eLife Assessment

This work presents an important method for depleting ribosomal RNA from bacterial single-cell RNA sequencing libraries, enabling the study of cellular heterogeneity within microbial biofilms. The approach convincingly identifies a small subpopulation of cells at the biofilm's base with upregulated PdeI expression, offering invaluable insights into the biology of bacterial biofilms and the formation of persister cells. Further integrated analysis of gene interactions within these datasets could deepen our understanding of biofilm dynamics and resilience.

eLife Assessment

This work presents an important method for depleting ribosomal RNA from bacterial single-cell RNA sequencing libraries, enabling the study of cellular heterogeneity within microbial biofilms. The approach convincingly identifies a small subpopulation of cells at the biofilm's base with upregulated PdeI expression, offering invaluable insights into the biology of bacterial biofilms and the formation of persister cells. Further integrated analysis of gene interactions within these datasets could deepen our understanding of biofilm dynamics and resilience.

eLife Assessment

This study presents a useful theoretical model of molecular evolution and attempts to use it to resolve the paradox of rapid evolution of ribosomal RNA genes. While intuitive, the model's underlying issue is grouping many factors under "variance in reproductive success" without explicitly modeling the molecular processes. This limitation, along with insufficient consideration of technical challenges in alignment and variants calling, provides incomplete support for the authors' claim that the observed paradoxical patterns in rRNA genes can largely be explained by homogenizing processes, such as gene conversion, unequal crossover and replication slippage.

eLife Assessment

This is a valuable study on the diffusion rates of drug molecules in human-derived cells, presenting convincing data indicating that their diffusion behavior depends on their charged state. It proposes that blocking drug protonation enhances diffusion and fractional recovery, suggesting improved intracellular availability of weakly basic drugs. The findings are significant for drug design and understanding the biophysical behavior of small molecules in cells.

eLife Assessment

This is a useful revised manuscript that shows a set of data including the first cryo-EM structures of human PIEZO1 as well as structures of disease-related mutants in complex with the regulatory subunit MDFIC, which generate different inactivation phenotypes. The molecular basis of PIEZO channel inactivation is of great interest due to its association with several pathologies. This manuscript provides some structural insights that may help to ultimately build a molecular picture of PIEZO channel inactivation. While the structures are of use and clear conformational differences can be seen in the presence of the auxiliary subunit MDFIC, the strength of the evidence supporting the conclusions of the paper, especially the proposed role for pore lipids in inactivation, is incomplete.

eLife Assessment

In this manuscript, Kaplan et al. study mesenchymal Meis2 in whisker formation and the links between whisker formation and sensory innervation. These useful findings analyze the impact of the conditional deletion of Meis2 using the Wnt1 driver on whisker development and their interaction with trigeminal nerves. The evidence supporting the conclusions is incomplete lacking mechanistic links to the phenotype described and detailed information on the methods used to analyze single-cell RNA sequencing data. The work will be of interest to developmental and skin biologists.

eLife assessment

The work introduces a valuable new method for depleting the ribosomal RNA from bacterial single-cell RNA sequencing libraries and shows that this method is applicable to studying the heterogeneity in microbial biofilms. The evidence for a small subpopulation of cells at the bottom of the biofilm which upregulates PdeI expression is solid. However, more investigation into the unresolved functional relationship between PdeI and c-di-GMP levels with the help of other genes co-expressed in the same cluster would have made the conclusions more significant.

eLife Assessment

The paper reports the important discovery that the mouse dorsal inferior colliculus, an auditory midbrain area, encodes sound location. The evidence supporting the claims is solid, being supported by both optical and electrophysiological recordings. The observations described should be of interest to auditory researchers studying the neural mechanisms of sound localization and the role of noise correlations in population coding.

eLife Assessment

This useful study investigates the impact of disrupting the interaction of RAS with the PI3K subunit p110α in macrophage function in vitro and inflammatory responses in vivo. Solid data overall supports a role for RAS-p110α signalling in regulating macrophage activity and so inflammation, however for many of the readouts presented the magnitude of the phenotype is not particularly pronounced. Further analysis would be required to substantiate the claims that RAS-p110α signalling plays a key role in macrophage function. Of note, the molecular mechanisms of how exactly p110α regulates the functions in macrophages have not yet been established.

eLife Assessment

This important study investigates the molecular mechanisms underpinning how the tumor necrosis factor alpha-induced protein (TIPE) regulates aerobic glycolysis to promote tumor growth in melanoma. Convincing data using multiple independent approaches provides new insights into the molecular mechanisms underpinning aerobic glycolysis in melanoma cells. The work will be of interest to biomedical researchers working in cancer and metabolism.

eLife Assessment

The manuscript reports on an important comparison of a range of approved clinical inhibitors for BTK used for the treatment of chronic lymphocytic leukemia (CLL). The authors provide compelling evidence for their claims, using a combination of HDX-MS and NMR spectroscopy. The novelty is that this study also seeks to evaluate resistance mutation bias. The manuscript will be of high interest to scientists working on protein drug interactions.

eLife Assessment

This useful work provides insight into agonist binding to nicotinic acetylcholine receptors, which is the stimulus for channel activation that regulates muscle contraction at the neuromuscular junction. The authors use in silico methods to explore the transient conformational change from a low to high affinity agonist-bound conformation as occurs during channel opening, but for which structural information is lacking owing to its transient nature. The simulations indicating that ligands flip ~180 degrees in the binding site as it transitions from a low to high affinity bound conformation are solid. A limitation is the approximation of binding energies using Poisson-Boltzmann Surface Area and mismatch between calculated and experimental binding energies for two of the four ligands tested. Nonetheless, this work presents an intriguing picture for the nature of a transient conformational change at the agonist binding site correlated with channel opening.

eLife Assessment

Zhang et al. present important findings that reveal a new role for TET2 in controlling glucose production in the liver, showing that both fasting and a high-fat diet increase TET2 levels, while its absence reduces glucose production. TET2 works with HNF4α to activate the FBP1 gene upon glucagon stimulation, while metformin disrupts TET2-HNF4α interaction, lowering FBP1 levels and improving glucose homeostasis. While the results are solid, more details about the mechanisms and methods are needed to strengthen the study's conclusions.

