eLife assessment

Saijilafu et al. describe that MLCK and MLCP bidirectionally regulate NMII phosphorylation ultimately impinging on axonal growth during regeneration in the central and peripheral nervous systems. However, the evidence is in most cases incomplete, since some key controls are missing, some major claims are too broad to be supported by data and some claims and evidence present internal contradictions. In sum, this knowledge is potentially useful for the field due to the relevance of identifying mechanisms that regulate axonal regeneration, providing some claims inconsistencies are better supported and properly discussed.

eLife assessment

This study presents a useful demonstration that a specific protein fragment may induce the loss of synapses in Alzheimer's disease. The evidence supporting the data is solid but incomplete and would benefit from additional experiments. The application of the findings is limited because blocking the formation of the protein fragment has not benefited patients in several clinical trials.

eLife assessment

Examination of (a)periodic brain activity has gained particular interest in the last few years in the neuroscience fields relating to cognition, disorders, and brain states. Using large EEG/MEG datasets from younger and older adults, the current study provides compelling evidence that age-related differences in aperiodic EEG/MEG signals can be driven by cardiac rather than brain activity. Their findings have important implications for all future research that aims to assess aperiodic neural activity, suggesting control for the influence of cardiac signals is essential.

eLife assessment

This study demonstrates the potential role of 17α-estradiol in modulating neuronal gene expression in the aged hypothalamus of male rats, identifying key pathways and neuron subtypes affected by the drug. While the findings are useful and provide a foundation for future research, the strength of supporting evidence is incomplete due to the lack of female comparison, a young male control group, unclear link to 17α-estradiol lifespan extension in rats, demonstration of physiological effects of the treatment, and insufficient analysis of glial cells and cellular senescence in CRH neurons.

eLife assessment

This study presents a valuable combination of X-ray and cryo-EM structures of the bacterial adhesin PrgB, an atypical microbial cell surface-anchored polypeptide that binds DNA. There is convincing support for the claims regarding the overall function and importance of individual domains. The model for PrgB's binding of eDNA is thought-provoking, but the evidence for it based on low-resolution volumes of cryoEM data is incomplete. If additional experimental evidence for the model is produced, this work will be impactful in the field of bacterial adhesins, conjugation, and biofilm formation, as it focuses on a clinically relevant Gram-positive pathogen, whereas most work in the field has been focused on Gram-negative model systems.

eLife assessment

This valuable work describes a novel role of Vangl2, a core planar cell polarity protein, in mechanistically linking the inflammatory NF-kB pathway to selective autophagic protein degradation. Using solid methods, the authors also establish the functional significance of the proposed mechanism in sepsis. The work may advance our understanding of NF-kB control, particularly in the context of aberrant inflammation. However, some gaps remain, and additional studies are needed to unequivocally establish the role of Vangl2 in regulating NF-kB signaling.

eLife assessment

Tilk and colleagues present a computational analysis of tumor transcriptomes to investigate the hypothesis that the large number of somatic mutations in some tumors is detrimental such that these detrimental effects are mitigated by an up-regulation by pathways and mechanisms that prevent protein misfolding. The authors address this question by fitting a model that explains the log expression of a gene as a linear function of the log number of mutations in the tumor and show that specific categories of genes (proteasome, chaperones, ...) tend to be upregulated in tumors with a large number of somatic mutations. Some of the associations presented could arise through confounding, but overall the authors present solid evidence that mutational load is associated with higher expression of genes involved in mitigation of protein misfolding – an important finding with general implications for our understanding of cancer evolution.

eLife assessment

This important manuscript reveals signatures of co-evolution of two nucleosome remodeling factors, Lsh/HELLS and CDCA7, which are involved in the regulation of eukaryotic DNA methylation. The results suggest that the roles for the two factors in DNA methylation maintenance pathways can be traced back to the last eukaryotic common ancestor and that the CDC7A-HELLS-DNMT axis shaped the evolutionary retention of DNA methylation in eukaryotes. The evolutionary analyses are solid, although more refined phylogenetic approaches could have strengthened some of the claims. Overall, this study could be used by researchers studying DNA methylation pathways in different organisms, and it should be of general interest to colleagues in the fields of evolutionary biology, chromatin biology and genome biology.

eLife assessment

The specific questions taken up for study by the authors – in mice of HDAC and Polycomb function in the context of vascular endothelial cell (EC) gene expression relevant to the blood-brain barrier, (BBB) – are potentially useful in the context of vascular diversification in understanding and remedying situations where BBB function is compromised. The strength of the evidence presented is incomplete, and to elaborate, it is known that the culturing of endothelial cells can have a strong effect on gene expression. This is a significant issue as we are not given how long the cells were cultured and how the above point was addressed.

eLife assessment

This study presents fundamental new insight into the regulatory apparatus of PI3Kγ, a kinase in signaling pathways that control the immune response and cancer. A suite of biophysical and biochemical approaches provide convincing evidence for new sites of allosteric control over enzyme activity. The rigorous findings provide structure and dynamic information that may be exploited in efforts to control PI3Kγ activity in a therapeutic setting.

eLife assessment

This fundamental study has successfully identified four key transcription factors (MECOM, PAX8, SOX17, and WT1) that exhibit synergistic effects and are potentially responsible for the transformation of fallopian tube secretory epithelial cells into high-grade serous 'ovarian' cancer cells. Convincing data strongly support the drawn conclusion and significantly contribute to our understanding of the etiology of this devastating cancer. The implications of this finding are substantial, as it provides molecular insights that can potentially pave the way for innovative diagnostics and therapeutics in the field of gynecological oncology. Enhancing the clarity and impact of this study would be achieved through improvements in data presentation.

eLife assessment

The bacterial neurotransmitter:sodium symporter homoglogue LeuT is an well-established model system for understanding the basis for how human monoamine transporters, such as the dopamine and serotonin, couple ions with neurotransmitter uptake. Here the authors provide convincing data to show that the K+ catalyses the return step of the transport cycle in LeuT by binding to one of the two sodium sites. The paper is an important contribution, but it's still unclear exactly where K+ binds in LeuT, and how to incorporate K+ binding into a transport cycle mechanism.

