR1 mRNA which are implicated in toxic protein accumulation that underpins ensuing neurological pathologies. The authors provide solid evidence that RPS26 may be implicated in mediating the RAN translation of FMR1 mRNA. This article should be of broad interest to researchers in the variety of disciplines including post-transcriptional regulation of gene expression and neurobiology.

eLife Assessment

This valuable study uses a massive and long-term experimental data set to provide solid evidence on how tree diversity affects host-parasitoid communities of insects in forests. The work will be of interest to ecologists working on biodiversity conservation, community ecology, and food webs.

eLife Assessment

This important study provides new insights into the mechanisms that underlie perceptual and attentional impairments of conscious access. The paper presents convincing evidence of a dissociation between the early stages of low-level perception, which are impermeable to perceptual or attentional impairments, and subsequent stages of visual integration which are susceptible to perceptual impairment but resilient to attentional manipulations. This study will be of interest to scientists working on visual perception and consciousness.

eLife Assessment

This important manuscript sets out to identify sleep/arousal phenotypes in larval zebrafish carrying mutations in Alzheimer's disease (AD)-associated genes. The authors provide detailed phenotypic data for F0 knockouts of each of 7 AD-associated genes and then compare the resulting behavioral fingerprints to those obtained from a large-scale chemical screen to generate new hypotheses about underlying molecular mechanisms. The data presented are solid, although extensive interpretation of pharmacological screen data does not necessarily reflect the limited mechanistic data. Nonetheless, the authors address most reviewer concerns in their revised version, providing invaluable new analyses. Phenotypic characterization presented is comprehensive, and the authors develop a well-designed behavioral analysis pipeline that will provide considerable value for zebrafish neuroscientists.

eLife Assessment

This study examined how multidimensional social relationships influence social attention in rhesus macaques, linking individual and group-level behaviors to attentional processes. The findings that oxytocin altered social attention and its relationship to both social tendencies and dyadic relationships are important, as recent technological advances allow for the exploration of neuronal activities and mechanisms in free-moving macaques. This work is convincing and will be of interest to those studying the interplay between social dynamics and information processing in primates.

eLife Assessment

This study reveals a novel mechanism of glutamine synthetase (GS) regulation in Methanosarcina mazei, demonstrating that 2-oxoglutarate (2-OG) directly promotes GS activity by stabilizing its dodecameric assembly. Using mass photometry, activity assays, and cryo-electron microscopy, the authors show that GS transitions from a dimeric, inactive form at low 2-OG concentrations to a fully active dodecameric complex at saturating 2-OG levels, highlighting 2-OG as a key effector in C/N sensing. The findings are valuable, supported by solid data, and provide new insights into archaeal GS regulation, though further clarification of interactions with known partners like Glnk1 and sp26 is needed.

eLife Assessment

This important paper reports functional interactions between L1TD1, an RNA binding protein (RBP), and its ancestral LINE-1 retrotransposon which is not modulated at the translational level. The evidence for the association between L1TD1 and LINE-1 ORF1p is solid. The work implies that the transposon-derived RNA binding protein in the human genome can interact with the ancestral transposable element from which this protein was initially derived. This work spurs interesting questions for cancer types, where LINE1 and L1TD1 are aberrantly expressed.

eLife Assessment

The study reports valuable findings from a very rich EEG-fMRI dataset including 107 participants, which was collected during nocturnal naps. The authors link activity in memory-related brain regions (e.g., hippocampus, thalamus, and medial prefrontal cortex), and their functional connectivity, to the occurrence of canonical sleep rhythms, namely spindles and slow oscillations in non-rapid eye movement sleep. This work could contribute to further understanding of sleep neural dynamics, although the evidence for some of the main claims is incomplete at present.

eLife Assessment

The authors use deep mutational scanning to assess the effect of ~6,600 protein-coding variants in MC4R, a G protein coupled receptor associated with obesity. They develop new, more precise approaches to deep mutational scanning, enabling them to probe molecular phenotypes directly relevant to the development of drugs that target this receptor. In this important work, the authors provide compelling evidence that variants impact signaling through MC4R in different ways, that some defective variants are amenable to a corrector drug and that deep mutational scanning data could guide compound optimization.

eLife Assessment

This manuscript describes an important study of the giant virus Jyvaskylavirus. The characterisation presented is compelling. The work will be of interest to virologists working on giant viruses as well as those working with other members of the PRD1/Adenoviridae lineage.

eLife Assessment

This manuscript presents solid evidence suggesting that the loss of ZNRF3 and RNF43, two E3 ubiquitin ligases, leads to dysregulation of EGFR signaling in cancer. The authors propose that EGFR is a direct substrate of ZNRF3/RNF43. While the authors provide immunoprecipitation data showing increased detection of ubiquitinated species, this evidence does not definitively establish that EGFR itself is ubiquitinated by RNF43/ZNRF3. The absence of direct evidence for EGFR ubiquitination is a major limitation, although the findings are useful as they may provide novel insights into the mechanisms underlying EGFR-driven cancers and open new therapeutic avenues.