eLife Assessment

Identifying chromatin interactions with high sensitivity and resolution at the genome-wide scale continues to be technically challenging. This study introduces findings based on the improved MNase-based proximity ligation method, MChIP-C, which enables genome-wide measurement of chromatin interactions at single-nucleosome resolution. The evidence presented in this manuscript is convincing, and the technological advancements will be valuable for the study of 3D genome architecture.

eLife Assessment

This important work advances our understanding of DNA methylation and its consequences for susceptibility to DNA damage. This work presents evidence that DNA methylation can accentuate the genomic damage propagated by DNA damaging agents as well as potentially being an independent source of such damage. The experimental results reported are sound but the evidence presented to support the conclusions drawn is incomplete and other interpretations are possible. The work will be of broad interest to biochemists, cell and genome biologists.

eLife Assessment

Ferredoxins are ubiquitous electron transfer proteins that drive essential metabolic processes across all domains of life. This fundamental contribution to the field provides the first description of how specific amino acids, though a series of hydrogen bonds, control the ability of iron-sulfur clusters in ferrodoxins to accept and donate electrons. The evidence supporting the conclusions is compelling as is the combined use of neutron crystallography with X-ray crystallography and classical spectral/redox studies.

eLife Assessment

This manuscript describes valuable new material of small, unusually preserved fossils from deep in the Cambrian of China and argues they represent very early bilaterian animals such as annelids or panarthropods. The authors present convincing evidence of the fossilisation of specimens as microbial pseudomorphs, however, the fossils show few details and it is difficult to assess their affinity. The broader claims made about the timing and nature of the Cambrian explosion are inadequately supported by the material, given that bilaterians were already known to exist during that period.

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 solid to support an interaction between NRL and the DHX9 helicase. However, the evidence for an interaction between the NRL transcription factor and R-loops is less conclusive. The significance of the study could be enhanced by examining the functional role of NRL interactions with R-loops in the developing retina, which would offer new insights into the gene regulatory networks.

eLife Assessment

This study reports an important new scRNAseq atlas of the mouse cranial neural plate during neural induction, patterning, and morphogenesis. The study includes a robust analysis of scRNAseq datasets covering six distinct developmental stages, as well as data describing the global transcriptional response of neural plate cells to a key ventralizing signaling molecule, Sonic Hedgehog. The computational data and validation of gene expression patterns are convincing, making this a helpful resource for investigators studying the early development of the cranial neural plate and cranial mesoderm.

eLife Assessment

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

eLife Assessment

This study represents an important advance in our understanding of how certain inhibitors affect the behavior of voltage gated potassium channels. Robust molecular dynamics simulation and analysis methods lead to a new proposed inhibition mechanism with strength of support being mostly convincing, and incomplete in some aspects. This study has considerable significance for the fields of ion channel physiology and pharmacology and could aid in development of selective inhibitors for protein targets.

eLife Assessment

This is an important study demonstrating the importance of S100A4+ alveolar macrophages in the earlier stages of tumour development and suggesting a role in angiogenesis. As such this solid study is of interest to cancer biologists focused on early tumour development and those interested in the development of therapeutics that may specifically target early cancers.

eLife Assessment

This useful study partially succeeds in providing solid evidence in support of the therapeutic potential of the plant-derived compound eugenol for ameliorating symptoms associated with STZ-induced oxidative stress, identifying Nuclear factor E2-related factor (Nrf2) as a mediator of the effects induced by eugenol. Although the study provides interesting data, there remain concerns associated with the STZ model and the rather superficial mechanistic assessment.

eLife Assessment

This work is important because it elucidates how immune cells migrate across the blood brain barrier. In the revised version of this study, the authors present a convincing framework to visualize, recognize and track the movement of different immune cells across primary human and mouse brain microvascular endothelial cells without the need for fluorescence-based imaging using microfluidic devices. This work will be of interest to the cancer biology, immunology and medical therapeutics fields.

eLife Assessment

This important study describes mRNA shortening during cellular stress and interestingly observes that this shortening is dependent on localization in stress granules. Surprisingly, this mRNA shortening does not appear to require the shortening of poly A tails. These are novel, paradigm-shifting findings, using cutting-edge technologies and convincing data, that should be of broad interest to the RNA community and beyond.

eLife Assessment

This valuable study has the potential to shed mechanistic light on how attention mechanisms that influence competition between multiple visual stimuli are modulated by the relative neural similarity of these stimuli. The study provides convincing data that will also be used for future modeling efforts. The study will be of interest to researchers working on the neural basis of visual attention.

eLife Assessment

This valuable study examines how different exercise training intensities affect intestinal barrier function and gut microbiota composition over a 6-week period in mice. The evidence supporting the main claims about exercise-induced intestinal injury and microbiota changes is solid, featuring comprehensive histological analysis, molecular characterization, and metabolomic profiling, though key mechanistic insights and causal relationships remain to be established. The findings have practical implications for understanding exercise-induced gastrointestinal stress, particularly the observation that daily moderate exercise may be more damaging to intestinal integrity than vigorous exercise with rest days. Additional experimental validation would strengthen these conclusions.

eLife Assessment

This important study provides a comprehensive assessment of mitochondrial function across age and sex in mice. The strength of evidence supporting this resource is compelling, given the exhaustive number of tissues profiled and in-depth analyses performed.

eLife Assessment

This study provides important insights into postnatal lung development and the mechanisms underlying bronchopulmonary dysplasia (BPD), a condition with high morbidity and mortality in newborns. Through the use of neonatal hyperoxia, cell-type-specific inactivation of Tgfbr2, and other injury models, the research focuses on the role of TGF-β signaling in BPD pathogenesis, highlighting impaired myofibroblast proliferation as a key factor. The inactivation of Etc2 in Pdgfra-lineaged cells disrupts myofibroblast cytokinesis, leading to alveolar simplification and reduced cell numbers. The use of transgenic mice and single-cell transcriptomics offers a detailed and high-quality dataset, advancing our understanding of BPD and serving as a invaluable resource for developmental biology and neonatal pulmonary research. The study's comprehensive approach, robust data, and methodological rigor make it a compelling contribution to the field, providing both mechanistic insights and a resource for further research into BPD pathogenesis.

eLife Assessment

This study reveals that the malaria parasite protein PfHO, although lacking typical heme oxygenase activity, is essential for the survival of Plasmodium falciparum. Structural and localization analyses demonstrated that PfHO plays a critical role in maintaining the apicoplast, specifically in gene expression and biogenesis, suggesting an adaptive function for this protein in parasite biology. While the findings convincingly support the authors' claims, further investigation into apicoplast gene expression and the specific function of PfHO remains a future challenge. The topic and results are important and will be of interest to researchers studying various aspects of malaria, Plasmodium physiology, host-pathogen interactions, and heme metabolism.