eLife assessment

There was a range of opinion among three highly expert reviewers from different perspectives in the field. This is a significant topic and it was felt that the contribution at present is valuable to those in the field. However, it was agreed after consultation that the description of the simulation methodology was inadequate.

eLife assessment

This valuable study is of relevance for those interested in mechanism required for infections of humans by Klebsiella pneumoniae. The authors apply TraDIS (high-density TnSeq) to K. pneumoniae with the goal of identifying genes required for survival under various infection-relevant conditions. In general, the evidence supporting the identity of the identified genes is convincing, but testing additional individual genes to validate the list inferred from TraDIS data, in addition to complementing the mutants, would help to provide full support for the claims made. Additional work would also help to unravel novel mechanisms beyond the ones reported.

eLife assessment

This valuable study reports on the structure and function of capsid size-determining external scaffolding protein encoded by a Vibrio phage satellite. The structural work is of high quality and the presented reconstructions are compelling, but some of the experiments could benefit from a more rigorous statistical analysis of capsid sizes and shapes. The paper offers an advance in the field of phage and virus structure and assembly with implications for understanding the evolution of phage satellites.

eLife assessment

This important study illustrates the value of museum samples for understanding past genetic variability in the genomes of populations and species, including those that no longer exist. The authors present genomic sequencing data for the extinct Xerces Blue butterfly and report convincing evidence of declining population sizes and increases in inbreeding beginning 75,000 years ago, which strongly contrasts to the patterns observed in similar data from its closest relative, the extant Silvery Blue butterfly. Such long-term population health indicators may be used to highlight still extant but especially vulnerable-to-extinction insect species – irrespective of their current census population size abundance.

eLife assessment

This paper is a valuable step in multi-subject behavioral modeling using an extension of the Variational Autoencoder (VAE) framework. Using a novel partition of the latent space and in tandem with a recently proposed regularization scheme, the paper provides a rich set of computational analyses analyzing social behavior data of mice with results that represent the state-of-the-art in this subfield. The strength of evidence is convincing, with the methodology being well documented and the results being reproducible, although some additional quantifications would have been helpful to fully gauge the circumstances where the approach would be most effectively applied.

eLife assessment

This article presents important results describing how the gathering, integration, and broadcasting of information in the brain changes when consciousness is lost either through anesthesia or injury. They provide convincing evidence to support their conclusions, although the paper relies on a single analysis tool (partial information decomposition) and could benefit from a clearer explication of its conceptual basis, methodology, and results. The work will be of interest to both neuroscientists and clinicians interested in basic and clinical aspects of consciousness.

eLife assessment

This valuable study focuses on the impact of growth feedback on the performance of artificial gene circuits capable of achieving adaptive responses, a significant problem in synthetic biology. Through solid computational analysis, the authors identify specific failure mechanisms, as well as core topologies associated with robust performance based on systematic analysis of over four hundred circuit topologies. The results will be of interest to those working on engineering gene circuits for diverse applications.

eLife assessment

This paper reports a valuable new set of new results. The main claim is that the projection from adult-born granule cells in the dentate gyrus to the hippocampal subfield CA2 is necessary for the retrieval of social memories formed during development. However, the reviewers agreed that evidence for this major claim is currently incomplete.

eLife assessment

This important study illustrates the value of museum samples for understanding past genetic variability in the genomes of populations and species, including those that no longer exist. The authors present genomic sequencing data for the extinct Xerces Blue butterfly and report convincing evidence of declining population sizes and increases in inbreeding beginning 75,000 years ago, which strongly contrasts to the patterns observed in similar data from its closest relative, the extant Silvery Blue butterfly. Such long-term population health indicators may be used to highlight still extant but especially vulnerable-to-extinction insect species – irrespective of their current census population size abundance.

eLife assessment

This study presents valuable new insights from the protist Tetrahymena regarding radial spokes, conserved protein complexes that are relevant for cilia motility. The work employs interdisciplinary approaches to provide convincing support for radial spoke composition with some experiments, but there are weaker areas with partially incomplete support, such as relying on knockouts alone rather than including localization studies of tagged proteins.

eLife assessment

The demonstration that the PARG dePARylation enzyme is required in S phase to remove polyADP-ribose (PAR) protein adducts that are generated in response to the presence of unligated Okazaki fragments is potentially valuable, but the evidence is incomplete, and identification of relevant PARylated PARG substrates in S-phase is needed to understand the role of PARylation and dePARylation in S-phase progression. Their observation that human ovarian cancer cells with low levels of PARG are more sensitive to a PARG inhibitor, presumably due to the accumulation of high levels of protein PARylation, suggests that low PARG protein levels could serve as a criterion to select ovarian cancer patients for treatment with a PARG inhibitor drug.

eLife assessment:

This valuable study provides molecular-level insights into the functional mechanism of bacterial ice-nucleating proteins, detailing electrostatic interactions in the domain architecture of multimeric assemblies. The evidence supporting the claims of the authors is solid, with results from protein engineering experiments, functional assays, and cryo-electron tomography, while the proposed structural model of protein self-assembly remains hypothetical. The work is of broad interest to researchers in the fields of protein structural biology, biochemistry, and biophysics, with implications in microbial ecology and atmospheric glaciation.

eLife assessment

This is an important study because it provides evidence that specific neuronal firing patterns in deep cerebellar nuclei map onto specific behavioral movement disorder phenotypes. The optogenetic manipulations and resulting neuronal and behavioral outcomes are highly compelling, but the development of the classifier tool was incomplete. This study contributes to the fields of cerebellar physiology and movement disorders because it puts forth a map of relationships between neuronal firing patterns and multiple distinct movement phenomena, providing a comprehensive view that goes beyond most studies which typically examine one phenomenon in isolation.

eLife assessment

This study provides valuable insight into the role of miR-199a/b-5p in cartilage formation. The evidence supporting the significance of the identified miRNA and its target mRNA transcripts is convincing, however further experiments and a broader contextual analysis are warranted to draw a more robust conclusion. This paper will likely primarily benefit scientists focused on diseases related to this biological process, such as osteoarthritis. Furthermore, researchers interested in miRNAs as a broader subject may find the computational model development methodology particularly helpful.

