eLife assessment

This is a useful study that shows changes in the chromatin landscape of GABAergic neurons in induced pluripotent stem cells (iPSCs) derived from both Dravet Syndrome (DS) patients and healthy donors. The strength of the evidence is currently incomplete because the authors compared iPSCs from different individuals, rather than isogenic controls, and they did not examine the expression of the gene and encoded protein (SCN1A or Nav1.1) that are thought to be responsible for the majority of DS cases in these iPSCs. The work would be of interest to scientists who study development, developmental disorders, and epigenetic contributions to disease.

eLife assessment

The delineation of MBOAT function is important with theoretical and practical implications in MAFLD, alcohol-induced hepatic steatosis, and lysosomal diseases. The strength of evidence is convincing using methodology in line with current state-of-the-art, with good support for the claims.

eLife assessment

The significance of this work is important in that the authors propose a novel method to therapeutically harness myeloid cells which can be otherwise immunosuppressive and hamper T cell and immunotherapy responses. The strength of evidence is convincing but requires critical pieces of in vivo work to validate the therapeutic efficacy of this approach.

eLife assessment

This important work presents data showing that all non-proneural phenotypes of the Inhibitor of DNA binding (Id) protein emc are mediated through inappropriate non-apoptotic caspase activity. Using the developing Drosophila retina as a model the authors convincingly show that emc acts by transcriptionally regulating the Death-Associated Inhibitor of Apoptosis 1 (diap1) gene, which impacts on Notch signaling by caspase-dependent increase of Delta protein. These findings are interesting for the caspase/apoptosis field as they add more non-apoptotic functions of caspases to the list, as well as for the Id field, which examines how Id proteins inhibit cell differentiation.

Summary

1. 📚 Second Edition Overview: This is the second, revised and expanded edition of the book. The first edition was titled "Como Fazer Anotações Inteligentes. Uma Técnica Simples para Impulsionar a Escrita, Aprendizado e Pensamento - para Estudantes, Acadêmicos e Escritores de Livros de Não Ficção".

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6. 👤 Author's Background: Written by Dr. Sönke Ahrens, a writer and researcher in education and social sciences, known for the award-winning book "Experimento e Exploração: Formas de Revelação do Mundo" (Springer).

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eLife assessment

Through a theoretical approach, this study makes important contributions to our understanding of the evolutionary causes of the ageing process. Using a simple individual-based model and computational simulations, the authors provide convincing evidence that ageing can be a trait under natural selection, opening the door for further discussion in the context of lifespan extension research.

eLife assessment

The fundamental study presents a two-domain thermodynamic model for TetR which accurately predicts in vivo phenotype changes brought about as a result of various mutations. The evidence provided is solid and features the first innovative observations with a computational model that captures the structural behavior, much more than the current single-domain models.

eLife assessment

The work is a valuable contribution to understanding the mechanism of nuclear export of tRNA in budding yeast. The authors present solid evidence that Dbp5 functions in parallel with Los1 and Msn5 in tRNA export, in a manner dependent on Gle1 for activation of its ATPase activity but independently of Mex67, Dbp5's partner in mRNA export. It further presents biochemical evidence that Dbp5 can bind tRNA but that Gle1 and InsP6 are required for activating ATP hydrolysis by the Dbp5-tRNA complex, suggesting a possible mechanism for tRNA export by Dbp5.

eLife assessment

This study presents valuable findings on the contrasting responses of two bacteria to the phytoplankton-derived compound azelaic acid. Metabolomics and transcriptomics evidence convincingly shows the assimilation pathway in one marine bacterium and a stress response in a second bacterium. The study provides evidence that azelaic acid can alter marine microbial community structure in mesocosm experiments, though the mechanisms underlying this shift in community structure remain to be explored in future studies.

eLife assessment

This valuable study considers empirical macroecological patterns in microbiome data across multiple taxonomic scales. The work convincingly shows that the Stochastic Logistic Growth model is a more appropriate choice of null model than the neutral theory of biodiversity. The work will be of particular interest to microbial ecologists.

eLife assessment

The findings of this study are valuable as they provide new insights into the role of acetylcholine in modulating sensory processing in the auditory cortex. This paper reports a systematic measurement of cell activity in the auditory cortex before and after the microiontophoretic application of Ach during an oddball and cascade sequence of auditory stimuli. The evidence presented is convincing, as the study used a rigorous experimental design and statistical analysis. The manuscript will interest researchers in auditory neuroscience and neuromodulation, as well as clinicians and individuals with auditory processing disorders.

eLife assessment

This is an important and interesting account of the ability of Ym1 crystals to promote type 2 immunity in vivo, in mice. The data presented are compelling, building on and significantly advancing evidence this group has previously published on the type 2 immunogenicity of other protein crystals. The work will be of relevant interest to immunologists and researchers working on type 2 inflammatory disease, in the lung and in others tissues.