eLife Assessment

The authors present a critique of current usage of principal component analysis in geometric morphometrics, making a compelling case with benchmark data that standard techniques perform poorly. The work is an important contribution to the field and will hopefully lead to a reassessment of the methodology most scientists in morphometrics currently use. This work challenges a very commonly used analytical approach and is bound to raise some controversy in the community, but the authors' critique is based on a well-founded and well-thought out analysis.

eLife Assessment

The authors examined the evolution of hepatitis C virus (HCV) in a cohort of 14 subjects with recent HCV infections. By using computational methods, they showed that viral fitness declines as the virus mutates to escape the immune response and can rebound later in infection as HCV accumulates additional mutations. The study contributes to an important aspect of viral evolution. The combination of approaches is highly compelling; however, some aspects of the manuscript are incomplete and would greatly benefit from additional revision, mainly to increase their clarity.

eLife Assessment

This manuscript offers an exploration of the immune cells in the oyster Crassostrea gigas, by correlating distinct hemocyte morphotypes with specific single-cell transcriptional profiles. The evidence supporting the conclusion is convincing, deriving from the comprehensive dataset that not only captures unicellular diversity but also associates these cells with distinct immune roles, making it an important resource for the broader research community. There are some concerns on the data presentation that leave some questions.

eLife Assessment

This important study provides evidence for the role of neutrophil extracellular traps in chronic kidney damage (CKD) induced by chemotherapy and suggests a therapeutic approach to mitigate the kidney pathology caused by the NETs. The study utilizes a sound murine in vivo model of CKD with low-dose administration cisplatin and a genetic model for impairment of NET formation by deletion of the enzyme Pad4. In its current form, the study was seen as incomplete as there is not yet formal demonstration of NET production by neutrophils in the model of CKD used. Additionally, the accuracy and clarity of data presentation could be improved.

eLife Assessment

This important study substantially advances our understanding of noncoding somatic mutations by identifying a novel class of mutations that affect 3'UTR polyadenylation signals enriched in tumor suppressor genes in cancer. The evidence supporting the conclusions is convincing, with rigorous statistical analyses. The work will be of broad interest to cancer researchers.

eLife Assessment

This paper presents valuable findings on how autophagosomes are positioned along microtubules for their efficient fusion with lysosomes, providing significant insights into the mechanism. The evidence supporting the conclusions is solid, with high-quality fluorescence microscopy combined with Drosophila genetics. This work will be of broad interest to cell biologists interested in autophagy and related cell biology fields.

eLife Assessment

This study provides valuable evidence indicating that SynGap1 regulates the synaptic drive and membrane excitability of parvalbumin- and somatostatin-positive interneurons in the auditory cortex. Since haplo-insufficiency of SynGap1 has been linked to intellectual disabilities without a well-defined underlying cause, the central question of this study is timely. While in their revision the authors successfully addressed questions related to changes in thalamocortical presynaptic excitability, the support for the authors' conclusions is incomplete as concerns around the interpretability of the spontaneous/mini EPSCs, interpretation of results related to excitability, restriction of anatomical analysis of excitatory synapses to the somatic region, and technical problems regarding phase plots remain unresolved.

eLife assessment

In this valuable study, the authors analyze droplet size distributions of multiple protein condensates and their fit to a scaling ansatz, highlighting that they exhibit features of first- and second-order phase transitions. The experimental evidence is solid, and it prompts further research into the nature of the link between percolation and phase separation.

eLife Assessment

This important work advances our understanding of how memories interact to facilitate or interfere with one another, also informing our understanding of how humans build knowledge. The study provides compelling evidence that semantic relatedness proactively benefits memory using clean experimental design, rigorous statistics, large N samples, and well-characterized stimuli. The study also demonstrates the boundaries of these proactive benefits, showing that when studied items have weaker semantic relationships, proactive interference may be observed. This research will be of interest to memory researchers as well as cognitive psychologists, neuroscientists, and educators more broadly.

eLife Assessment

This study presents a valuable finding about the role of Perk (Protein kinase RNA-like endoplasmic reticulum kinase) and Atf4 (Activating Transcription Factor-4) in the integrated neurodegenerative and regenerative responses following the optic nerve injury. The authors present solid evidence, combining newly generated transcriptomic data with publicly available datasets to strengthen their findings. Despite some limitations in data quality and interpretation, the study is likely to be of interest to researchers studying optic neuropathies and axonal regeneration.

eLife Assessment

The authors are interested in the developmental origin of the neurons of the cerebellar nuclei. In this study, they identify a population of neurons with a specific complement of markers that originate in a distinct location from where cerebellar nuclear precursor cells have been thought to originate that show distinct developmental properties. The discovery of a new germinal zone giving rise to a new population of neurons is an exciting finding, and it enriches our understanding of cerebellar development. The important claims, better explained in the current version, are well supported by solid evidence with the authors using a wide range of technical approaches, including transgenic mice that allow them to disentangle the influence of distinct developmental organizers

eLife Assessment

This study reports a valuable finding for the treatment of colorectal cancer (CRC), as the authors demonstrated that the enzyme CPT1A plays an significant role in the response to radiotherapy in CRC patients. However, the reviewers found that the results presented are still incomplete.

eLife Assessment

This is a valuable study of the physiological mechanisms promoting network activity during fever in the mouse neocortex. Most of the supporting evidence is solid, however, there is incomplete support for the conclusion that the E/I balance is unchanged with temperature.

eLife Assessment

This important study describes a computational tool termed FliSimBA (Fluorescence Lifetime Simulation for Biological Applications), which uses simulations to rigorously assess experimental limitations in fluorescence lifetime imaging microscopy (FLIM), including diverse noise factors, hardware effects, and sensor expression levels. The evidence from simulation and experimental measurements supporting the usefulness of FlimSimBA is solid. The authors may improve the application of the tool to a wide range of biological samples by providing the simulation package, currently in MATLB, in other common languages such as Python, and having better descriptions of the fitting algorithm and model assumptions. The work will interest scientists who wish to perform quantitative FLIM imaging for cells and tissues.