eLife Assessment

This manuscript presents a clever and powerful approach to examining differential roles of Nav1.2 and Nav1.6 channels in excitability of neocortical pyramidal neurons, by engineering mice in which a sulfonamide inhibitor of both channels has reduced affinity for one or the other channels. Overall, the results in the manuscript are compelling and give important information about differential roles of Nav1.6 and Nav1.2 channels. Activity-dependent inactivation of NaV1.6 was also found to attenuate seizure-like activity in cells, demonstrating the promise of activity-dependent NaV1.6-specific pharmacotherapy for epilepsy.

eLife Assessment

This valuable study provides a novel framework for leveraging longitudinal field observations to examine the effects of aging on stone tool use behaviour in wild chimpanzees. However, the analysis and interpretation are currently incomplete and would benefit from a more robust consideration of additional sources of variance for the data (e.g., foraging ecology, nut and tool properties, etc.). Despite the low sample size of five individuals, this study is of broad interest to ethologists, primatologists, archaeologists, and psychologists.

eLife Assessment

The conclusions of this work are based on valuable simulations of a detailed model of striatal dopamine dynamics. Establishing that a lower dopamine uptake rate can lead to a 'tonic' level of dopamine in the ventral but not dorsal striatum, and that dopamine concentration changes at short delays can be tracked by D1 but not D2 receptor activation, is of value and will be of interest to dopamine aficionados. However, the simulations are incomplete, providing only partial support for the key claims. Several things can be done to strengthen the conclusions, including, for example, but not exclusively, a demonstration of how the results would change as a function of changes in D2 affinity.

eLife Assessment

This valuable study provides convincing evidence that specific proteins on the surface of cancer cells undergo a particular form of recycling and are redirected toward the cell-cell contact with T cells, a type of immune cell. However, the characterization of the consequences of T cell activation resulting from perturbing the recycling pathway is incomplete. Furthermore, relevant literature has not been sufficiently cited.

eLife Assessment

This study presents valuable insights into the role of two proteins, Rab27A and SYTL5, which control vesicle transport and delivery. While the data is clear, the overall evidence is somewhat incomplete. Strengthening the mechanistic aspect would enhance the study, making it of greater interest to cell biologists studying membrane trafficking and mitochondria.

eLife Assessment

This important study characterizes the mechanics and stability of bolalipids from archaeal membranes using molecular dynamics simulations. A mesoscale model of bolalipids is presented and evaluated across a series of membrane configurations. The evidence supporting the conclusions is convincing, demonstrating that mixtures of bolalipids and regular bilayer lipids in archaeal membranes enhance fluidity and stability.

eLife Assessment

This important study explores the commander-independent function of COMMD3-Arf1 in endosomal recycling. The evidence supporting the authors' claims is solid; however, the inclusion of additional validation experiments and control conditions would have further strengthened the study. The findings will be of significant interest to cell biologists working on membrane trafficking.

eLife Assessment

This manuscript makes a valuable contribution to the field by uncovering a molecular mechanism for miRNA intracellular retention, mediated by the interaction of PCBP2, SYNCRIP, and specific miRNA motifs. These findings advance our understanding of RNA-binding protein-mediated miRNA sorting and provide deeper insights into miRNA dynamics. While the conclusions are supported by solid experimental evidence, additional controls and clarification of the precise intracellular interactions would further strengthen the study.

eLife Assessment

This important study explores the conserved role of IgM in both systemic and mucosal antiviral immunity in teleosts, challenging established views on the differential roles of IgT and IgM. The findings have theoretical and practical implications for immunology and aquaculture. However, the strength of the evidence is incomplete due to insufficient validation of the monoclonal antibodies used to deplete IgM, which limits confidence in the main claims. Addressing these methodological weaknesses would significantly enhance the study's impact.

eLife Assessment

This study reveals that PRMT1 overexpression drives tumorigenesis of acute megakaryocytic leukemia (AMKL) and that targeting PRMT1 is a viable approach for treating AMKL. While the evidence, based largely on one cell line, is convincing, further validations in additional experiment settings will solidify the conclusion. These findings have important implications for the treatment of AMKL with PRMT1 over expression in the future.

eLife Assessment

This useful study reports analyses of Neuropixel recordings in the medial prefrontal cortex and hippocampus of rats in a spatial navigation trial, focusing on classifying prefrontal neurons based on SWR modulation and anatomical location. However, the evidence for claims of a clear link between SWR modulation and neuronal encoding, and the evidence for anatomical organization, is currently incomplete. Further analyses might strengthen the evidence for some conclusions, and some of the strong claims of the paper should likely be moderated.

eLife Assessment

Using electrophysiological recordings in freely moving rats, this valuable study investigates the role of different gamma frequency bands in the development of spatial representations in the hippocampus. Solid evidence supports the idea that gamma-modulated neurons are crucial for generating specific neuronal sequences. These findings will be of interest to neuroscientists studying spatial navigation and neuronal dynamics.

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 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.