eLife assessment

The paper represents a novel application of recursion theory to the long call vocalisations of orangutans to demonstrate repetitive, rhythmic sub-structuring. The authors use detailed acoustic analyses to show compelling evidence for self-embedded and nested isochronic motifs. These fundamental results have the potential to significantly advance current approaches used to compare nonhuman communication systems with human language.

eLife assessment

This study presents useful observations about how the human brain uses long-term priors (acquired during our lifetime of listening) to make predictions about expected sounds - an open question in the field of predictive processing. However, the evidence as currently presented is incomplete. Both the theoretical background and analysis approach should be strengthened.

eLife assessment

Overall, this is a significant study, and it is able to highlight mast cells in amphibians and their putative capability to respond to and combat fungal infections. Therefore, this study is important for the field. However, the manuscript is incomplete from the standpoint that there is functional data lacking on how these mast cells are activated and their precise functional properties. Such experiments would add substantial impact and rigor and fully support the conclusions.

eLife assessment

This valuable study applies voltage clamp fluorometry to provide new information about the function of serotonin-gated ion channels 5-HT3AR. The authors convincingly investigate structural changes inside and outside the orthosteric site elicited by agonists, partial agonists, and antagonists, helping to annotate existing cryo-EM structures. This work confirms that the activation of 5-HT3 receptors is similar to other members of this well-studied receptor superfamily. The work will be of interest to scientists working on channel biophysics but also drug development targeting ligand-gated ion channels.

eLife assessment

The authors present a comprehensive set of tools to compactly characterize the time-frequency interactions across a network. The utility of the toolbox is compelling and demonstrated through a series of exemplar brain imaging datasets. This fundamental work adds to the repertoire of techniques that can be used to study high-dimensional data.

eLife assessment

This work uses an interdisciplinary approach combining microfluidics, structural biology, and genetic analyses to provide valuable findings that show that pathogenic enteric bacteria exhibit taxis toward human serum. The data are solid and show that the behavior utilizes the bacterial chemotaxis system and the chemoreceptor Tsr, which senses the amino acid L-serine. The work provides an ecological context for the role of serine as a bacterial chemoattractant and could have clinical implications for bacterial bloodstream invasion during episodes of gastrointestinal bleeding.

eLife assessment

This important study contributes insights into the regulatory mechanisms of a protein governing cell migration at the membrane. The integration of approaches revealing protein structure and dynamics provides convincing data for a model of regulation and suggests a new allosteric role for a solubilized phospholipid headgroup. The work will be interesting to researchers focusing on signaling mechanisms, cell motility, and cancer metathesis.

eLife assessment

In this valuable manuscript, Yao et al. describe new methods for assessing the intracellular itinerary of Botulinum neurotoxin A (BoNT/A), a potent toxin used in clinical and cosmetic applications. The current manuscript challenges previously held views on how the catalytic portion of the toxin makes its way from the endocytic compartment to the cytosol, to meet its substrates. The approach taken is deemed innovative and the experiments are carefully performed, however, they are somewhat incomplete with respect to the drawn conclusions, as it is possible that the scope of their findings could be restricted to the specific neuron model and molecular tools that were used. This paper could be of interest to both cell biologists and physicians.

eLife assessment

In this study, camera trapping and species distribution models are used to show that human disturbance in mountain forests in the eastern Himalayas pushes medium-sized and large mammal species into narrower habitat space, thus increasing their co-occurrence. While the collected data provide a useful basis for further work, the study presents incomplete evidence to support the claim that increased co-occurrence may indicate positive interactions between species.

eLife assessment

This fundamental study addresses a long-standing mystery in splicing regulation: does splicing occur co- or post-transcriptionally? The authors provide compelling evidence demonstrating that splicing can occur post-transcriptionally at a transcription site proximal zone, changing the way we think about splicing.

eLife assessment

This is an important study using 3D mapping of neuronal activation throughout the brain after pair-bonding in the monogamous vole, which can be broadly applied to other species and behaviors. The authors provide compelling evidence that there is some synchrony between male and female partners that have formed a pair bond, the strength of which is based on the number of ejaculations received by the female. Same-sex pairs also form a pair bond and were found to have activation in the same brain regions as mixed sex couples. An overall low level of sex differences in the degree and location of brain activation was observed, which was unexpected. This work will be of interest to those interested in social behavior and its neural mechanisms, or brain systems or behavior more broadly.

eLife assessment

This important study reports on an improved deep-learning-based method for predicting TCR specificity. The evidence supporting the overall method is compelling, although the inclusion of real-world applications and clear comparisons with the previous version would have further strengthened the study. This work will be of broad interest to immunologists and computational biologists.

eLife assessment

Studies of synaptic development and plasticity in the nematode C. elegans have been limited by the difficulty of rapid, accurate assessments of synaptic structure. Here, with a series of convincing studies, the authors introduce and validate a valuable computational pipeline, "WormPsyQi," that allows rapid, reproducible quantitation of fluorescent synaptic puncta while minimizing human error and bias. The authors also describe a new set of strains carrying synaptic markers. Together, these tools should provide groups studying this model system with the ability to quantitatively characterize chemical and electrical synapses, even in densely packed regions in 3D space such as the nerve ring.