eLife Assessment

In this manuscript, Wang et al describe the identification, and provide initial mechanistic characterization, of a potent probiotic strain with activity against Salmonella enterica infection. The evidence provided is compelling, with multiple and varied methodologies used to support the claims made by the authors. The findings reported are valuable to the probiotic and enteric infection subfields.

eLife Assessment

Huson & Regehr characterize the spiking responses of UBCs to various patterns of synaptic stimulation and dissect the contributions of relevant glutamate receptors to their transformations. This study presents valuable findings describing how trains of mossy fiber stimulation control cerebellar unipolar brush cell discharges. The evidence that UBCs transform signals in diverse ways depending on their complement of AMPA, mGluR1, and mGluR2 receptors is solid.

eLife Assessment

This study provides important morphological observations related to the potential roles of Hebbian plasticity in establishing brain connectivity, by examining synapses formed by functionally distinct groups of retinal ganglion cell (RGC) axons in albino mouse dorsolateral geniculate nucleus (dLGN). Here, inappropriately projecting contralateral RGCs undergo developmental rewiring alongside ipsilateral RGCs, such that Hebbian theory would predict them to have separate synaptic targets. The authors provide compelling support for some presence of Hebbian rewiring, using combined confocal imaging and serial electron microscopy (EM) reconstructions to show that contralateral RGCs form completely segregated synaptic inputs onto islands of dLGN thalamocortical neurons, as well as somewhat segregated synaptic input onto local inhibitory interneurons. These findings will be of interest to researchers studying synaptic connectivity and plasticity during development.

eLife Assessment

This valuable study compares ChIP-seq and ChEC-seq2 techniques to investigate RNA polymerase II (RNAPII) binding patterns in yeast, revealing that ChEC-seq2 captures distinct regulatory events associated with active transcription missed by ChIP-seq. The authors use ChEC-seq2 data to build a stochastic model of RNAPII kinetics, providing convincing new insights into transcription regulation and the role of the nuclear pore complex. The paper highlights the importance of careful methodological comparisons in understanding RNAPII dynamics.

eLife Assessment

This study presents convincing evidence of the role of an intestine-released neuropeptide, FLP-2, in the oxidative stress response of C. elegans, as well as for the neural circuit pathway that regulates its release in response to sensing reactive oxygen species (i.e., H2O2). These valuable results advance the understanding of gut-brain signaling and the neural circuit basis of behavioral responses to stress.

eLife Assessment

This important manuscript describes a creative approach using dual-component gRNAs to create a new class of molecular proximity sensors for genome editing. The authors demonstrate that this tool can be coupled with several different gene editing effectors, showing convincingly that the tool functions as intended. This study not only introduces a first-of-its kind approach, but through careful measurements also enables future further development of the technology.

eLife Assessment

This study is part of an ongoing effort to clarify the effects of cochlear neural degeneration on auditory processing in listeners with normal audiograms. Here the authors provide important new data demonstrating associations between cochlear neural degeneration, non-invasive assays of auditory processing, and speech perception. Based on a cross-species comparison, these findings pose compelling evidence that cochlear synaptopathy is associated with a significant part of hearing difficulties in complex environments for some listeners with normal hearing thresholds, such as older individuals.

eLife Assessment

Although others have proposed that OHC electromotility subserves cochlear amplification by acting as a "fluid pump", and evidence for this has been found using electrical stimulation of excised cochleae, this important study substantially advances our understanding of cochlear homeostasis. This is the first report to test the pumping effect in vivo and consider its implications for cochlear homeostasis and drug delivery. The manuscript provides convincing evidence for OHC-based fluid flow within the cochlea.

eLife Assessment

This study presents valuable findings related to seasonal brain size plasticity in the Eurasian common shrew (Sorex araneus), which is an excellent model system for these studies. The evidence supporting the authors' claims is convincing. However, the authors should be careful when applying the term adaptive to the gene expression changes they observe; it would be challenging to demonstrate the differential fitness effects of these gene expression changes. The work will be of interest to biologists working on neuroscience, plasticity, and evolution.

eLife Assessment

This study used a novel continuous dot motion decision-making task to measure participants' perception and uncertainty/confidence in a social context. The social element is that participants can see another player's responses as well as their own. The study is a useful contribution to social decision-making primarily by introducing a new task and offering solid evidence on how participants are impacted by others' decisions during continuous perceptual choices. The manuscript could be improved through streamlining, more consistent use of terms such as "dyadic" and clarification about the differences between primary uncertainty and metacognitive confidence.

eLife Assessment

This valuable study uses consensus-independent component analysis to highlight transcriptional components (TC) in high-grade serous ovarian cancers (HGSOC). The study presents a convincing preliminary finding by identifying a TC linked to synaptic signaling that is associated with shorter overall survival in HGSOC patients, highlighting the potential role of neuronal interactions in the tumor microenvironment. This finding is corroborated by comparing spatially resolved transcriptomics in a small-scale study; a weakness is in being descriptive, non-mechanistic, and requiring experimental validation.

eLife Assessment

This study presents a valuable finding on the molecular mechanisms that govern GABAergic inhibitory synapse function. The authors propose that Endophilin A1 serves as a novel regulator of GABAergic synapses by acting as a component of the inhibitory postsynaptic density. Although the study employs a variety of approaches to address this question, the current analysis is incomplete and requires further experiments to substantiate the claims fully. The findings are likely to interest a broad audience of scientists focusing on inhibitory synaptic transmission, the excitation-inhibition balance, and its disruption in disorders such as epilepsy.

eLife Assessment

Computational simulation of neuron function depends on a collection of morphological properties and ion channel biophysics. This manuscript introduces DendroTweaks, a useful web application and Python library that, compared to existing modeling tools, eases interactive graphical exploration, development, and validation of single-neuron models. The authors provide a convincing demonstration that their software aids with building intuition and rapid prototyping of biophysical models of neurons, which improves the accessibility of dendritic simulation.

eLife Assessment

This important study addresses the question of how large-scale events such as the COVID-19 pandemic can change peoples' beliefs and their updates. Using a well-validated task, the authors find that belief updating becomes less optimistically biased during COVID-19, compared to prior to it. While they have solid evidence for specific changes of positive learning rates in their RL model and should be commended for more extensive modeling of the task than many previous studies, comprehensive model confusion and recovery analyses could further strengthen their claims by clarifying the specificity of their findings. As with many manipulations outside the experimenters' control, it remains unclear which psychological factor impacted by the pandemic drives the group differences, and sample sizes are by necessity on the smaller side as data cannot readily be acquired.

