Evaluated articles

eLife Assessment

This report explores the role of matrix metalloprotease MMP21 in left-right patterning in Xenopus. Based on a series of compelling experiments, the authors demonstrate that MMP21 can be secreted and acts upstream of dand5 without affecting cilia flow. The experiments are interesting and valuable; however, the claims by the authors lack consideration of other models that could also explain their findings.

eLife Assessment

This important study addresses a topic that is frequently discussed in the literature but is under-assessed, namely correlations among genome size, repeat content, and pathogenicity in fungi. Contrary to previous assertions, the authors found that repeat content is not associated with pathogenicity. Rather, pathogenic lifestyle was found to be better explained by the number of protein-coding genes, with other genomic features associated with insect association status. While the results are considered solid, confidence in the results would be deepened if the authors were to comprehensively account for potential biases stemming from the underlying data quality of the analyzed genomes.

eLife Assessment

This manuscript demonstrates that Oct4 overexpression synergizes with Notch inhibition (Rbpj knockout) to promote the conversion of adult murine Müller glia (MG) into bipolar cells. These findings are important as the authors used rigorous genetic lineage tracing (GLAST-CreER; Sun-GFP) to confirm that neurogenesis indeed originates from MGs, addressing a key issue in the field. The single-cell multiomic analyses are convincing, and while functional studies of MG-derived bipolar cells would strengthen the conclusions, they are beyond the scope of this study.

eLife Assessment

The manuscript presents some useful accounts of experiences funding team projects within the BRAIN Initiative. These would be more appropriate to add to the companion manuscript since the present manuscript contains some overlapping analyses and does not stand well on its own. Therefore the evidence supporting the conclusions is incomplete.

eLife Assessment

The authors provide a useful summary of ten years of Brain Initiative funding including the historical development, the specific funding mechanisms, and examples of grants funded and work produced. The authors also conduct analyses of the impact on overall funding in Systems and Computational Neuroscience, the raw and field normalized bibliographic impact of the work, the social media impact of the funded work, and the popularity of some tools developed. The evidence for impact is incomplete due to the omission of a comparison group of funded grants.

eLife Assessment

This important computational study investigates homeostatic plasticity mechanisms that neurons may employ to achieve and maintain stable target activity patterns. The work extends previous analyses of calcium-dependent homeostatic mechanisms based on ion channel density by considering activity-dependent shifts in channel activation and inactivation properties that operate on faster and potentially variable timescales. The model simulations demonstrate the potential functional importance of these mechanisms, but the evidence is incomplete and would be strengthened by more in-depth analyses and explicit exposition.

eLife Assessment

This fundamental study concerns a model for transgenerational epigenetic inheritance, the learned avoidance by C. elegans of the PA14 pathogenic strain of Pseudomonas aeruginosa. The authors test the impact of procedural alterations made in another study, by Gainey et al., which claimed that transgenerational inheritance in this paradigm lacks robustness, despite this observation having been reported in multiple papers from the Murphy lab. The authors of the present study show that by following a non-standard avoidance protocol, Gainey et al. likely biased their measurements in a way that made it hard to observe learned avoidance. The authors also highlight the importance of bacterial growth conditions, showing that expression of the trigger molecule, the bacterial P11 RNA, which is necessary and sufficient to drive the transgenerational inheritance of the avoidance phenotype, is influenced by temperature. As expression of P11 was not verified by Gainey et al., this provides another explanation for the inability to observe transgenerational epigenetic inheritance. Together, the authors provide compelling and powerful arguments that the original phenomenon is robust and that it can be reproduced in the Murphy lab by following their original protocol precisely, including the use of azide to immobilize the worms at the food source. Overall, this study not only provides guidance for investigators in this experimental paradigm, but it also provides additional understanding of the differences between naïve preference, learned preference, and transgenerational epigenetic inheritance. The present study is therefore of broad interest to anyone studying genetics, epigenetics, or learned behavior.

eLife Assessment

This study provides a novel and critically important insight into the long-term use of DREADDs to modulate neuronal activity in nonhuman primates. The methods are compelling, demonstrating the peak dynamics and the subsequent stability of chemogenetic effects for 1.5 years, informing experimental designs and interpretation of highly impactful chemogenetic studies in macaques. The protocols, data, and outcomes can serve as guidelines for future experiments. Therefore, the findings will be of significant interest to the field of chemogenetics and may also be of broader interest to researchers and clinicians who seek to utilize viral vectors and/or related genetic technologies.

eLife Assessment

This valuable study combines real-time keypoint tracking with transdermal activation of sensory neurons to investigate sensory neuron recruitment in freely moving mice, and builds on the authors' prior work in stationary mice. The evidence supporting the utility of the system is solid, although a more thorough classification of the behavioral responses to nociceptor stimulation would strengthen the work. Importantly, future analyses could include other cutaneous sensory neuron subtypes, and could also be adapted for studying more complex behaviors. The work will be of interest to sensory biologists and pain researchers.