eLife assessment

This fundamental work quantifies the stochastic dynamics of neural population activity in the lateral intraparietal area (LIP) of the macaque monkey brain during single perceptual decisions. These single-trial dynamics have been subject to intense debate in neuroscience, and they have implications for modelling decision-making in various fields including neuroscience and psychology. Through a combination of state-of-the-art recordings from many LIP neurons and theory-driven data analyses, the authors provide solid evidence for the notion that single-trial neural population dynamics in LIP encode the decision variable postulated by the drift-diffusion model of decision-making.

eLife assessment

This study offers a compelling molecular model for the organization of rootlets, a critical organelle that links cilia to the basal body, ensuring proper anchoring. While previous research has explored rootlet structure and organization, this study delivers an unprecedented level of resolution, important to the centrosome and cilia field. The model proposed by the authors will serve as a reference for future studies.

eLife assessment

The authors developed a tool to improve our understanding of tissue-specific activation of Free Fatty Acid receptor 2 (FFA2). Convincing in vitro and in vivo validation of the tool is presented via the development of new antibody reagents that constitute an important advance in the field. Some of the technical details could be presented more clearly.

eLife assessment

This manuscript describes an important web resource for kinases connected to cytokines. The compelling information will be highly used by researchers across a number of fields including analysts, modelers, and wet lab experimentalists – and clinician-researchers – who are looking to improve our understanding of pathologies and means to correct them through modulating the immune response.

eLife assessment

This valuable work by Rivera et al. probes to understand how the regulation of oligodendrocyte progenitor cell (OPC) remyelination and function contributes to the treatment of multiple sclerosis. The authors provide incomplete evidence for the platelets to mediate OPC differentiation and remyelination. Both reviewers have raised significant questions. This work will be of broad interest to biologists in general.

eLife assessment

The authors used ribosome profiling in conjunction with standard biochemical approaches to investigate the role of eIF2A in translation initiation in yeast under optimal growth conditions or stress. The convincing data demonstrate that eIF2A does not play a substantial role in translation initiation in yeast. These important findings challenge the current view that eIF2A substitutes for eIF2 under stress and are thus anticipated to spur future investigation on the role(s) of eIF2A. Considering the broad scope of cellular functions attributed to eIF2A, this study should be of interest to a wide spectrum of biomedical researchers ranging from those studying mechanisms of translation regulation to virologists and cancer biologists.

eLife assessment

This important study proposes a new method for tracking neurons recorded with Neuropixel electrodes across days. The methods and the strength of the evidence are convincing, but the authors do not adequately address whether their approach can be generalized to other brain areas, species, behaviors, or tools. Overall, this method will be potentially of interest to many neuroscientists who want to study long-term activity changes of individual neurons in the brain.

eLife assessment

This important study analyses the role of post-translational modifications of tubulin regulate the function of the microtubule cytoskeleton in vivo? The authors generate a large panel of tubulin mutants designed to lack specific modifications and describe their effects using endogenous editing and touch receptor neurons in C. elegans as an in vivo model. While the work presents an impressive amount of data, it is in part incomplete, since the presence and absence of specific tubulin modifications and their effects on microtubules are not demonstrated in all cases.

eLife assessment

This study presents a valuable finding on the spontaneous emergence of structured activity in artificial neural networks endowed with specific connectivity profiles. The evidence supporting the claims of the authors is potentially solid but still incomplete at this stage, as the authors would ideally demonstrate that similar properties are observed with more diverse inputs and in more complex environments. The work will be of interest to systems and computational neuroscientists.

eLife assessment

The study presents an important ecosystem designed to support literature mining in biomedical research, showcasing a methodological framework that includes tools like Pubget for article collection and labelbuddy for text annotation. The solid evidence presented for these tools suggests they could streamline the analysis and annotation of scientific literature, potentially benefiting research across a range of biomedical disciplines. While the primary focus is on neuroimaging literature, the applicability of these methods and tools might extend further, offering an advance in the practices of meta-research and literature mining.

eLife assessment

This study provides valuable insights into how chromatin-bound PfMORC controls gene expression in the asexual blood stage of Plasmodium falciparum. By interacting with key nuclear proteins, PfMORC is predicted to affect expression of genes relating to host invasion and variable subtelomeric gene families. Correlating transcriptomic data with in vivo chromatin analysis, the study provides convincing evidence for the role of PfMORC in epigenetic transcriptional regulation.

eLife assessment

This important study addresses the question of how wing morphology and kinematics changed as insect species miniaturized. The authors found no significant correlation between body size and wing kinematics across eight hoverfly species, and instead argue that evolutionary changes in wing size and shape enabled flight in smaller species. However, if the integrative approach to animal biomechanics is strong, the evidence supporting the general conclusion that changes in wing morphology, rather than kinematics, correlate with miniaturization is incomplete and would benefit from more detailed biomechanical analysis and improved methods for phylogenetic comparison.

eLife assessment

Bos and colleagues address the question of how two major inhibitory interneuron classes in the neocortex differentially affect cortical dynamics. They perform stability and gain analysis of simplified models with nonlinear transfer functions to show how, under specific conditions, inhibitory modulation can counter-intuitively increase both response gain and circuit stability. This effect depends on the connection strengths within the circuit model, providing valuable guidance as to when and why it arises. Support for the main conclusions is generally solid, but could be strengthened by additional analyses

eLife assessment

This work presents valuable findings that the human frontal cortex is involved in a flexible, dual role in both maintaining information in short-term memory, and controlling this memory content to guide adaptive behavior and decisions. The evidence supporting the conclusions is convincing, with a well-designed task, best-practice decoding methods, and careful control analyses. The work will be of broad interest to cognitive neuroscience researchers working on working memory and cognitive control.

eLife assessment

This work presents some valuable information regarding the molecular mechanisms controlling the regeneration of pancreatic beta cells following induced cell ablation in zebrafish. Specifically, the data suggest that Calcineurin is a regulator of beta cell regeneration. However, the study lacks the critical lineage tracing results to support the conclusion about the origin of the regenerated beta cells and thus is deemed incomplete.

eLife assessment

This valuable study investigates the effect of noncaloric monosaccharides, sugar substitutes that are commonly used by diabetic patients, on angiogenesis in the zebrafish embryo. The authors show that noncaloric monosaccharides and glucose similarly induce excessive blood vessel formation due to the increased formation of tip cells by endothelial cells through the foxo1a-marcksl1a pathway. This solid study is of interest for the medical community in charge of the prevention and of the treatment of diabetes and other metabolic diseases.