eLife Assessment

The study presents important findings on inositol-requiring enzyme (IRE1α) inhibition on diet-induced obesity (overnutrition) and insulin resistance where IRE1α inhibition enhances thermogenesis and reduces the metabolically active and M1-like macrophages in adipose tissue. The evidence supporting the conclusions is convincing but can be enhanced with information/data on the validity, specificity, selectivity, and toxicity of the IRE1α inhibitor and supported with more detail on the mechanisms by which adipose tissue macrophages influence adipocyte metabolism. The work will be of interest to cell biologists and biochemists working in metabolism, insulin resistance, and inflammation.

eLife Assessment

This study provides important insights into the question of how interacting brain areas produce behaviour during the execution of a skilled multi-directional reaching task. Using a combination of single neuron and neural population analysis, as well as optogenetic stimulation and computational models, the authors provide solid evidence of an asymmetrical influence between mouse premotor and motor cortex during the execution of a well-practiced behaviour. This asymmetry can only be captured by some but not all population analysis methods, which is a key lesson to the field in and of itself. Analyzing how activity that is shared and private to these areas relates to different aspects of movements, and linking the model predictions to the actual data, would further strengthen this work.

eLife Assessment

This study presents an important finding that ant nest structure and digging behavior depend on ant age demographics for a ground-dwelling ant species (Camponotus fellah). By asking whether ants employ age-polyethism in excavation, the authors address a long-standing question about how individuals in collectives determine the overall state of the task they must perform, and their results may prove to be a key consideration for interpreting results from other studies in the field of social insect behavior. While the experimental evidence that the age of the ants and the group composition affect the digging of tunnels is solid, some of the analyses and modeling are seem superfluous, as they do not further support the results or contribute to a deeper understanding of the system.

eLife Assessment

This important paper takes a novel approach to the problem of automatically reconstructing long-range axonal projections from stacks of images. The key innovation is to separate the identification of sections of an axon from the statistical rules used to constrain global structure. The authors provide convincing evidence that their method is a significant improvement over existing measures in circumstances where the labelling of axons and dendrites is relatively dense, but the robustness to image noise remains to be tested.

eLife Assessment

This study presents a valuable finding that altruistic tendency during moral decision-making is context-dependent (present in the gain domain but absent in the loss domain) and its absence in the loss domain can be restored by the neuropeptide oxytocin. However, the evidence supporting this claim is somewhat incomplete and would benefit from better overall framing and clarity on its approaches. Overall, this study will be of interest to social scientists and neuroscientists who work on moral decision-making and oxytocin.

eLife Assessment

This valuable contribution combines high-resolution histology with magnetic resonance imaging in a novel way to study the organisation of the human amygdala. The main findings convincingly show the axes of microstructural organisation within the amygdala and how they map onto the functional organisation. Overall, the approach taken in this paper showcases the utility of combining multiple modalities at different spatial scales to help understand brain organisation.

eLife Assessment

The focus of this study is the development of a compelling method for analyzing network communication in the brain through an exhaustive computational analysis of virtual lesions. Using human neuroimaging data, the authors identified brain regions that exert the greatest influence over others. These important results revealed the characteristic connectivity profile of such brain regions and provided a network analysis method that will find applicability beyond the datasets used.

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 solid evidence that cortical and STN beta oscillations are sensitive to movement context and may play a role in the coordination of movement redirection.

eLife Assessment

The central claim in this valuable manuscript is that microglia in the PVH sculpt the density of AgRP inputs to the PVH in a spatially restricted manner. The anatomical results are solid but the analysis of how microglia activity affects body weight when lactating dams are fed a high-fat diet is incomplete.

eLife Assessment

This study provides useful information on the potential role of ERbB4 expression in parvalbumin-positive cells on olfactory behaviour and circuit dynamics in the olfactory bulb. The question is timely and novel, and findings could shed light on the critical role that ErbB4 may play in modulating olfactory bulb cell function and olfactory perception. Although the authors use a comprehensive set of experiments for their analysis, the evidence is incomplete as many of the experiments are underpowered and the model for selective knockout of ErbB4 in olfactory parvalbumin cells is not validated.

eLife Assessment

This is a valuable work that convincingly reveals that place cells in the hippocampus that exhibit repeated firing fields incorporate information about non-positional variables in each firing field. They reveal that individual firing fields of a single place cell can exhibit tuning to different head orientations, suggesting hippocampal neurons are flexible in terms of how they incorporate non-positional inputs.

eLife Assessment

This paper reports the synthesis of covalent inhibitors bearing a unique fragment as a protected covalent warhead for irreversible binding to histidine in carbonic anhydrase (CA) enzymes. These findings are important due to the broad utility of the approach for covalent drug discovery applications and could have long-term impacts on related covalent targeting approaches. The data convincingly support the main conclusions of the paper.

eLife Assessment

This important study by Liu and colleagues uses lineage tracing of hematopoietic stem and progenitor cells in situ to infer the clonal dynamics of adult hematopoiesis. The authors apply a new mathematical analysis framework enabling a wider range of clonal estimation and the revised study 1) provides evidence of polyclonal adult hematopoiesis, 2) provides insights on clonal dynamics during fetal liver hematopoiesis, and 3) reveals unexpectedly high polyclonality in a mouse model of bone marrow failure (Fanconi anemia), arguing against the prevalent views of clonal attrition in this context. The evidence in this extensively revised and improved study is compelling, with methods, data and analyses more rigorous than the current state-of-the-art, which will be of broad interest not only to stem cell and developmental biologists working on hematopoiesis, but also to researchers working on other systems.

eLife Assessment

This useful study holds importance within the focused scope of endometriosis treatment, providing initial evidence of a potential new therapeutic target. The strength of the evidence is solid, as the methods, data, and analyses support the authors' conclusions regarding the specific aims. The study provides promising preliminary evidence of KMO implication in endometriosis, but it falls short of establishing a strong rationale for proposing KNS898 as a treatment for endometriosis given the limitations in evidence and mechanistic insights.

