eLife assessment

This valuable manuscript demonstrates that the glycosyltransferase UGGT slows the degradation of endoplasmic reticulum (ER)-associated degradation substrates through a mechanism involving re-glucosylation of asparagine-linked glycans following release from the calnexin/calreticulin lectins. The evidence supporting this conclusion is solid using genetically-deficient cell models and biochemical methods to monitor the degradation of trafficking-incompetent ER-associated degradation substrates, although the manuscript could be improved through additional studies directed towards defining potential functional differences between UGGT1 and UGGT2 and additional insights into the impact of UGGT on the nature of substrate glycosylation within the ER. This work will be of specific interest to those interested in mechanistic aspects of ER protein quality control and protein secretion.

eLife assessment

The study provides valuable insights into OCD patients' acquisition of automaticity, skill learning, and the impact of intrinsic rewards on action sequence completion. The data provide incomplete evidence for the main claims as it is not clear that the participants' performance on the task meets the criteria for habitual behaviour.

eLife assessment

In this study, Ger and colleagues present a valuable new technique that uses recurrent neural networks to distinguish between model misspecification and behavioral stochasticity when interpreting cognitive-behavioral model fits. Evidence for the usefulness of this technique, which is currently based primarily on a relatively simple toy problem, is considered incomplete but could be improved via comparisons to existing approaches and/or applications to other problems. This technique addresses a long-standing problem that is likely to be of interest to researchers pushing the limits of cognitive computational modeling.

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. The work will be of interest to neuroscientists and psychologists working in the domain of sensory processing and perception.

eLife assessment

This valuable study advances our understanding of the brain nuclei involved in rapid-eye movement (REM) sleep regulation. Using a combination of imaging, electrophysiology, and optogenetic tools, the study provides convincing evidence that inhibitory neurons in the preoptic area of the hypothalamus influence REM sleep. This work will be of interest to neurobiologists working on sleep and/or brain circuitry.

eLife assessment

This important study seeks to advance the current understanding of intergenerational olfactory changes associated with odor-induced fear conditioning in mice. Whilst the overall approach employed by the authors is appropriate and the evidence presented in support of claims is solid, there is general agreement that specific points - particularly the lack of effect in the F1 generation - deserve further attention.

eLife assessment

This useful study explores how archerfish adapt their shooting behavior to environmental changes, particularly airflow perturbations. It will be of interest to experts interested in mechanisms for motor learning. While the evidence for an internal model for adaptation is solid, evidence for adaptation to light refraction, as initially hypothesized, is inconclusive. As such, the evidence supporting an egocentric representation might be caused by alternative mechanisms to airflow perturbations.

eLife assessment

This valuable study uses a novel experimental design to elegantly demonstrate how we exploit stimulus structure to overcome working memory capacity limits. While the behavioural evidence is convincing, the neural evidence is incomplete, as it only provides partial support for the proposed information compression mechanism. This study will be of interest to cognitive neuroscientists studying structure learning and memory.

eLife assessment

This is an important theoretical study providing insight into how fluctuations in excitability can contribute to gradual changes in the mapping between population activity and stimulus, commonly referred to as representational drift. The authors provide convincing evidence that fluctuations can contribute to drift. Overall, this is a well-presented study that explores the question of how changes in intrinsic excitability can influence distinct memory representations.

eLife assessment

This study provides important findings based on convincing evidence demonstrating that females and males have different strategies to regulate energy consumption in the brain in the context of low energy intake. While food deprivation reduces energy consumption and visual processing performance in the visual cortex of males, the female cortex is unaffected, likely at the expense of other functions. This study is relevant for scientists interested in body metabolism and neuroscience.

eLife assessment

Zhang et al. deliver an important transcriptomic atlas of the human spinal cord, combining single-cell and spatial transcriptomics to unveil molecular insights. While convincingly overcoming Visium limitations using snRNA-seq, the manuscript is criticized for its largely observational approach and lack of quantitative analysis, especially in supporting claims about sex differences in motor neurons and DRG-spinal cord neuronal interactions.

eLife assessment

This study investigated the factors related to understudied genes in biomedical research. It showed that understudied genes are largely abandoned at the writing stage, and it identified a number of biological and experimental factors that influence which genes are selected for investigation. The study is a valuable contribution to this branch of meta-research, and while the evidence in support of the findings is solid, the interpretation and presentation of the results (especially the figures) needs to be improved.

eLife assessment

This study presents findings on the structure and dynamics of the Type I ABC importer and bacterial osmolarity regulator OpuA, addressing the question of whether the substrate binding domains physically interact in a salt-dependent manner. Based on a collective assessment of the single-molecule fluorescence resonance energy transfer and cryogenic electron microscopy data, the researchers convincingly conclude that the substrate domains directly interact. These findings are valuable and it will be interesting to see if future studies can provide further evidence of this direct interaction and define it in further detail.

eLife assessment

The authors propose that the asymmetric segregation of the NuRD complex in C. elegans is regulated in a V-ATPase-dependent manner, that this plays a crucial role in determining the differential expression of the apoptosis activator egl-1 and that it is therefore critical for the life/death fate decision in this species. The proposed model is interesting and the work could be important if proven correct. However, the current evidence is inadequate to support the major claims.

eLife assessment

The identification of existing and new agents for the treatment of T-cell leukemias is clearly significant to the field of cancer biology and experimental therapeutics. This manuscript identifies an important role of Cannabis based derivatives in the treatment of T-ALL in disease-relevant cell-based and in vivo models of the disease. The work has provided new mechanistic insights into how these drugs are working, with convincing evidence. However, further work to define the exact molecular target of these drugs and expanding the work beyond a limited number of cell lines would strengthen the conclusions and impact of this work.

eLife assessment

This study presents a valuable finding on how the GAP DLC1, a deactivator of the small GTPase RhoA, regulates RhoA activity globally as well as at Focal Adhesions. Using a new acute optogenetic system coupled to a RhoA activity biosensor, the authors present solid evidence that DLC1 amplifies local Rho activity at Focal Adhesions. Nevertheless, the proposed mechanism could be further supported by a deeper analysis of the data.