eLife assessment

In this important study, Baniulyte and Wade provide solid evidence that translation of a short ORF denoted toiL positioned upstream of the topAI-yjhQP operon is responsive to different ribosome-targeting antibiotics, consequently controlling translation of the TopAI toxin as well as Rho-dependent transcription termination. Strengths of the study include combining a genetic screen to identify 23S rRNA mutations that affect topA1 expression and a creative approach to map the different locations of ribosome stalling within toiL induced by different antibiotics, with ribosome profiling and RNA structure probing by SHAPE to examine consequences of different antibiotics on toiL-mediated regulation. The work could be improved by examining the physiological consequences of topAI-yjhQP activation on antibiotic exposure and by resolving discrepancies between the SHAPE data and the translation rate of toiL.

eLife assessment

This meta-analysis presents valuable findings that reexamine the function of butterfly eyespots in predator avoidance and report for conspicuousness over mimicry. The analysis is robust, but the evidence supporting the importance of conspicuousness is incomplete due to the limitations of the literature, and this debate would benefit from additional experiments that would strengthen these claims. This paper is of interest to evolutionary biologists and ecologists working on the evolution of morphology and predator-prey interactions.

eLife assessment

Bonnifet et al. present data on the expression and interacting partners of the transposable element L1 in the mammalian brain. The work includes important findings addressing the potential role of L1 in aging and neurodegenerative disease. However, several aspects of experimental evidence presented are preliminary and the study remains incomplete in its current form.

eLife assessment

This study provides important computational insights into the dynamics of PROTAC-induced degradation complexes. The findings are solid and hold significant implications for advancing cancer treatments, particularly for breast and prostate cancers. However, the major conclusions of the work could be strengthened with a more thorough analysis. This work will be of broad interest to both biochemists and biophysicists.

eLife assessment

This study presents a valuable finding on the role of the Inferior Colliculus in sensory prediction, cognitive decision-making, and reward prediction. The evidence supporting the claims of the authors is solid. The work will be of interest to neurobiologists working on auditory processing.

eLife assessment

In this report, the authors present valuable findings identifying a novel worm-specific protein (sdg-1) that is induced upon loss of dsRNA import via SID-1, but is not required to mediate SID-1 RNA regulatory effects. The genetic and genomic approaches are well-executed. The existing data are solid, but the study would benefit from additional supporting evidence. The manuscript's central findings could also be refined to avoid overstating the results. These findings will be of interest to those working in the germline epigenetic inheritance field.

eLife assessment

The fruit fly brain hosts neurosecretory neurons (Insulin Producing Cells or IPCs) that integrate many inputs and release insulin directly into the hemolymph. In this fundamental study, the population of IPCs are shown to be heterogeneous in their receptor diversity, exhibiting a range of responses to neuromodulation. The authors convincingly demonstrate, using a battery of experimental techniques and relying on the mapped whole brain connectome, how the heterogeneity in the responses across individual IPCs occur simultaneously and together modulate insulin release to maintain metabolic homeostasis. This work will be of interest to neuroscientists and physiologists, in particular for how cellular diversity results in a better control of homeostasis in short time scales.

eLife assessment

This paper provides a useful analysis of the variation of the burden of strokes across geographic regions, finding differences in the relationship between strokes and their comorbidities. This dataset and the correlations found within will be a resource for directing the focus of future investigations. The results are technically solid, but there are cases where statistical analyses are yet to be carried out to support statements of statistical significance.

eLife assessment

This valuable study, which implicates a specific Wolbachia gene in driving the male-killing phenotype in a moth, contributes to a growing body of literature from the authors in which they have nicely teased apart the loci responsible for male killing across diverse insects. Solid evidence supports the conclusions, though improvements to the statistical analysis for certain assays would strengthen the inferences further.

eLife assessment

This important study advances our understanding of the mechanisms underlying chromatin-mediated gene regulation by SET DOMAIN-CONTAINING PROTEIN 7 (SDG7). The evidence supporting the author's claims – centered on a combination of imaging approaches with molecular and genetic experiments – is convincing, although certain aspects can be improved. The work will be of broad interest to molecular biologists studying epigenetic regulation of gene expression.

eLife assessment

The authors conduct a valuable GWAS meta-analysis for COVID-19 hospitalization in admixed American populations and prioritized risk variants and genes. The evidence supporting the claims of the authors is solid. The work will be of interest to scientists studying the genetic basis of COVID pathogenesis.

eLife assessment

This fundamental study provides convincing evidence for pectin modification as a requirement for RALF peptide signalling altering the apoplastic pH, adding further support for a key role of RALF peptides in linking the assembly and dynamics of the extracellular matrix with cellular activity and function. Data that have been added in comparison to a previous version have enhanced the study. The study should be of interest to anyone studying signaling and specifically to plant cell biologists.

eLife assessment

This valuable study provides new insight into the disassembly of vimentin filaments and the dependence of this mechanism on net charge, albeit with incomplete evidence. In particular, the experimental replicates are limited (in most cases n=1), there is a lack of quantitative analysis to substantiate claims, inconsistency of the proposed mechanisms with previously published work, and lack of biochemical evidence supporting the observations in cells. Addressing these concerns would strengthen the manuscript and help support the proposed hypothesis on vimentin disassembly.

eLife assessment

The fundamental study by Ding and colleagues identifies subpopulations of neurons recorded in the monkey subthalamic nucleus (STN) with distinct activity profiles and causal contributions during perceptual decision-making. The combination of neuronal recording, microstimulation, and computational methods provides convincing evidence for a heterogenous neural population that could support multifaceted roles in decision formation. This study should be of wide interest to computational and experimental neuroscientists interested in cognitive function.

eLife assessment

This paper investigates how isoform II of transcription factor RUNX2 promotes cell survival and proliferation in oral squamous cell carcinoma cell lines. The authors used gain and loss of function techniques to provide incomplete evidence showing that RUNX2 isoform silencing led to cell death via several mechanisms including ferroptosis that was partially suppressed through RUNX2 regulation of PRDX2 expression. The study provides useful insight into the underlying mechanism by which RUNX2 acts in oral squamous cell carcinoma, but the conclusions of the authors should be revised to acknowledge that ferroptosis is not the only cause of cell death.