eLife Assessment

This study highlights an important discovery: a bacterial pathogen's effector influences plant responses that in turn affect how the leafhopper insect vector for the bacteria is attracted to the plants in a sex-dependent manner. The research is backed by convincing physiological and transcriptome analyses. This study unveils a complex interdependence between the pathogen effector, male leafhoppers, and a plant transcription factor in modulating female attraction to the plant, shedding light on previously unexplored aspects of plant-bacteria-insect interactions.

eLife Assessment

The toxin mycolactone is produced by Mycobacterium ulcerans which is responsible for the Buruli ulcer lesions. The authors performed a valuable study showing the effects of mycolactone on blood vessel integrity. This convincing data provides new therapeutic targets to accelerate the healing of Buruli ulcer lesions.

eLife Assessment

The investigators studied the membrane-targeting sequence (MTS) of bactofilin A (BacA) in Caulobacter crescentus to explore its role in membrane binding and polymerization. They used various techniques, including microscopy, liposome binding assays, and simulations, to show that membrane targeting may be crucial for BacA polymerization. While their findings on membrane association are valuable, the absence of direct polymerization assays and lack of proper controls in some experiments make the study incomplete.

eLife Assessment

This study presents an important finding regarding a significant, understudied question: How does adaptation affect spatial frequency processing in the human visual cortex? Using both psychophysics and neuroimaging the authors conclude that adaptation induces changes in perceived spatial frequency and population receptive field size (pRF) size, depending on the adaptation state. Specifically, adapting to a low spatial frequency increases perceived spatial frequency and results in smaller pRFs, whereas adapting to a high spatial frequency decreases perceived spatial frequency and leads to broader pRFs. These results offer an explanation for previous seemingly conflicting findings regarding the effects of adaptation on size illusions and the evidence is solid; however, including a clear, direct comparison between pRF sizes in the high-adapted and low-adapted conditions would further strengthen the argument.

eLife Assessment

This valuable study investigates how the neural representation of individual finger movements changes during the early period of sequence learning. By combining a new method for extracting features from human magnetoencephalography data and decoding analyses, the authors provide incomplete evidence of an early, swift change in the brain regions correlated with sequence learning, including a set of previously unreported frontal cortical regions. The addition of more control analyses to rule out that head movement artefacts influence the findings, and to further explain the proposal of offline contextualization during short rest periods as the basis for improvement performance would strengthen the manuscript.

eLife Assessment

This study presents valuable insights into the organization of second-order circuits for gustatory neurons, particularly how they integrate opposing taste inputs and the metabolic states that regulate feeding behavior. An elegant, compelling combination of multiple techniques discovered the target neurons for gustatory integration. However, the functional and behavioral evidence for the function of these neurons is incomplete.

eLife Assessment

This study presents an important finding on durotaxis in various amoeboid cells that is independent of focal adhesions. The evidence supporting the authors' claims is compelling. The work will be of interest to cell biologists and biophysicists working on rigidity sensing, the cytoskeleton, and cell migration.

eLife Assessment

This work describes a new software platform for machine-learning-based segmentation of and particle-picking in cryo-electron tomograms. The program and its corresponding online database of trained models will allow experimentalists to conveniently test different models and share their results with others. The paper provides convincing evidence that the software will be valuable to the community.

eLife Assessment

The authors report that a secreted ubiquitin ligase of Shigella, called IpaH1.4, mediates the degradation of a host defense factor, RNF213. The data are solid and represent an important contribution to our understanding of cell-autonomous immunity and bacterial pathogenesis, as they provide new mechanistic insight into how the cytosolic bacterial pathogen Shigella flexneri evades IFN-induced host immunity.

eLife assessment

This fundamental work describes an understudied bird migration pattern using data from an Arctic raptor. With an extensive dataset and comprehensive analyses, the observed pattern is convincing. This study will be of interest to researchers exploring the ecological drivers of bird migration.

eLife Assessment

Treatment of Pseudomonas aeruginosa (PA) infections is challenging because of intrinsic and acquired antibiotic resistance to most antibiotic drug classes. Therefore, by using donor B cells in subjects with cystic fibrosis who undergo intermittent or chronic airway PA infections, the authors aimed to isolate B-cell receptors against PA virulence factors and examined their biological activities. The data are solid and the protective antibodies identified in this study could be useful for protection against PA.

eLife Assessment

This study presents an important finding on durotaxis in various amoeboid cells that is independent of focal adhesions. The evidence supporting the authors' claims is compelling. The work will be of interest to cell biologists and biophysicists working on rigidity sensing, the cytoskeleton, and cell migration.

eLife Assessment

This study presents an important finding on durotaxis in various amoeboid cells that is independent of focal adhesions. The evidence supporting the authors' claims is compelling. The work will be of interest to cell biologists and biophysicists working on rigidity sensing, the cytoskeleton, and cell migration.

eLife Assessment

This manuscript reports important findings on the impact of maternal obesity on offspring metabolism. It presents solid evidence that maternal obesity induces genomic methylation alterations in oocytes, which can be partly transmitted to F2 in females, and that melatonin is involved in regulating the hyper-methylation of high fat diet oocytes by increasing the expression of DNMTs via the cAMP/PKA/CREB pathway. This study would be of interest to biologists in the fields of epigenetics and metabolism.

eLife Assessment

This valuable study advances our understanding of how Nipah virus fusion protein F (NiV-F) organizes into nanoclusters on cell and viral membranes using biochemical and super-resolution microscopy methods. The conclusions are supported by solid evidence and the revision has addressed most of the reviewers' concerns. The relationship between clustering and fusion is of high interest and an interesting hypothesis to continue investigating in future studies.

eLife Assessment

This important work presents a novel approach to infer causal relations in non-stationary time series data. To do so, the authors introduce a novel machine-learning model of Temporal Autoencoders for Causal Inference to identify and measure the direction and strength of time-varying causal interactions. The authors provide solid evidence for their claims through thorough numerical validation and comprehensive exploration of the method on both synthetic and real-world datasets. This is a timely contribution that may have theoretical and practical implications for diverse real-life applications.

eLife Assessment

This study describes the application of machine learning and Markov state models to characterize the binding mechanism of alpha-Synuclein to the small molecule Fasudil. The results suggest that entropic expansion can explain such binding. However, the simulations and analyses in their present form are inadequate.