eLife assessment

This study presents valuable findings characterising the genomic features of E. coli isolated from neonatal meningitis from seven countries, and documents bacterial persistence and reinfection in two case studies. The genomic analyses are solid, although the inclusion of a larger number of isolates from more diverse geographies would have strengthened the generalisability of findings. The work will be of interest to people involved in the management of neonatal meningitis patients, and those studying E. coli epidemiology, diversity, and pathogenesis.

eLife assessment

This work reports a valuable finding on glucocorticoid signaling in male and female germ cells in mice, pointing out sexual dimorphism in transcriptomic responsiveness. The convincing evidence provided supports an inert GR signaling despite the presence of GR in the female germline and GR-mediated alternative splicing in response to dexamethasone treatment in the male germline. The work may interest basic researchers and physician-scientists working on reproduction and stress-related disease conditions.

eLife assessment

This solid study presents a useful dataset regarding chromatin remodeling by the BAF complex in the context of meiotic sex chromosome inactivation. Using knockouts of the BAF complex subunit ARID1A, there appears to be pachynema arrest and a failure to repress sex-linked genes, which is supported by an increase in chromatin accessibility, as assessed by ATAC-seq.

eLife assessment

This manuscript describes rigorous experiments that provide a wealth of virologic, respiratory physiology, and particle aerodynamic data pertaining to aerosol transmission of SARS-CoV-2 between infected Syrian hamsters. The significance of the paper is fundamental because infection is compared between alpha and delta variants, and because viral load is assessed via numerous assays (gRNA, sgRNA, TCID) and in tissues as well as the ambient environment of the cage. The strength of evidence is compelling.

eLife assessment

This study follows the career trajectories of the winners of an early-career funding award in the United States, and finds that researchers with greater mobility, men, and those hired at well-funded institutions experience greater subsequent funding success. Using data on K99/R00 awards from the National Institutes of Health's grants management database, the authors provide compelling evidence documenting the inequalities that shape faculty funding opportunities and career pathways, and show that these inequalities disproportionately impact women and faculty working at particular institutions, including historically black colleges and universities. Overall, the article is an important addition to the literature examining inequality in biomedical research in the United States.

eLife assessment

This study presents a valuable finding on the mechanisms underlying general anesthesia, with a focus on microglial regulation. The evidence supporting the claims of the authors is solid, although some of the novelty of these findings may be reduced based on the recent publication of a similar study. The work will be of interest to medical biologists working on mechanisms of anesthesia, microglia, and neuron-microglia interaction.

eLife assessment

Urtecho et al. use genome-integrated massively parallel reporter assays to catalog and characterize promoters throughout the Escherichia coli genome. The result is a state-of-the-art atlas of promoters, coupled with information on their regulation, that is readily accessible through the website http://ecolipromoterdb.com. This compelling work provides an important resource for researchers studying bacterial transcriptional regulation.

eLife assessment

This paper reports the development of SCA-seq, a new method derived from PORE-C for simultaneously measuring chromatin accessibility, genome 3D and CpG DNA methylation. Most of the conclusions are supported by convincing data. SCA-seq has the potential to become a useful tool to the scientific communities to interrogate genome structure-function relationships.

eLife assessment

The paper addresses the important question of how numerical information is represented in the human brain. Experimental findings are interpreted as providing evidence for a sensorimotor mechanism that involves channels, each tuned to a particular numerical range. However, the logic of the channel concept as employed here, as well as the claims regarding a sensorimotor basis for these channels, is incomplete and thus requires clarification and/or modification.

eLife assessment

The study by Chardon et al. is fundamental to advancing our understanding of presynaptic control of motor neuron output. Large-scale computer simulations were performed using well-established single motor neuron models to provide compelling evidence regarding the time-varying patterns of inputs that control motor neuron ensembles. The work will interest the community of motor control, motor unit physiology, neural engineering, and computational neuroscience.

eLife assessment

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

eLife assessment

The study used slice physiology and modeling to investigate neurotransmitter release at the cerebellar parallel fiber-to-molecular layer interneuron synapse, revealing that each docking site can accommodate up to two synaptic vesicles simultaneously. The evidence presented is convincing. These important findings validate a two-step docking model and shed light on the mechanisms underlying short-term synaptic plasticity and strategies for achieving synaptic reliability, which plays a critical role in information processing in the brain.

eLife assessment

This valuable study combines electrophysiology and neuroanatomy with pharmacological and optogenetic manipulation in the Drosophila genetic model system to pinpoint the neural substrate that is influenced by altered activity during a critical period (CP) of larval locomotor circuit development. Increasing activity during the CP causes permanent network changes, manifesting in increased recovery times from seizures and altered intersegmental coordination during locomotion, thus indicating that a setpoint of network excitability is determined during the CP. Next, compelling experiments demonstrate that this goes along with increased excitation/inhibition ratios to single identified motoneurons and most importantly, for excitability setpoint determination during the CP excitatory and inhibitory inputs are integrated such that the effect of CP hyperexcitation is rescued by the stimulation of endogenous inhibitory inputs to the motoneurons. This provides novel insight into how developing neural network excitability is tuned and how it can be entrained during the CP.

eLife assessment

This valuable manuscript reveals sex differences in bi-conditioning Pavlovian learning and conditional behavior. Males learn hierarchical context-cue-outcome associations more quickly, but females show more stable and robust task performance. These sex differences are related to cellular activation in the orbitofrontal cortex. Although the evidence for the claims is solid, the claim of sex differences in context-dependent discrimination behaviour is not fully supported by the data. Nevertheless, the results will be of interest to many behavioural neuroscientists, particularly those who investigate sex-specific behaviours.

eLife assessment

Identifying chromatin interactions with high sensitivity and resolution remains technically challenging using genome-wide approaches. This study presents findings using the refined MNase-based proximity ligation method called MChIP-C, which allows for the measurement of chromatin interactions at single-nucleosome resolution on a genome-wide scale. Overall, the evidence in this manuscript is solid, and the technological advances will be valuable for the study of 3D genome structure.