eLife assessment

Mark and colleagues developed and validated a valuable method for examining subspace generalization in fMRI data and applied it to understand whether the entorhinal cortex uses abstract representations that generalize across different environments with the same structure. Evidence supporting the empirical findings - which show abstract entorhinal representations of hexagonal associative structures across different stimulus sets - is solid but could be further supported through additional analyses, discussion, and clarifications.

eLife assessment

In this important study, the authors have partially revealed the mechanism behind lip thickening in cichlid fishes, which has evolved independently across three lakes in Africa. To explore this phenomenon, the authors utilized histological comparison, proteomics, and transcriptomics, all of which are well suited for their objectives. With convincing evidence, this contribution holds significant value for the field.

eLife assessment

This study presents an interesting mechanism for the regulation of RNA levels, establishing an important regulatory connection between protein arginine methyltransferase 1 and the splicing factor SFPQ. While these findings have theoretical implications beyond a single field, the evidence is incomplete, with only partial support for the main claims.

eLife assessment

This important study shows how a combination of the latest generation of Oxford Nanopore Technology long reads with state-of-the art variant callers enables bacterial variant discovery at an accuracy that matches or exceeds the current "gold standard" with short reads. The work thus heralds a new era, in which Illumina short-read sequencing no longer rules supreme. While the inclusion of a larger number of reference genomes would have enabled an even more fine-grained analysis, the evidence as it is supports the claims of the authors convincingly. The work will be of interest to anyone performing sequencing for outbreak investigations, bacterial epidemiology, or similar studies.

eLife assessment

Notario Manzano et al. offer a valuable first analysis of proteins within tunneling nanotubes (TNTs), membranous bridges connecting cells. This work distinguishes TNTs from extracellular vesicles, but further experimental and analytical tools are needed to refine the TNT proteome. Solid data supports a role for tetraspanins CD9 and CD81 in TNT function. The proposed model for CD9 and CD81 is over-interpreted and requires additional evidence for stronger support.

eLife assessment

This valuable study demonstrates that the behavior of the cells in the presomitic mesoderm in zebrafish embryos depend on both an intrinsic program and external information, providing new insight into the biology underlying embryo axis segmentation. There is convincing support for the findings with a thorough and quantitative single-cell real-time imaging approach, both in vitro and in vivo, developed by the authors.

eLife assessment

This study provides valuable information about the microbiome and metabolome, and their correlation with acute myocardial infarction. However, the relationship established between these variables is limited to a correlation, and therefore the strength of the evidence is incomplete.

eLife assessment

This important study advances our understanding of the mechanisms of neuronal large dense-core vesicle (LDCV) secretion, which mediates neuropeptide and neurotrophin release. It describes a negative regulatory process involving the interaction of the Rab3-effector Rabphilin-3A with the SNARE fusion protein SNAP25, which limits LDCV secretion and neurite growth. The evidence in support of the authors' claims is generally convincing, but some conclusions, e.g regarding the role of Rabphilin-3A-controlled neurotrophin signaling in neurite growth, are incompletely supported. This study will be of interest to the fields of cell biology, cellular neuroscience, and neuroendocrinology.

eLife assessment

This is an important paper on the role of engrams and relevant conditions that influence memory and forgetting. The variety of methods used, namely, behavioural, labeling, interrogation, immunohistochemistry, microscopy, pharmacology, computational, are exemplary and provide convincing evidence for the role of engrams in the dentate gyrus in memory retrieval and forgetting. This examination will be of interest broadly across behavioural and neural science communities.

eLife assessment

This important study evaluates a model for multisensory correlation detection, focusing on the detection of correlated transients in visual and auditory stimuli. Overall, the experimental design is sound and the evidence is compelling. The synergy between the experimental and theoretical aspects of the paper is strong, and the work will be of interest to both neuroscientists and psychologists working in the domain of sensory processing and perception.

eLife assessment

The authors combined neurophysiological (electroencephalography [EEG]) and neurochemical (magnetic resonance spectroscopy [MRS]) measures to empirically evaluate the neural noise hypothesis of developmental dyslexia. Their results are solid, supported by consistent findings from the two complementary methodologies and Bayesian statistics. Additional analyses, particularly on the neurochemical measures, are necessary to further substantiate the results. This study is useful for understanding the neural mechanisms of dyslexia and neural development in general.

eLife assessment

This important work advances our understanding of factors influencing efficacy assessments and biomarker viability for complement-directed gene therapy against age-related macular degeneration. The data presented is convincing and offers insights and teachings for the design of gene therapy and complement-targeted therapeutics in the eye and more broadly for future ocular biomarker studies.

eLife assessment

This study presents a useful approach for revealing large-scale brain attractor dynamics during resting states, task processing, and disease conditions using insights from Hopfield neural networks. The evidence supporting the findings is solid across the many datasets analysed. The work will be of broad interest to neuroscientists using neuroimaging data with interest in computational modelling of brain activity.

eLife assessment:

This valuable study investigates the oscillatory activity of gonadotropin-releasing hormone (GnRH) neurones in mice using GCaMP fiber photometry. It demonstrates three distinct patterns of oscillatory activity that occur in GnRH neurons comprising low-level rapid baseline activity, abrupt short-duration oscillations that drive pulsatile gonadotropin secretion, and, in females, a gradual and prolonged oscillating increase in activity responsible for the relatively short-lived preovulatory LH surge. The evidence presented in the study is solid, offering theoretical implications for understanding the behaviour of GnRH neurones in the context of reproductive physiology, and will be of interest to researchers in neuroendocrinology and reproductive biology.

eLife assessment

Somatostatin-expressing neurons of the entopeduncular nucleus (EPNSst+) co-release GABA and glutamate in their projection to the lateral habenula, a structure that is key for reward-based learning. Combining fiber photometry and computational modeling, the authors provide compelling evidence that EPNSst+ neural activity represents movement, choice direction, and reward outcomes in a probabilistic switching task but, surprisingly, neither chronic genetic silencing of these neurons nor selective elimination glutamate release affected behavioral performance in well-trained animals. This valuable study shows that despite its representation of key task variables, EPNSst+ neurons are dispensable for ongoing performance in a task requiring outcome monitoring to optimize reward. This study will be of interest to those interested in reward learning and/or reward-related behavior and systems or behavioral neuroscience more broadly.