eLife Assessment

This important manuscript demonstrates that UGGT1 is involved in preventing the premature degradation of endoplasmic reticulum (ER) glycoproteins through the re-glucosylation of their N-linked glycans following release from the calnexin/calreticulin lectins. The authors include a wealth of convincing data in support of their findings, although extending these findings to other types of substrates, such as secreted proteins, could further demonstrate the global importance of this mechanism for protein trafficking through the secretory pathway. This work will be of interest to scientists interested in ER protein quality control, proteostasis, and protein trafficking.

eLife Assessment

This work is an important contribution to understanding the role of FGF signaling in the induction of primitive-like cells in a 2D system of human gastrulation. The authors provide compelling evidence showing that endogenous FGF ligands, acting through FGF receptors localized basolaterally, are determinant in the acquisition of a primitive streak cell fate. These observations will be of broad relevance to the FGF field.

eLife Assessment

The study provides valuable findings regarding the identification of a new bacteriophage that uses the Pseudomonas aeruginosa exopolysaccharide Psl as a receptor, thus suggesting a novel approach to control biofilms. While much of the data presented is solid, additional work and clarifications are still required to fully support some of the main claims. This manuscript will interest those working on biofilms, specifically in Pseudomonas, on phage physiology and discovery, and on alternatives to controlling bacterial pathogens.

eLife Assessment

Abdelmageed et al. demonstrate POLK expression in neurons and report an important observation that POLK exhibits an age-dependent change in subcellular localization, from the nucleus in young tissue to the cytoplasm in old tissue. Despite potentially exciting and novel findings, many of the authors' claims are provided with incomplete support (e.g. lack of validation of the POLK antibody, characterization of the subcellular compartment, etc).

eLife Assessment

This valuable study by Ganesh and colleagues examined how both the value and salience of sensory information can affect economic decision-making. The results provide insights into how different sources of uncertainty found in the real world, including those related to the perception of objects and those related to values associated with objects, can together influence decision-making behavior in systematic ways. The evidence is solid but overlaps with previous studies and could be improved by clarifying novelty and experimental details and considering additional models.

eLife Assessment

This important study introduces an approach to discovering antibiotic resistance determinants by leveraging diverse susceptibility profiles among related mycobacterial species, with particular relevance to high-level resistance against natural product-derived antibiotics. The research provides convincing evidence for the role of ADP-ribosylation enzymes in rifamycin resistance among mycobacteria, whilst also demonstrating that antibiotic susceptibility is not correlated with growth rate or intracellular compound concentration. Although some broader claims require additional experimental support, this work lays a significant foundation for understanding the complexity of antibiotic resistance mechanisms in mycobacteria and opens new avenues for future antimicrobial research.

eLife Assessment

This important manuscript provides insights into the competition between Splicing Factor 1 (SF1) and Quaking (QKI) for binding at the ACUAA branch point sequence in a model intron, regulating exon inclusion. The study employs rigorous transcriptomic, proteomic, and reporter assays, with both mammalian cell culture and yeast models. Nevertheless, while the data are convincing, broadening the analysis to additional exons and narrowing the manuscript's title to better align with the experimental scope would strengthen the work.

eLife Assessment

This study presents an important finding on the role of telomeres in modulating interleukin-1 signaling and tumor immunity in TNBC. The evidence supporting these findings is solid, presented through comprehensive analyses including TNBC clinical samples, tumor-derived organoids, cancer cells, and xenografts. The work will be of broad interest to cell and medical biologists focusing on TNBC.

eLife Assessment

This study presents a valuable finding on how the sensorimotor control system deals with redundancy within our body, based on a novel bimanual task. The evidence supporting the authors' claims is convincing, as demonstrated over four different experiments. The work will be of interest to researchers from the motor control community and related fields, and further investigation into the interpretation of the findings could increase the generalisation of the study to a broader audience.

eLife Assessment

The contributions of ipsilateral cortical pathways to motor control are yet not fully understood. Here, the authors present important insights into their role in locomotion following unilateral spinal cord injury. Their data provide convincing evidence in rats that stimulation of ipsilateral motor cortex improves the injured side's ability to support weight and leads to improved locomotion, a result that may inspire new treatments for spinal or cerebral injuries.

eLife Assessment

This study provides convincing evidence for functional subpopulations of β-cells responsible for Ca2+ signal initiation and maintenance using novel three-dimensional light sheet microscopy imaging and analysis of pancreatic islets. The findings are important as they help decode the mechanistic underpinnings of islet calcium oscillations and the resulting pulsatile insulin secretion. The work will be of general interest to cell biologists and of particular interest to islet biologists.

eLife Assessment

The manuscript by Hills, et al. presents data that support multiple conclusions regarding the gene expression patterns of cells, especially chemosensory neurons. The evidence is largely solid, with transcriptomic analysis combined and validated by spatially resolved expression in tissue sections, but is incomplete in other ways with some claims not fully supported. This large-scale single-cell transcriptomics dataset is an important resource, alongside a thorough exploration of the molecular features of the different cell types within the mouse vomeronasal organ, including expression of chemosensory receptors.

eLife Assessment

This valuable study uses fluorescence lifetime imaging and steady-state and time-resolved transition metal ion FRET to characterize conformational transitions in the isolated cyclic nucleotide binding domain of a bacterial CNG channel. The data are compelling and support the authors' conclusions. The results advance the understanding of allosteric mechanisms in CNBD channels and have theoretical and practical implications for other studies of protein allostery. A limitation is that only the cytosolic fragments of the channel were studied.

eLife Assessment

The paper will be of broad interest to fungal biologists and fungal immunologists seeking to understand the biosynthesis of the fungal cell wall, in particular of ß-1,6-glucan synthesis and the importance of this so far understudied constituent of the cell wall for cell wall integrity and immune response. The study is of fundamental significance and adds structural clarity to the genetic, and biochemical basis of this difficult-to-analyze carbohydrate. It opens the potential for understanding its role in immune recognition and potentially as a drug target. Overall, the data is compelling, properly controlled and analyzed.

eLife Assessment

This valuable work presents the latest version of CTFFIND, which is the most popular software for determination of the contrast transfer function (CTF) in cryo-electron microscopy. CTFFIND5 estimates and considers acquisition geometry and sample thickness, which leads to improved CTF determination. The paper describes compelling evidence that CTFFIND5 finds better CTF parameters than previous methods, in particular for tilted samples (e.g. for cryo-electron tomography) or where thickness is an issue (e.g. cellular samples, or electron microscopy at low voltages).