eLife assessment

This manuscript is an important contribution, assessing the role of intraspecific consumer interference in maintaining diversity using a mathematical model. Consistent with long-standing ecological theory, the authors convincingly show that predator interference allows for the coexistence of multiple species on a single resource, beyond the competitive exclusion principle. The model matches observed rank-abundance curves in several natural ecosystems. However, a more detailed synthesis of relevant prior studies is needed to clarify the contribution of this manuscript in the context of existing knowledge.

eLife assessment

This fundamental study substantially advances our physical understanding of the sharp increase and saturation of the viscosity of non-confluent tissues with increasing cell density. Through the analysis of a simplified model this study provides compelling evidence that polydispersity in cell size and the softness of cells together can lead to this phenomenon. The work will be of general interest to biologists and biophysicists working on development.

eLife assessment

The authors present a valuable open-source tool for three-dimensional analysis of dissected slices of human brains including 3D reconstruction and high-resolution 3D segmentation. Convincing evidence is provided based on experiments on both real and synthetic data. This tool would be useful to researchers in the neuropathology and neuroimaging field.

eLife assessment

This important work addresses an interesting question for the vertebrate olfactory community of whether mice can discriminate odorant intermittency to help them navigate the environment. The data were collected and analyzed using solid methodology, however, the paper seems to fall short in demonstrating that animal is actually sensitive to intermittency but not other flow parameters. The work will be of interest to researchers working on sensory neurobiology and animal behavior.

eLife assessment

This manuscript describes a valuable new circuit mapping and profiling technique called Multiplexed projEction neuRons retrograde barcodE (MERGEseq) that combines transcriptome and projectome data at a single-cell resolution. The authors provide solid evidence that MERGEseq can be used to identify projection targets and cell type/layer/transcriptome differences of projection neurons in the mouse prefrontal cortex, and validation experiments are rigorous. While this report is a proof-of-principle that MERGEseq is useful for circuit mapping and profiling and many potential details will influence conclusions, this technique could easily be adapted to other regions with known projection targets and adds to a growing arsenal of combinatorial circuit mapping and profiling tools.

eLife assessment

This important study describes an atypical role of the odorant binding protein Obp56g in mating plug formation in Drosophila melanogaster suggesting that Obps may play roles in reproduction in addition to their originally described roles in olfaction. Mutant males lacking Obp56g fail to induce the formation of a mating plug in the female reproductive tract-leading to ejaculate loss and reduced sperm storage. The evidence supporting the claims of the authors is solid and compelling. The work will be of interest to biologists studying Obps and seminal fluid protein function and their evolution.

eLife assessment

This work is relevant to understanding how people represent uncertain events in the world around them and make decisions, with broad applications to economic behavior. It addresses a long-standing empirical puzzle from a novel perspective, where the authors propose that sequential effects in perceptual decisions may emerge from rational choices under cognitive resource constraints rather than adjustments to changing environments. Two new computational models have been constructed to predict behavior under two different constraints, among which the one assuming higher cost for more precise beliefs is better supported by new experimental data. The conclusion may be further strengthened by comparison with alternative models and (optionally) evidence from additional data.

eLife assessment

This important paper provides web based interface for cross-tissue analysis of omics datasets from – so far – two different human populations, with compelling evidence that the tool can be used to make meaningful scientific discoveries. Conceptually, these analyses are relevant for any systems biologist or bioinformatician who is interested in integrating large population datasets. Currently, the resource is already of use for scientists studying the HMDP or using GTEx data, and we hope to see updates in the coming years that incorporate more populations and more datatypes, which could make it a general tool for a wide community.

eLife assessment

This study investigates the presence of DNA adenine methylation (6mA) and the associated function of TET enzyme, a DNA methylation mark eraser, in Drosophila. The study presents valuable findings on the scarcity of 6mA in the Drosophila genome and challenges previous findings regarding the role of TET in 6mA modification. The evidence supporting the claims is solid, and the paper has the potential to stimulate re-evaluations of the significance and regulatory mechanisms of 6mA DNA modifications in Drosophila.

eLife assessment

This fundamental work significantly advances our understanding of the regulation of neurotransmitter and hormone secretion by exploring the mechanisms by which the protein complexin interacts with the release machinery and the calcium sensor synaptotagmin. The authors identify structural requirements within the protein for complexin's dual role in preventing premature vesicle release and enhancing evoked exocytosis. The evidence supporting the author's conclusions is compelling and the findings are of broad interest to neuroscientists and cell biologists.

eLife assessment

In this manuscript, the authors recorded the activity of D1- and D2-MSNs in the dorsal striatum and analyzed their firing activity in relation to single-limb gait in normal and 6-OHDA lesioned mice. This important work extends previous studies showing that the striatum multiplexes various aspects of locomotion, including velocity and movement transitions, by demonstrating that striatal neurons also encode single-limb gait. The authors present solid evidence to show that gait deficits induced by severe unilateral dopamine depletion are associated with an imbalance in the gait-modulation of striatal pathways, however, the reviewers also point out that the evidence supporting the conclusion that striatal neurons encode single-limb gait is incomplete.

eLife assessment

The work addresses an important methodological aspect by optimizing an activity-dependent labelling of neural circuits in behaving flies. The authors provide convincing evidence to support the broad applicability of this method. However, a more comprehensive description of the methodology would greatly enhance its dissemination and adoption. Additionally, the authors successfully implement the method, providing solid evidence for the activity-dependent labelling of P1 neurons during aggression and courtship.