eLife Assessment

This manuscript by Kaur et al. identifies differential gene expression observed in distinct mouse lung cell populations, namely myeloid and lymphoid cells, upon short-term exposure to e-cig aerosols with various flavors. Their findings are potentially useful because the single-cell sequencing data provides a reference for future studies of genes and cellular pathways that are most affected by e-cig aerosols and their components. However, the evidence is incomplete due to limited statistical analyses and few biological replicates, as well as a lack of experimental validation.

eLife Assessment

This important study suggests that adolescent mice exhibit less accuracy than adult mice in a sound discrimination task when the sound frequencies are very similar. While the evidence supporting this observation is solid, demonstrating that this effect arises from cognitive differences between adolescent and adult mice requires more thorough documentation of task performance, as well as control of impulsivity and baseline licking. The authors should also clarify how difficult and easy trials are interleaved in the task and provide a more comprehensive discussion of the cortical inactivation results in relation to the overall task difficulty.

eLife Assessment

Huang and colleagues examined neural responses in mouse anterior cingulate cortex (ACC) during a discrimination-avoidance task. The authors present useful findings that ACC neurons encode primarily post-action variables over extended periods rather than the outcomes or values of those actions. Though the methodological approach was sound, the evidence ruling out alternative explanations is incomplete and requires substantial control analyses.

eLife Assessment

This valuable study proposes using a rigorous computational model to assess memory deficits in Alzheimer's Disease with the goal of developing an early diagnosis tool for the disease. Using an established mouse model of the disease, the authors studied multiple behavioral tasks and ages with the goal of showing similarities in behavioral deficits across tasks. Using the model, the authors indicate specific deficits in memory (overgeneralization and overdifferentiation) in mice with the transgene for the disease. However, the evidence presented is incomplete as certain concerns remain regarding the interpretation of the behavioral results and the validation of the model fit.

eLife Assessment

This useful study describes a novel method for imaging NAD(P)H fluorescence lifetime and thus metabolic states in the Drosophila brain. These solid findings support recent work demonstrating the importance of energy homeostasis to sustain memory formation and maintenance. Further efforts to demonstrate the adequacy of the statistical methods and the significance of the observed differences in FLIM signals in the α/β KCs would greatly enhance the manuscript. The approach will be helpful for researchers working with systems where genetic manipulation is challenging.

eLife Assessment

This study presents important information about the role of mu opioid receptors in synaptic communication between the medial habenula and the interpeduncular nucleus. The authors provide solid evidence that mu opioid receptor activation has differential effects on glutamate release from substance P neurons and cholinergic neurons, with a canonical reduction in release from the former but a novel increase in release from the latter. They also show that blocking potassium channels can unmask a nicotinic cholinergic synaptic response that is also facilitated by mu opioid receptor activation. This work will be of interest to those studying the interpeduncular nucleus, as well as the larger neuroscience community studying opioids and motivated behavior.

eLife Assessment

The medicinal leech preparation is an amenable system in which to understand the neural basis of locomotion. Here a previously identified non-spiking neuron was studied in leech and found to alter the mean firing frequency of a crawl-related motoneuron, which fires during the contraction phase of crawling. The findings are valuable and the experiments were diligently done and generally solid; however, the presentation could improve. The work could be taken to the next level by further experiments, and by providing more overall context for the study.

eLife Assessment

This study provides proof-of-principle data for the use of trained immunity to modulate macrophage interactions with tumours. The study makes a valuable contribution to the field of trained immunity. However, the study is incomplete without vivo data, which would have made the claims in the paper stronger by providing meaningful context for the in vitro experiments that were conducted.

eLife Assessment

Using fMRI-based pRF mapping, this important study presents a novel method to estimate visual field (VF) and VF loss/or potential restoration, through analysis of contrast sensitivity patterns in the early visual cortex. While the approach is very interesting and the evidence supporting the claims of the authors is solid, some methodological concerns need to be addressed. The work will be of interest to researchers in vision/clinical vision, neuroscience, and brain imaging.

eLife Assessment

This study aims to identify the proteins that compose the electrical synapse, which are much less understood than those of the chemical synapse. The study is useful in terms of both method development and biological advances, as the authors identified more than 50 new proteins and used immunoprecipitation and immunostaining to validate their interaction. However, the current experimental data are considered incomplete, as many key experimental details are missing.

eLife Assessment

This valuable study shows that an odorant that is typically thought of as a repellant actually activates both attractant and repellant olfactory neurons in C. elegans. Solid evidence is provided that nematode worms can integrate signals using different pathways to drive different behavioral responses to the same cue. These findings will be of interest to scientists interested in combinatorial coding in sensory systems.