eLife Assessment

This computational study integrates detailed electrophysiology and mechanical contraction predictions, which are often modeled separately. The findings of this important work are that abnormal ECGs that are associated with higher risk of sudden cardiac death are predicted to have almost no relationship with left ventricular ejection fraction, which is conventionally used as a risk factor for arrhythmia. The conclusions are based on compelling evidence for the need of incorporating additional risk factors for assessing post-myocardial infarction patients.

eLife Assessment

This work describes a circadian regulation in the expression of HERP, a regulator of endoplasmic reticulum calcium, in primary astrocytic cultures. This work is important because it highlights the potential importance of circadian rhythms in astrocytes, even though making a direct comparison between these rhythms in vitro and in vivo remains challenging. The technical approaches used in this work (RNA-seq, siRNA, Ca2+ imaging) are a solid support for data interpretation.

eLife Assessment

This valuable study provides solid support for the participation of the BMP-binding domain of MuSK, a tyrosine kinase mostly known for its role at the neuromuscular junction, in the maintenance and activation of muscle stem cells (SCs). These mononucleated cells, located between the muscle fiber basal lamina and its plasma membrane, are normally quiescent, but following muscle damage, become activated, proliferate, and mediate muscle regeneration. These cells are known to respond to a variety of signaling pathways, but this study makes the case for BMP acting via binding to MuSK in maintaining the quiescent state.

eLife Assessment

This valuable study reveals extensive binding of eukaryotic translation initiation factor 3 (eIF3) to the 3' untranslated regions (UTRs) of efficiently translated mRNAs in human pluripotent stem cell-derived neuronal progenitor cells. The authors provide solid evidence to support their conclusions, although this study may be enhanced by addressing potential biases of techniques employed to study eIF3:mRNA binding and providing additional mechanistic detail. This work will be of significant interest to researchers exploring post-transcriptional regulation of gene expression, including cellular, molecular, and developmental biologists, as well as biochemists.

eLife Assessment

The authors use single molecule imaging and in vivo loop-capture genomic approaches to investigate estrogen mediated enhancer-target gene activation in human cancer cells. These potentially important results suggest that ER-alpha can, in a temporal delay, activate a non-target gene TFF3, which is in proximity to the main target gene TFF1, even though the estrogen responsive enhancer does not loop with the TFF3 promoter. To explain these results, the authors invoke a transcriptional condensate model. The reviewers were split on the strength and interpretation of the evidence presented, which is considered incomplete at this stage. We encourage a revision which buttresses the findings with additional control experiments and careful consideration of alternative explanations and mathematical models. Further, the depth of the discussion on existing literature could be improved. This work will be of interest to those studying transcriptional gene regulation and hormone-aggravated cancers.

eLife Assessment

In this manuscript, the authors sought to elucidate mechanistic intricacies of inflammatory responses, with emphasis on T cell dysfunction, to S. aureus-induced pneumonia in the context of aging process using Terc deficient mice. Conceptually, the study is very interesting with a set of useful findings. Although some experimental approaches are appropriate, the work as shown in the revised manuscript remains significantly underpowered and the absence of rigorous controls make this study incomplete in support of its claims.

eLife Assessment

In this useful study, the authors present convincing evidence linking the enzyme D-alanine-D-alanine ligase (Ddl), crucial for cell wall fortification, to organic acid exposure in Staphylococcus aureus. While it's established that organic acids impede bacterial growth, the researchers reveal a novel coping mechanism where S. aureus maintains elevated levels of D-alanine, the substrate for Ddl, to counteract this inhibition. This discovery illuminates a bacterial strategy for organic acid tolerance, offering new insights for microbiologists and potentially informing future antimicrobial approaches.

eLife Assessment

The authors have developed a robust machine learning approach to predict radio sensitivity in patients with NPC based on a defined gene signature. Some key aspects of this signature have been validated in vitro using relevant cell lines which strengthens the conclusions of this important and convincing study. The publication will be of interest to clinicians working on this indication as well as a more broader readership made up of scientists working on radiation biology and those with a bioinformatics/machine learning background.

eLife Assessment

This study represents a potentially useful tool for extracting quantitative data from intravital microscopy directed at in vivo cancer models. In general, this is an area of interest as accessible non-proprietary tools are needed and some evidence of the tool's utility is provided. However, the work in its current form is incomplete as it is heavily reliant on proprietary software to segment, track, and correct the data. In addition, there are significant reservations regarding the methods used to produce statistics in the software, limiting its applicability and the potential advance over other approaches.

eLife Assessment

The study identifies the adhesion G-protein-coupled receptor A3 (ADGRA3) as a potential target for activating adaptive thermogenesis in white and brown adipose tissue, providing valuable information for scientists in the field of adipose tissue biology and metabolism. Although the authors have addressed some concerns raised by reviewers, the interpretations remain somewhat limited, and the work is deemed incomplete. The evidence supporting ADGRA3's role in thermogenesis is insufficient, necessitating more rigorous experiments to validate the receptor's relevance in adipose tissue. Additionally, the lack of experiments using primary cultures, despite feedback from multiple reviewers, highlights significant shortcomings.

eLife Assessment

This manuscript reports important data providing evidence that a 42 amino acid region of Rev7 is necessary and sufficient for interaction with the Rad50-Mre11-Xrs2 complex in budding yeast. The authors conclude that Rev7 inhibits the Rad50 ATPase and the Mre11 nuclease with the exception of ssDNA exonuclease activity. The convincing data largely support the conclusions, although the effect of Rev7 on homologous recombination is less well documented and the observed effect on resection is moderate. Specifically, the result that the Rev7 C-terminal truncation lacking the 42 amino acid region still suppresses homologous recombination is unexpected and unexplained.

eLife Assessment

The authors established a useful syndetome differentiation protocol from human induced pluripotent stem cells, guided by single-cell transcriptomic analysis. Their findings could significantly impact the field, particularly for patients needing tendon cell therapy. However, the evidence presented is currently incomplete, as the authors did not yet test the applicability of their protocol across multiple human induced pluripotent stem cell lines.

eLife Assessment

The study describes a link between beta-amyloid monomers, regulation of microglial activity and assembly of neocortex during development. It brings valuable findings that have theoretical and practical implications in the field of neuronal migration, neuronal ectopia and type II lissencephaly. Unfortunately, the evidence is incomplete and the manuscript would benefit from additional experiments to clarify the relationship between Ric8a and APP and bolster the findings.