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 appears to affect expression of genes relating to host invasion and subtelomeric var genes. Correlating transcriptomic data with in vivo chromatin insights, the study provides solid evidence for the central role of PfMORC in epigenetic transcriptional regulation through modulation of chromatin compaction.

eLife assessment

The findings presented by Huff and colleagues describe different motor patterns of swallowing following optogenetic activation of the Postinspiratory Complex (PiCo) in a group of mice exposed to Chronic Intermittent Hypoxia (CHI). The presented results are important, and the experimental procedures are rigorous and technically remarkable, but drawing meaningful conclusions is currently not obvious due to some bias in statistical comparisons that require consideration. The strength of the evidence is currently incomplete and would benefit from additional experiments. Overall this work would be of interest to the field of respiratory physiology and pathophysiology since a disruption of swallowing and possibly discoordination with breathing may be involved in diseases characterized by the presence of hypoxic conditions such as obstructive sleep apnea.

eLife assessment

This important study provides convincing evidence of the criticality of estradiol – estrogen receptor-mediated upregulation of kisspeptin within neurons of the preoptic area to generate an ovulation-inducing luteinizing hormone surge. The use of in vivo CRIPSR-Cas9 is novel in this system and provides a road map for future studies in reproductive neuroendocrinology. This paper will be of interest to reproductive neuroscientists and endocrinologists.

eLife assessment

This is an important paper that revises the canonical model of how olfactory sensory neurons choose which odor receptor to express. The data presented in the paper are convincing and the model proposed is provocative and likely to enable future work.

eLife assessment

The authors of this manuscript address the following question in the immunology field: what are the transcriptional regulators that allow macrophages to assume different functional phenotypes in response to immune stimuli? They generate a computational map of the gene regulatory networks involved in determining macrophage phenotypes and experimentally validate the role of putative regulatory factors in a myeloid cell line. This study represents a valuable approach to understanding how gene regulation impacts macrophage polarization but the analyses remain incomplete without further validation in primary cells or by examining the identified genes in the in vivo setting.

eLife assessment

The large-conductance Ca2+ activated K+ channel has been reported to promote breast cancer progression. The present study presents convincing evidence that an intracellular subpopulation of this channel reprograms breast cancer cells towards the Warburg phenotype, one of the metabolic hallmarks of cancer. This important finding advances the field of cancer cell metabolism and has potential therapeutic implications. However, additional experiments are needed to ascribe the metabolic reprogramming to BK channels located in mitochondria.

eLife assessment

This important study reveals the RelA/Stat3-dependent gene program in the liver influences intestinal homeostasis. The evidence supporting the conclusions is compelling, although some additional experiments will strengthen the study. The work will be of interest to scientists in gastrointestinal research fields.

eLife assessment

In this convincing study, the authors examine the interactions between stellate cells and PV+ interneurons in the medial entorhinal cortex, shedding light on the circuit mechanisms that underlie grid cell activity. Huang et al., focus on the spatial distribution of synaptic inputs and report that closely located neuron pairs receive common inputs, suggesting a structured functional organization in the entorhinal cortex. Advanced dual whole-cell patch recordings further reveal patterns of postsynaptic activation, indicating intensive interactions within clusters of these neurons, with weaker interactions between clusters. These important findings offer significant insights into the functional dynamics of the entorhinal cortex.

eLife assessment

This study provides important new insights into how multisensory information is processed in the lateral cortex of the inferior colliculus, a poorly understood part of the auditory midbrain. By developing new imaging techniques that provide the first optical access to the lateral cortex in a living animal, the authors provide convincing in vivo evidence that this region contains separate subregions that can be distinguished by their sensory inputs and neurochemical profiles, as suggested by previous anatomical and in vitro studies. Additional information and analyses are needed, however, to allow readers to fully appreciate what was done, and the comparison of multisensory interactions between awake and anesthetized mice would benefit from being explored in more detail.

eLife assessment

This study reports useful findings on the influence of acute stress on prosocial behavior and its neural correlates. The approach is solid, combining neuroimaging and neuroendocrine measures with computational cognitive modeling. The results will be of interest to researchers seeking to better characterize the influence of stress on neural computations mediating complex social behavior.

eLife assessment

This study by Nandy and colleagues examined relationships between behavioral state, neural activity, and trial-by-trial variability in the ability to detect weak visual stimuli. They present useful findings indicating that certain changes in arousal and eye-position stability, along with patterns of synchrony in the activity of neurons in different layers of cortical area V4, can show modest correspondences to changes in the ability to correctly detect a stimulus. At present, however, the findings are based on data and analyses that are somewhat incomplete but could be improved with further revisions.

eLife assessment

The study by Zhu et al. provides important insights into cell-specific genome-wide histone modifications in the frontal cortex of individuals with schizophrenia, as well as shedding light on the role of age and antipsychotic treatment in these associations. The evidence supporting the conclusions is solid, although more details regarding methodology would be helpful, and the integration of additional data could further enhance the novelty of the study.

eLife assessment

This important study combines experiments and fluid mechanics modeling to determine the mechanism of the ultrafast ejection of the polar tube of the Microsporidia parasite and of transport through this tube. The methods and the analysis, based on the variation of the viscosity of the external medium, are compelling and allow for the first time to discriminate among proposed ejection mechanisms. This approach where simple physical principles are used for distinguishing between mechanisms when the precise geometry is inaccessible through imaging is potentially applicable to other systems in microbiology.

eLife assessment

This interesting and important manuscript combines in vitro and in vivo experiments to investigate the reciprocal regulation between mitochondria-associated membranes and Notch signaling in skeletal muscle atrophy, with implications beyond the single subfield of muscle atrophy. The methods, data, and analyses are solid and broadly support the claims.

eLife assessment

This important study reports the identification of a new amino acid sequence motif (i.e., "internal beta-signal") on outer membrane proteins, which is recognized by beta-assembly machinery in gram-negative bacteria. The authors carried out rigorous experiments, providing compelling evidence in support of their conclusions. This work significantly advances our understanding of the biogenesis of outer membrane proteins.

eLife assessment

This important study examines the effects of prenatal alcohol exposure and maternal diet on offspring DNA methylation, revealing that alcohol can alter epigenetic patterns and impact brain and organ development in the fetus, with some changes preventable by a diet rich in folate and choline. The work identifies several differentially methylated regions linked to adverse health outcomes from alcohol exposure, but the evidence is somewhat incomplete, as the paper currently lacks comprehensive methodological details and sensitivity analyses. Further analysis of the functional relevance of these DNA methylation changes, particularly addressing the current technical and statistical shortcomings, would increase the study's novelty and significance.