Editors Assessment:

This new software paper presents RiboSnake, a validated, automated, reproducible analysis pipeline implemented in the popular Snakemake workflow management system for microbiome analysis. Analysing16S rRNA gene amplicon sequencing data, this uses the widely used oQIIME2 [ tool as the basis of the workflow as it offers a wide range of functionality. Users of QIIME2 can be overwhelmed by the number of options at their disposal, and this workflow provides a fully automated and fully reproducible pipeline that can be easily installed and maintained. Providing an easy-to-navigate output accessible to non bioinformatics experts, alongside sets of already validated parameters for different types of samples. Reviewers requested some clarification for testing, worked examples and documentation, and this was improved to produce a convincingly easy-to-use workflow. Hopefully opening up an already very established technique to a new group of users and assisting them with reproducible science.

This evaluation refers to version 1 of the preprint

eLife assessment

This important study combines prospective cohort, metabolomics and machine learning to identify a panel of nine circulating metabolites that improved the ability in risk prediction of progression from prediabetes to diabetes. The findings are convincing, and using current state-of-the-art methods the data and analyses support the claims. This paper provides insights into the integration of these metabolites into clinical and public health practice.

eLife assessment

This important study adopts a comprehensive approach: functional connectivity, biochemistry, and psychophysics to reveal a holistic understanding of the relationship between GABA-ergic inhibition in the human MT+ region and visuo-spatial intelligence. The evidence supporting the conclusion is convincing. The result advances our understanding of how the human MT+ is assemble into complex cognition as an intellectual hub, and will be of interest to researchers in psychology, cognitive science, and neuroscience.

eLife assessment

This important study combined multiple approaches to gain insight into why rising estradiol levels, by influencing hypothalamic neurons, ultimately lead to ovulation. The experimental data were robust, but evidence for the conclusion that the findings explain how estradiol acts in the intact female was incomplete because of the lack of experimental conditions that better approximate physiological conditions. This work will be of interest to reproductive biologists working on ovarian biology and female fertility.

eLife assessment

This important study introduces the MRAD database, an advancement in Alzheimer's disease research that provides a powerful tool for evaluating risk and protective factors through Mendelian randomization analysis. The evidence supporting the database's utility is solid, with findings backed by robust data, though addressing methodological concerns and ensuring more rigorous validation of associations would further strengthen its impact. This resource represents a significant leap forward in the field, offering unprecedented opportunities for researchers and clinicians to uncover key insights into Alzheimer's etiology, potentially revolutionizing how Alzheimer's research is approached and accelerating the discovery of new prevention strategies and treatments.

eLife assessment

This useful study focuses on heart failure with preserved ejection fraction (HFpFE), common in patients with HIV. Researchers used induced human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to stimulate HEFpEF) and found that inflammatory cytokines alter Ca2+ transients. SGLT2 inhibitors and mitochondrial antioxidants reversed this effect. While the study is incomplete and preliminary, its strength lies in introducing hiPSC-CMs as a tool for investigating HFpEF mechanisms. A major weakness was found to be limited functional assessment relevant to HFpEF.

eLife assessment

This work by Shin et al. demonstrated that a different form of PTH (R25C PTH) generated a comparable anabolic signal to rhPTH 1-34 using a large animal model. This valuable finding may have therapeutic potential in promoting bone formation or the healing process, and the methods seem solid, although there remains a concern regarding the small sample size and surgical procedure.

eLife assessment

This is a methodologically state-of-the-art systematic review and meta-analysis of studies that addressed the question of whether the administration of multiple antibiotics simultaneously prevents antibiotic resistance development in individuals. The findings are solid. Rather than providing a precise answer, the synthesis of studies eligible for analysis leads to the conclusion that "our analysis could not identify any benefit or harm of using a higher or a lower number of antibiotics regarding within-patient resistance development." This article is important as it articulates the existing knowledge gap, but also serves as an example for careful future use of the meta-analysis methodology, when existing data just don't allow conclusions.

eLife assessment

This study provides direct evidence showing that Kv1.8 channels provide the basis for several potassium currents in the two types of sensory hair cells found in the mouse vestibular system. This is an important finding because the nature of the channels underpinning the unusual potassium conductance gK,L in type I hair cells has been under scrutiny for many years. The experimental evidence is compelling and the analysis is rigorous. The study will be of interest to cell and molecular biologists, and vestibular and auditory neuroscientists.

eLife assessment

This valuable study is a companion to a paper introducing a theoretical framework and methodology for identifying Cancer Driving Nucleotides (CDNs). While the evidence that recurrent SNVs or CDNs are common in true cancer driver genes is solid, the evidence that many more undiscovered cancer driver mutations will have CDNs, and that this approach could identify these undiscovered driver genes with about 100,000 samples, is limited.

eLife assessment

Calcium channels are key regulators of synaptic strength and plasticity. The authors generate new endogenous tags of the Drosophila channel Cac as well as auxiliary subunits to investigate distinct calcium channel functions at the fly NMJ, Is and Ib. They demonstrate functions for voltage-gated calcium channel subunits in promoting synaptic strength, diversity, and plasticity with a series of convincing analyses. The work is important and has broad implications. In addition, the newly developed tools should be quite beneficial for fly biologists.

eLife assessment

Feeding, the circadian rhythm, and the gut microbiota are all intimately linked, motivating new approaches to identify causal relationships while minimizing confounding factors. The authors employ an innovative combination of the stool softener lactulose and a defined 3-member gut microbiota to acutely induce gut bacterial metabolism in mice during the daytime, resulting in changes in the ileal expression of clock genes and altered feeding behavior. Together, this study utilizes solid methods to provide important new insights into the role of gut microbiota in the circadian rhythm, setting the stage for follow-on studies aimed at better understanding the mechanisms responsible.

eLife assessment

This important study examined neuronal activity in the dentate nucleus of the cerebellum when monkeys performed a difficult perceptual decision-making task. The authors provide convincing evidence that the cerebellum represents sensory, motor, and behavioral outcome signals that are sent to the attentional system, but further analysis focusing on the disparity of performance between animals would improve the quality of the paper. This paper is of great general interest in that it shows the involvement of the cerebellum in cognitive processes at the neuronal level.