eLife assessment

This study presents valuable insights into the epigenetic landscape in adult kidney podocytes. A series of solid experiments demonstrate that genes that are regulated by a key kidney transcription factor, Mafb, are essential for H3K4me3 methylation and recruitment of Wt1 to Nphs1 and Nphs2. This new information provides insights into the potential relationship and coordination of transcription factors in regulating target genes in podocytes in glomerular diseases, although the conclusion that MafB is generally required for Wt1 to bind to podocyte-specific promoters is incomplete and should be extended beyond two or three genes.

eLife assessment

This useful study seeks to address the importance of physical interaction between proteins in higher-order complexes for covariation of evolutionary rates at different sites in these interacting proteins. Following up on a previous analysis with a smaller dataset, the authors provide solid evidence that the exact contribution of physical interactions, if any, remains difficult to quantify. A weakness of the study is that alternative hypotheses, specifically the importance of similar expression levels and patterns of genes that encode interacting proteins -- for which there is already substantial evidence in the literature -- are not sufficiently considered. The work will be of relevance to anyone interested in protein evolution.

eLife assessment

This study provides a valuable resource that documents the protein-protein interactions (PPI) network for alpha-arrestins in both human and Drosophila based on affinity purification/mass spectrometry and the SAINTexpress method followed by a series of bioinformatic and functional assessments. Through these, the authors confirmed the roles of known and novel interactions, including proteins involved in RNA splicing and helicase, GTPase-activating proteins, and ATP synthase. This study represents a convincing example of how to adopt comparative molecular interactions and how to interpret the functional implications.

eLife assessment

This important study identifies the mitotic localization mechanism for Aurora B and INCENP (parts of the chromosomal passenger complex, CPC) in Trypanosoma brucei. The mechanism is different from that in the more commonly studied opisthokonts and there is solid support from RNAi and imaging experiments, targeted mutations, immunoprecipitations with crosslinking/mass spec, and AlphaFold interaction predictions. The results could be strengthened by biochemically testing proposed direct interactions and demonstrating that the targeting protein KIN-A is a motor. The findings will be of interest to parasitology researchers as well as cell biologists working on mitosis and cell division, and those interested in the evolution of the CPC.

eLife assessment

This study presents a useful characterization of mechanisms underlying glycosuria-mediated increase in compensatory glucose production in Glut2 knockout mice. The strength of support is incomplete but the data represent a starting point for further studies regarding the role of the HPA axis and acute phase proteins in regulating blood glucose during glycosuria.

eLife assessment

This important study enhances our understanding of the relationship between metabolic syndrome (MetS) and brain health from two large-scale datasets and crosses different scales of investigation. The results range from solid to inadequate, with the overall effects of MetS on the brain well supported, but the claimed inference of non-fasting blood glucose reflecting insulin resistance and suggestions of causative link to cognitive function need to be revised or tempered. Overall this study will be of great interest to researchers and clinicians seeking to understand metabolic syndrome.

eLife assessment

This manuscript provides a useful reconstruction of the structure of the sirtuin-class histone deacetylase Sirt6 bound to a nucleosome based on cryo-EM observations, and additional characterization of the flexibility of the histone tails in the complex based on molecular dynamics simulations. While similar structures have recently been published, this solid study supports the conclusions of those papers and also includes new insights into the potential dynamics of Sirt6 bound to a nucleosome, insights that help explain its substrate specificity. Unfortunately, the authors do not mention the other recent publications until the end of their Discussion, and therefore provide little opportunity for comparison or context for the results presented.

eLife assessment

This manuscript describes valuable new findings on the impact of chromatin context on the outcomes of microhomology-mediated end joining of DNA double-strand breaks (DSBs), specifically a preference for DSB-proximal microhomologies in repair within a heterochromatic compared to a euchromatic locus. The authors develop the Drosophila spermatogonia as a model for repair at induced DSBs in a mitotically-active tissue and leverage this system to provide convincing evidence that the local environment impacts the preference for repair mechanism and outcome. The work could be strengthened by the use of additional euchromatin insertion(s) to robustly validate the findings.

eLife assessment

This important study combines experiments and mathematical modelling to enhance our understanding of the interplay between the two flight muscles in birds during slow flight. The evidence for the findings is compelling, derived from new methods for measuring wing shape and force production combined with previously validated methods in muscle physiology. This work will be of broad interest to comparative biomechanists.

eLife assessment

This study shows that the yeast transcription factor Sfp1 binds to a subset of its target gene mRNAs, increases their half-lives, and affects RNA polymerase II backtracking. These, and other related findings, provide important new insights into mechanisms by which a transcription factor can affect post-transcriptional steps in gene regulation. The main claims are partially backed by the evidence presented. However, the evidence remains incomplete as the methods used to estimate RNA degradation rates and the biochemistry of Sfp1-RNA complexes require further validation.

eLife assessment

This in principle useful study suggests that the G-protein subunit Gng13 is required for limiting injury and inflammation following H1N1 influenza infection via anti-inflammatory effects from ectopic tuft cells. There appears to be support for Gng13 helping to limit influenza injury in the transgenic mouse models used here, but evidence for these effects being mediated by tuft cells is incomplete, giving conflicting data from mice that lack tuft cells entirely.

eLife assessment

This paper presents what could be a useful approach for association testing, using the output of neural networks that have been trained to predict functional changes from DNA sequences. The approach presented by the author is an interesting addition to statistical genetics. It is, however, unclear whether the method not only detects more associations but also whether the quality of these associations (i.e., the likelihood that they are causal associations) is as good or better than what one finds with conventional methods. The enrichment analyses are encouraging but without rigorous assessment of statistical power and a better understanding of the pitfalls of the method, the evidence for this being an advance that will find application in the field remains incomplete.

eLife assessment

This important study uses a combination of computational modeling and glutamate imaging to show how a particular synaptic organization referred to as space-time wiring contributes minimally to a dendritic computation that occurs in the retina. The evidence supporting the claims of the authors is compelling, incorporating new findings regarding dynamic receptive field properties, an improvement over previous modeling and experimental results based on static visual stimuli. The work will be of interest to retinal neurobiologists and neurophysiologists interested in dendritic computations.