eLife assessment

How secretion is regulated during cell division and how membrane trafficking factors cooperate with the cytoskeleton during cell division remain poorly understood. In this work the authors find potential direct interactions between the polymeric septin cytoskeleton and the exocyst complex, using fission yeast as a model organism. The work provides a valuable body of new information that will be of great interest to the cell biology community. The evidence is strong and rigorous in many places but is incomplete in other respects.

eLife assessment

This useful study examined the associations of a healthy lifestyle with comprehensive and organ-specific biological ages defined using common blood biomarkers and body measures. Its large sample size, longitudinal design, and robust statistical analysis provide solid support for the findings, which will be of interest to epidemiologists and clinicians.

eLife assessment

The study reports an important finding on the role of the global metabolic regulator Crp/cAMP in the formation of antibiotic persister Escherichia coli. The evidence supporting the claims is solid including metabolomic analysis and characterization of many mutant strains. However, batch culture-based methodologies are unreliable for studying the properties of persister cells that comprise only a fraction of the population and therefore leave the work incomplete.

eLife assessment

This study provides compelling data regarding the molecular characterization of a rare tumor type with few treatment options. This fundamental work significantly advances our mechanistic understanding of solitary fibrous tumours, a critical first step towards targeted precision medicine approaches. The results of this study will be of broad interest to cancer biologists and experimental oncologists.

eLife assessment

This is a useful study that generated a rich inventory of genetic interactions with the potential to produce new insight into the molecular function of Bam-associated proteins. The interactions with genes of unknown function are of special interest as they may suggest experiments to find the functions of these genes. The overall data provided to support their conclusions is solid, but there is a major concern with known polar effects on certain mutations, which should be addressed by complementation.

eLife assessment

This valuable study confirms the roles of Dact1 and Dact2, two factors involved in Wnt signaling, during zebrafish gastrulation and demonstrates their genetic interactions with other Wnt components to modulate craniofacial morphologies. The limitation of the study is that it does not distinguish primary from secondary effects for each factor, precluding an unambiguous interpretation of their roles in craniofacial morphogenesis. The findings of a new potential target of dact1/2-mediated Wnt signaling are potentially of value; however, experimental evidence supporting their functional significance remains incomplete due to inconsistent results and the inherent limitations of the overexpression study.

eLife assessment

This important study utilizes the nematode C. elegans and mammalian cell culture to investigate the role of MML-1/Mondo in conserved regulation of metabolism and aging. The evidence supporting the conclusions is convincing and covers a range of areas including localization, upstream pathways, and conservation. The paper will be of interest to a broad range of biologists studying aging, metabolism, and transcriptional regulation.

eLife assessment

This fundamental study reports the deep evolutionary conservation of a core genetic program regulating spermatogenesis in flies, mice, and humans. Convincing data were presented and supported the main conclusion. This work will be of interest to evolutionary and reproductive biologists.

eLife assessment

This manuscript describes an unexpected role of cellular caspases in cleaving Drp1, a protein involved in mitochondrial fission, in virus-infected cells. Drp1 cleavage augments mitochondrial fission, reinforcing MAVS-dependent type-1 IFN response against multiple viruses. The findings presented in this manuscript are important and the strength of evidence is solid. Additional studies may allow for more robust mechanistic substantiation of the proposed model.

eLife assessment

This important work substantially advances our understanding of sperm motility regulation during fertilization process by uncovering the midpiece/mitochondria contraction associated with motility cessation and structural changes in the midpiece actin network as its mode of action involved. The evidence supporting the conclusion is solid, with rigorous live cell imaging using state-of-art microscopy, although more functional analysis of the midpiece/mitochondria contraction would have further strengthened the study. The work will be of broad interest to cell biologists working on the cytoskeleton, mitochondria, cell fusion, and fertilization.

eLife assessment

This useful study draws on published single-cell and spatial transcriptomic data of colon cancer liver metastasis to clarify the pro- and anti-tumorigenic properties of NK cells. The authors discover increased GZMK+ resting NK cells in the tumor tissue and reduced abundance of KIR2DL4+ activated NK cells. However, the evidence is currently incomplete, as the models used to validate the hypothesis and claims are not adequate and lack the necessary controls.

eLife assessment

This manuscript presents a valuable machine-learning-based approach to the automated detection of urine and fecal deposits by rodents, key ethological behaviors that have traditionally been very poorly studied. The strength of evidence for their claim, however, that the method provides "easy, efficient, and unbiased spatiotemporal analysis of scent marking during behavioral experiments" is incomplete. In particular, there were concerns about the generalizability of the approach, the relatively limited detection capabilities of the method, and a lack of rationale for specific design choices. This manuscript could be of interest to researchers in animal behavior, neuroscience, and automated animal tracking.

eLife assessment

This valuable study presents a machine learning model to recommend effective antimicrobial drugs from patients' samples analysed with mass spectrometry. The evidence supporting the claims of the authors is convincing, although including a measure of statistical significance to compare different proposed models would further strengthen the support. This work will be of interest to computational biologists, microbiologists, and clinicians.

eLife assessment

The study offers a compelling molecular model for the organization of rootlets, a critical organelle that links cilia to the basal body, ensuring proper anchoring. While previous research has explored rootlet structure and organization, this study delivers an unprecedented level of resolution, valuable to the centrosome and cilia field. This research marks a significant step forward in our understanding of rootlets' molecular organization.

eLife assessment

Ctnnb1 encodes β-catenin, an essential component of the canonical Wnt signaling pathway. In this important study, the authors identify an upstream enhancer of Ctnnb1 responsible for the specific expression level of β-catenin in the gastrointestinal track. Deletion of this enhancer in mice and analyses of its association with human colorectal tumors provide compelling support that it controls the dosage of Wnt signaling critical to the homeostasis in intestinal epithelia and colorectal cancers.

eLife assessment

This valuable paper reports a theoretical framework and methodology for identifying Cancer Driving Nucleotides (CDNs), primarily based on single nucleotide variant (SNV) frequencies. A variety of solid approaches indicate that a mutation recurring three or more times is more likely to reflect selection rather than being the consequence of a mutation hotspot. The method is rigorously quantitative, though the requirement for larger datasets to fully identify all CDNs remains a noted limitation. The work will be of broad interest to cancer geneticists and evolutionary biologists.