eLife assessment

The work shows that the experimental application of serotonin to locust antennal lobes induces an increased feeding-related response to some odorants (even in food-satiated animals). To explain how the odorant-specific effects are seen despite similar consequences of 5-HT modulation on all projection neuronal types analyses by electrophysiology, the authors propose a simple quantitative model built around PNs with different downstream connections. These convincing observations are useful to guide further studies of serotonin and other modulatory mechanisms in the olfactory system.

eLife assessment

This manuscript provides solid evidence for the involvement of membrane actin, and its regulatory proteins, mDia1/3, RhoA, and Rac1 in the mechanism of synaptic vesicle re-uptake (endocytosis). These valuable data fill a gap in the understanding of how the regulation of actin dynamics and endocytosis are linked. The manuscript will be of interest to all scientists working on cellular trafficking and membrane remodeling

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, and computational, are exemplary and provide solid 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.

eLife assessment

This valuable study shows that, in mice, fresh cat saliva elicits a greater defensive response compared to old cat saliva. Additionally, the authors implicate the vomeronasal organ (VNO) and ventromedial hypothalamus (VMH) as part of a circuit that underlies this process. While the study has potential, the results are somewhat preliminary, and as such the evidence presented is incomplete.

eLife assessment

This important study advances our understanding of the potential mechanisms of deep-sea adaptation and sheds light on the evolutionary history of hadal snailfish. Through comparative genomic analysis, the authors provide convincing evidence and propose hypotheses on the timing of trench colonization, population structure, and adaptations to the hadal snailfish genome in response to their environment.

eLife assessment

This is an important study that addresses a significant question in microbiome research. The authors provide convincing evidence that certain bacterial groups within the fly microbiome have critical functions for host development. Additionally, dietary aspects such as microbial community progression in a natural food source are integrated into their host-microbe interaction analyses.

eLife assessment

This fundamental study explores the relationship between guanine-quadruplex structures and pathogenicity islands in 89 pathogenic strains. Guanine-quadruplex structures were found to be non-randomly distributed within pathogenicity islands and conserved within the same strains. Positive correlations were observed between Guanine-quadruplex structures and GC content across various genomic features, suggesting a link between these structures and GC-rich regions. These compelling findings shed light on the molecular mechanisms of Guanine-quadruplex structure-pathogenicity island interactions and will be of interest to all microbiologists.

eLife assessment

The findings in this fundamental study identify a novel substrate and mediator of oncogenesis downstream of mTORC1 and advance our understanding of the mechanistic basis of mTORC1-regulated cap-dependent translation and protein synthesis. The authors present convincing data using an array of biochemical, proteomic, and functional assays. These studies are of broad relevance to biochemists and cancer biologists and have potential translational relevance in cancer.

eLife assessment

This study explores the activation mechanisms of members of the kinesin-3 family, demonstrating common and unique regulation modes with solid evidence. The findings make for valuable contributions to the field of kinesin activation and regulation.

eLife assessment

This study explores the activation mechanisms of members of the kinesin-3 family, demonstrating common and unique regulation modes with solid evidence. The findings make for valuable contributions to the field of kinesin activation and regulation.

eLife assessment

The manuscript investigates how the tandem reader domains in BPTF co-recognize two types of modifications present on histone tails, H3K4me3 and H3 acetylation. The authors interpret their results in the context of the conformational restriction of histone tails due to interactions with nucleosomal DNA. The findings contribute new insights into how the nucleosomal context regulates the recognition of multiple histone modifications by tandem reader domains and should be of interest to the broader chromatin field.

eLife assessment

This valuable paper examines the link between the neuropeptide cholecystokinin (CCK) and motor learning and neural plasticity in the motor cortex. While CCK was known to be involved in neural plasticity in other brain regions and behavioral contexts, this study is the first to provide evidence that CCK manipulation causes deficits in motor learning. However, the evidence for specific effects regarding behavior, activity, and pathways is currently incomplete.

eLife assessment

In this important study, the authors propose that lenacapavir inhibits HIV-1 replication by inducing "lethal hyperstabilization" of the capsid, based on experiments that clearly demonstrate such an effect at high drug concentrations. Data supporting the model are incomplete at low drug concentrations, and a firm correlation between the in vitro effects and therapeutic mechanism of action has not yet been established.

eLife assessment

This important work presents a systematic survey of downstream target genes of the BMP pathway during body-axis establishment of the cnidarian Nematostella vectensis. BMP is a well-known developmental regulator, and this work identifies a previously unknown array of downstream targets. Combining genomic approaches and genetic manipulations, the authors present convincing evidence that Zswim4-6 acts as a negative feedback regulator of BMP activity in Nematostella. The authors also test a zebrafish homologue in over-expression assays and show solid evidence that it too dampens BMP signaling activity, leading to the suggestion that zswim4-6 is a conserved regulator of BMP signaling. This work will be of interest to researchers in the fields of both developmental biology and evo-devo.

eLife assessment

This study presents an important finding on the serial attentional resource allocation during parallel feature value tracking. The evidence supporting the claims of the authors is solid, although further clarification for high-/low-precision assigning, task effectivity of active tracking, and data analysis would have strengthened the study. The work will be of broad interest to psychology and cognitive science.

eLife assessment

This valuable study provides a combination of experiment and theory to investigate the role of a key signalling pathway as a patterning guide for local and global mechanical properties in a developing tissue. It poses solid evidence that local dynamical effects are not necessarily predictive of global tissue mechanics, although it does not offer an alternative mechanistic explanation. This multidisciplinary work will likely have an impact on the fields of tissue mechanics and developmental biology.

eLife assessment

The findings provided by Mohibi et al. are important to the field of lipid metabolism and cancer and provide insight for an in vivo role of FDX1. The evidence is solid, utilizing multiple modalities and both in vitro and in vivo lines of investigation.