eLife assessment

Glioblastoma is one of the most aggressive cancers without a cure. Glioblastoma cells are known to have high mitochondrial potential. This useful study demonstrates the critical role of the ribosome-associated quality control (RQC) pathway in regulating mitochondrial membrane potential and glioblastoma growth. Some assays are incomplete; further revision will improve the significance of this study.

eLife assessment

This important study by Lee et al. investigates the heterogeneous response of non-growing bacteria to the antimicrobial peptide (AMP) tachyplesin. In this response, a subpopulation of bacteria limits the accumulation of a fluorescent analog of the AMP, avoiding lethal damage. The study provides compelling data showing the differential accumulation of AMP in subpopulations and its correlation with antimicrobial efficacy. However, the evidence for increased efflux as the main survival mechanism remains incomplete.

eLife assessment

This study provides valuable insights, addressing the growing threat of multi-drug-resistant (MDR) pathogens by focusing on the enhanced efficacy of colistin when combined with artesunate and EDTA against colistin-resistant Salmonella strains. The evidence is solid, supported by comprehensive microbiological assays, molecular analyses, and in vivo experiments demonstrating the effectiveness of this synergic combination. However, the discussion on the clinical application challenges of this triple combination is incomplete, and it would benefit from addressing the high risk associated with using three potential nephrotoxic agents in vivo.

eLife assessment

This study presents valuable findings on how mitochondrial transplantation affects post-cardiac arrest myocardial dysfunction (PAMD). The authors demonstrate that mitochondrial transplantation enhances cardiac function, increases survival rates after the return of spontaneous circulation (ROSC). While the findings are promising, the organization of the paper, along with the analysis and interpretation of the results, are inadequate and need revision.

eLife assessment

This study provides an important advance in the molecular understanding of the lipopolysaccharide export mechanism and machinery in bacteria. By using advanced spectroscopy approaches, the experiments provide convincing biophysical support for the dynamic behavior of the multisubunit Lpt transport system. This work has implications for understanding bacterial cell envelope biogenesis and developing drugs that target Gram negative pathogens.

eLife assessment

This valuable study presents the development of a single turnover stopped-flow fluorescence experiment to study the kinetics of substrate unfolding and translocation by the bacterial ClpB disaggregase. Using non-physiological nucleotides to bypass the physiological regulation mechanism of ClpB, the authors convincingly show that the ClpB disaggregase is a processive motor with a slow unfolding step preceding rapid translocation. The results of this analysis are of value for future mechanistic studies on energy-dependent unfolding, degradation, and disaggregation molecular machines.

eLife assessment

This useful study describes a role for acetylation in controlling the stability of acetyl-CoA synthetase 2, which converts acetate to acetyl-CoA for de novo lipid synthesis. While many aspects of the study are solid, some evidence supporting these findings is incomplete. Including direct demonstration of target deacetylation by sirtuin 2, revisiting statistical analyses, and confirming generalizability to adipocyte cell lines would further strengthen the study. This work will be of interest to researchers studying lipid metabolism and related diseases.

eLife assessment

This study uses ex vivo live imaging of uteri post-mating to test the role of the sperm hook in the house mouse sperm in sperm movement that would be interesting to evolutionary biologists. The significance of the work is useful as live imaging can reveal information not seen in fixed images. The strength of evidence is incomplete as they cannot directly test the role of the sperm hook in facilitating movement along the uterine wall.

eLife assessment

This valuable study combines multidisciplinary approaches to examine the role of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) as a potential novel host dependency factor for Zika virus. The main claims are supported by the data but remain incomplete. The evidence would be strengthened by improving the western blot analyses and adjusting the toning of their claims in relation to the role of IGF2BP2 for viral replication. With the experimental evidence strengthened, this work will be of interest to virologists working on flaviviruses.

eLife assessment

This study provides a valuable strategy for treating mouse cutaneous squamous cell carcinoma (mCSCC) with serum derived from mCSCC-exposed mice. The exploration of serum-derived antibodies as a potential therapy for curing cancer is particularly promising but the study provides incomplete evidence for specific effects of mCSCC-binding serum antibodies. This study will be of interest to scientists seeking a novel immunotherapeutic strategy in cancer therapy.

eLife assessment

The manuscript reports valuable findings by resolving the crystal structure of Sedoheptulose-1,7-Bisphosphatase (SBPase) from the green algae Chlamydomonas reinhardtii, which is involved in the Calvin cycle. The data presented are solid, based on validated methodologies, and they help in understanding the structure and function of this enzyme.

eLife assessment

This potentially important study addresses the effects of aging on the sperm epigenome and its consequences for reproductive health. The evidence supporting the main claim remains incomplete. This study will be of interest to researchers working on aging and reproductive health.

eLife assessment

This important study addresses how 3' splice site choice is modulated by the conserved spliceosome-associated protein Fyv6. The authors provide compelling evidence Fyv6 functions to enable selection of 3' splice sites distal to a branch point and in doing so antagonizes more proximal, suboptimal 3' splice sites. The study would be improved through a more nuanced discussion of alternative possibilities and models, for instance in discussing the phenotypic impact of Fyv6 deletion.

eLife assessment

This valuable study provides integrated analyses of RNA sequencing and mapping data of the m6A RNA modification in the context of unbalanced genomes, using aneuploid Drosophila as a model, and suggests that the dosage compensation complex and m6A act in a feedback loop. The evidence is incomplete due to technical concerns, as quantitative assessments are being made using non-quantitative methods, and the study would be improved by further functional studies. If strengthened, the study will be of interest to RNA and developmental biologists.

eLife assessment

This important work substantially advances our understanding of the molecular mechanisms underlying the timing of the initiation of metamorphosis of the Ciona ascidian tadpole larva. Through the combination of gene knockdown experiments and fluorescent molecular reporters the authors provide compelling evidence about a crosstalk between different G protein mediated signalling pathways and are able to place different signalling molecules within a signalling network. The work will be of interest to molecular, developmental and marine biologists and to scientists working on animal metamorphosis.