eLife assessment

This is an important initial study of cell type and spatially resolved gene expression in and around the locus coeruleus, the primary source of the neuromodulator norepinephrine in the human brain. The data are generated with cutting-edge techniques, and the work lays the foundation for future descriptive and experimental approaches to understand the contribution of the locus coeruleus to healthy brain function and disease. The empirical support for the main conclusions is solid. This paper, and the associated web application, will be of great interest to neuroscientists working on arousal-based behaviors and neurological and neuropsychiatric phenotypes.

eLife assessment

The paper contains some useful analysis of existing data but there are concerns regarding the conclusion that there might be alternative mechanisms for determining the location of origins of DNA replication in human cells compared to the well known mechanism known from many eukaryotic systems, including yeast, Xenopus, C. elegans and Drosophila. The lack of overlap between binding sites for ORC1 and ORC2, which are known to form a complex in human cells, is a particular concern and points to the evidence for the accurate localization of their binding sites in the genome being incomplete.

eLife assessment

This fundamental study presents a method to restore muscle innervations in ALS mouse models using optogenetics. It is convincing that embryonic stem cell derived motor neurons can be transplanted into and applied to reinnervate the muscles in an ALS mouse model. The work will be of broad interest to researchers and medical biologists to develop new strategies for the treatment of neurodegenerative disorders resulting from denervated skeletal muscles.

eLife assessment

This important article provides insights into the neural centers and hormonal modulations underlying seasonal changes associated with photoperiod-induced life-history states in birds. The physiological and transcriptomic analyses of the mediobasal hypothalamus and pituitary gland offer convincing evidence for a timing mechanism for measuring day length, which is relevant for the field of seasonal biology. The study's experiments and findings have the potential to captivate the attention of molecular and organismal endocrinologists and chronobiologists.

eLife assessment

This is an important study that provides new insights into the development and function of medullary thymus epithelial cells (mTEC). The authors provide compelling evidence to support their claims as to the differentiation and lineage outcomes of CCL21+ mTEC progenitors, which further our understanding of how central tolerance of T cells is enforced within the thymus.

eLife assessment

This important study will provide evidence about a novel screen-triage-treat strategy for cervical cancer prevention. The trial will generate convincing evidence regarding the efficacy, effectiveness, cost-effectiveness, feasibility and acceptability in a range of geographically spread low-resource settings. The strategy should contribute to improving access to cervical cancer prevention to vulnerable women with low access to health care, and, therefore, at the highest risk of cervical cancer.

eLife assessment

This study presents useful findings regarding the role of formin-like 2 in mouse oocyte meiosis. The submitted data are supported by incomplete analyses, and in some cases, the conclusions are overstated. If these concerns are addressed, this paper would be of interest to reproductive biologists.

eLife assessment

Both reviewers positively received the manuscript, in general. The agreement was that the manuscript presented valuable findings, using solid techniques and approaches, that shed additional light into how the canine distemper virus hemagglutinin might engage cellular receptors and how that engagement impacts host tropism. While both reviewers appreciated the X-ray crystallographic data, they also felt that the AFM experiments could have been performed at a higher standard and that the interpretation of the results ensuing from those AFM experiments could have been explained more thoroughly and in simpler terms. An additional missed opportunity of the current manuscript is the lack of comparison of the crystal structure to that of the already published cryo-EM structure, for context.

eLife assessment

This important work employed global proteomic and phosphorylation site analysis to examine adipose tissue and skeletal muscle samples collected at baseline from a sample of 10 women, including those with and without PCOS, both before and after 5 weeks of electrical stimulation treatment. This work significantly enhances our knowledge by demonstrating that women with PCOS who exhibit protein hyperandrogenicity have elevated extramyocellular lipid levels and a decreased number of oxidative insulin-sensitive type I muscle fibers. The convincing evidence supporting these conclusions makes this research of broad interest not only to scientists but also to clinicians.

eLife assessment

This study presents a potentially valuable discovery which indicates that activation of the P2RX7 pathway can reduce the lung fibrosis after its establishment by inflammatory damage. If confirmed, the study could clarify the role of specific immune networks in the establishment and progression of lung fibrosis. However, the presented data and analyses are incomplete as they primarily rely on limited pharmacological treatments with modest effect sizes.

eLife assessment

The manuscript provides interesting evidence that miR-199b-5p regulates osteoarthritis and as such it may be considered as a potential therapeutic target. This finding may be useful to further advance the field. Although the study is considered potentially clinically relevant, the evidence provided was deemed insufficient and incomplete to support the conclusions drawn by the authors.

eLife assessment

This important study uses cutting-edge miniature two-photon microscopy to follow the structural dynamics of microglia in the somatosensory cortex of freely-moving mice across the sleep/wake cycle. Solid evidence revealed the brain-state-dependent regulation of microglial activity, highlighting alterations in microglial morphology during REM and NREM sleep phases compared to wakefulness. Furthermore, this study provides evidence for a critical role of norepinephrine from the locus coeruleus as a modulator of microglial morphology through the β2-adrenergic receptor (b2AR). Overall, the article is an impressive technical feat to bridge a crucial gap in understanding sleep state-induced dynamics of microglia and its modulation by norepinephrine signaling.

eLife assessment

Based on the observation of an increase in miR-182-5p in diabetic patients, the authors propose that miR-182-5p and its target gene LRP6 may play a role in dysregulated glucose tolerance and fatty acid metabolism in obese type 2 diabetics. The use of human livers complemented by supporting data in mice and cells are strengths, but the evidence presented remains incomplete. Nonetheless, the findings provide valuable insights into the role of miRNAs in the regulation of liver metabolism and insulin sensitivity in individuals with diabetes and fatty liver disease.

eLife assessment

This valuable study identifies an Ephrin type-B Receptor 2 (EPHB2) interactor, MYCBP2, as a potential regulator of EPHB2 stability and function. In contrast to expectations, based on MYCBP2 function in the ubiquitin pathway, loss of function of MYCBP2 resulted in less EPHB2 receptor and defective EPHB2 function. The paper is supported by a largely convincing set of biochemical, cell culture and in vivo experiments.

eLife assessment

This important study describes a method to decouple the mechanisms supporting pancreatic progenitor self-renewal and expansion from feed-forward mechanisms promoting their differentiation allowing in vitro expansion of hPSC-derived pancreatic progenitors. The strength of evidence is convincing in that the authors use appropriate and validated methodology in line with current state-of-the-art. The work will be of interest to the field of beta cell replacement therapy in diabetes.

eLife assessment

This valuable study seeks to disentangle the different selective forces shaping the evolutionary dynamics of transposable elements (TEs) in the wild grass Brachypodium distachyon. Using haplotype-length metrics, and genetic and environmental differentiation tests, the authors present in large parts convincing evidence that positive selection on TE polymorphisms is rare, and that the distribution of TE ages points to purifying selection being the main force acting on TE evolution in this species. A caveat of this study, as of other studies that seek to assess TE insertion polymorphisms with short reads, is that the rates of false negatives and false positives are difficult to estimate, which may have major effects on the interpretation. This study will be relevant for anyone interested in the role of TEs in evolution and adaptation.

eLife assessment

The important study describes exhaustive deep mutational scanning (DMS) of the gonadotropin-releasing hormone wild-type receptor and for two single point mutations reported to impact its folding and structure, monitoring how plasma membrane expression levels are affected by mutations. This important work is pioneering in exploring the interaction between mutations (epistasis) in a membrane protein, with a potential for explaining membrane protein evolution and genetic diseases. The evidence provided for some mutations is convincing, but it remains incomplete and harder to interpret for others without further validation of folding and stability properties of the mutants.

eLife assessment

This study elucidates the role of a specific hemocyte subpopulation in oxidative damage response by establishing connections between DNA damage response and the JNK-JAK/STAT axis to regulate energy metabolism. The identification of this distinct hemocyte subpopulation through single-cell RNA sequencing analysis and the finding of hemocytes that respond to oxidative stress are important. The method for single-cell RNA sequencing and related analyses are convincing and experiments linking oxidative stress to DNA damage and energy expenditure are solid. The finding of stress-responsive immune cells capable of influencing whole-body metabolism adds insights for cell biologists and developmental biologists in the fields of immunology and metabolism.

eLife assessment

This manuscript offers a valuable contribution to studying wildlife responses during and after COVID-19 lockdowns. It convincingly demonstrates that bird species in urban areas respond differently to human activity changes. What sets this study apart from others on avian responses to COVID-19 lockdowns is its use of passive acoustic monitoring. By concurrently measuring anthropogenic noise, a crucial reflection of changes in human activity due to COVID-19 lockdowns, this study reveals rare local-scale variations in bird responses to human activity. Only one study so far has used vocalization recordings to assess the effects of COVID-19 lockdowns on a bird species.

eLife assessment

This important study combines experimental and computational data to address crucial aspects of RNA methylation by a vital RNA methyltransferase (MTase). The authors have provided compelling, strong evidence, utilizing well-established techniques, to elucidate aspects of the methyl transfer mechanism of methyltransferase-like protein 3 (METTL3), which is a part of the METTL3-14 complex. This work will be of broad interest to biochemists, biophysicists, and cell biologists alike.

eLife assessment

This study provides useful evidence that GIF/MT-3 harbors sulfane sulfur, which may play a role in zinc coordination. The study includes a variety of well-designed assays to support the authors' hypothesis, revealing that sulfane sulfur is released from MT-3. The analysis and conclusions could benefit from a more rigorous approach to analyzing sulfur and zinc content in recombinant MT3 protein, leaving the evidence in parts incomplete.

eLife assessment

This useful study investigates two secreted Mycobacterium tuberculosis proteins, ESAT-6 and CFP10, using biochemical assays, including a Biolayer Interferometry assay. Solid experimental evidence demonstrates that ESAT-6 forms a tight interaction with CFP10 as a heterodimer at neutral pH and that ESAT-6 also forms a homodimer at acidic pH. Additional, more definitive evidence is required to describe how these proteins disrupt the phagosomal membrane.

eLife assessment

The study investigates the functional impact of cranial irradiation in mouse and proposes PAK3 as molecular element involved in radiation-induced cognitive decrement. The significance of the findings is useful for fields covering radiation, brain tumor and cognition. The strength of evidence is solid, although the referees expressed divergent views on the manuscript.

eLife assessment

In this important study, chromatin is simulated as a polymer at the scale of genes and 3D organization is analyzed at nucleosome resolution. There is convincing evidence for the emergence of microdomains due to the action of transcription factors, based on the simulation incorporating well-known biophysical properties of DNA, of nucleosomes, of linker histones, and of the transcription factor pair Myc:Max, as well as the 3D organization resulting from bending and looping of DNA. The work improves our knowledge of how the joint action of transcription factors and chromatin features affects chromatin structure and accessibility, which is of interest to anyone studying gene regulation.

eLife assessment

This paper provides useful information about how the ionome of Arabidopsis thaliana adapts to very high CO2-levels, backed up by solid evidence and carefully designed studies. However, the broader claims of the paper about climate change and food security - heavily emphasized in the abstract, introduction, and discussion - are inappropriate, as there is no direct link to the presented work.

eLife assessment

This valuable study analyzes a large cohort of Adolescent Idiopathic Scoliosis (AIS) patients, identifying an association with a variant in COL11A1 (Pro1335Leu). Experimental testing of this potentially pathogenic variant in vitro suggests a connection between Pax1, Col11a1, Mmp3, and estrogen signaling, thus providing solid support for the proposed link between hormonal and matrix components in the development of AIS.

eLife assessment

The effect of Vitamin D supplementation in reducing asthma via anti-inflammatory mechanisms is a topic of wide interest, with somewhat conflicting published data. Here, bioinformatic approaches help to identify a role of VDR in inducing the expression of the key regulator Ikzf3, which possibly suppresses the IL-2/STAT5 axis, consequently blunting the Th2 response and mitigating allergic airway inflammation. The evidence is solid and the findings are important for researchers in the field.