eLife assessment

The study is of importance for the cardiac modeling field by developing a novel mathematical model with sex difference. The data are compelling, and the model is helpful for mechanistic understanding, and thus is also important for experimental physiology. The model is based on experimental data and validated against some experimental data.

eLife assessment

The important work by Aballay et al. significantly advances our understanding of how G protein-coupled receptors (GPCRs) regulate immunity and pathogen avoidance. The authors provide convincing evidence for the GPCR NPR-15 to mediate immunity by altering the activity of several key transcription factors. This work will be of broad interest to immunologists.

eLife assessment

BMP signaling plays a vital role in skeletal tissues, and the importance of its role in microtia prevention is novel and promising. This important study will shed light on the role of BMP signaling in preventing microtia in the ear. Solid data broadly support the claims with only minor weaknesses.

eLife assessment

The study has added value to what we have already known in the potential pharmacological immunomodulatory therapies in LPS-induced sepsis, and especially the use of oral leucine might be of great interest to the readers engaged in this field. We believe this study is important and provides solid evidence on the potential use of leucine in sepsis.

eLife assessment

This useful study presents a novel method to analyze the correlation between the degree of pigmentation, and the gene expression profile of human-induced pluripotent stem cell-derived Retinal Pigmented Epithelial (iPSC-RPE) cells at the single cell level, trying to establish if this parameter might be of use as a guide for transplantation. The presented evidence is incomplete: pigmentation was not an indicator of functionality or maturity and the data, although obtained from a pertinent approach, is limited to in vitro conditions; further, this approach is not complete since no attempts were made to graft iPSC-RPE.

eLife assessment

This useful study introduces a simple mechanical model of C. elegans locomotion that captures aspects of the worm's behavioral repertoire beyond forward crawling. While the kinetic model (ElegansBot) provides a useful compromise and starting point to help understand the mechanical components of C. elegans behavior, the claim that this work improves on extant mechanical models is incomplete. In addition, the results of the application of the model to previously unstudied behaviors are primarily qualitative and do not produce new predictions.

eLife assessment

This study presents a valuable finding on developing a state-of-the-art generative model of brain electrophysiological signals to explain temporal decoding matrices widely used in cognitive neuroscience. The evidence supporting the authors' claims is convincing. The results will be strengthened by providing more clear mappings between neurobiological mechanisms and signal generators in the model. The work will be of interest to cognitive neuroscientists using electrophysiological recordings.

eLife assessment

In this important paper, Blin and colleagues develop a high-throughput behavioral assay to test spontaneous swimming and olfactory preference in individual Mexican cavefish larvae. The authors present compelling evidence that the surface and cave morphs of the fish show different olfactory preferences and odor sensitivities and that individual fish show substantial variability in their spontaneous activity that is relevant for olfactory behaviour. The paper will be of interest to neurobiologists working on the evolution of behaviour, olfaction, and the individuality of behaviour.

eLife assessment

This study by Chiu and colleagues is a valuable contribution to the study of the circuitry of aggressive behaviours and of mechanisms that generate persistent behavioural states. The authors find that activation of two interconnected sets of neurons results in an increase in female aggression. The data ruling out recurrent connectivity between these clusters underlying this persistent state are convincing.

eLife assessment

This important study reports on a new method for the fabrication and the analysis of the transport through nuclear pore complexes mimic. Methods, data and analyses are convincing and show a clear correlation between the size of the nuclear pore complex mimic and its transport selectivity. This work will be of high interest to biologists and biophysicists working on the mechanosensitivity of nucleocytoplasmic transport.

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

This useful study applies solid and previously validated methodology to identify archaically introgressed genes involved in high altitude adaptation. However, to test the robustness of the approach, this study would benefit from using at least one other method to detect adaptive introgression, and clarification on how the authors scored the networks in the signet analysis. With these parts strengthened, this paper would be of interest to population geneticists, anthropologists, and scientists interested in the genetic basis underlying high-altitude adaptation in Tibet.

eLife assessment

This valuable study reports on the genome evolution of a poorly studied fungal group. By combining long-read sequencing and various bioinformatics approaches, the authors show that the giant genome of Entomophthora muscae expanded due to extensive transposable element activity. The strength of evidence is largely solid, but some analyses are only partially supported due to different methodologies used to analyze the genomes that are being compared. This paper will be of relevance to fungal biologists as well as to evolutionary biologists interested in the study of genome size dynamics.

eLife assessment

The manuscript describes important findings supported by convincing data. The authors present persuasive genetic and biochemical evidence that supports the biological mechanism for optimal nodulation in soybean presented in this study. The results are of relevance to understanding the signaling pathway underpinning beneficial rhizobia symbiosis, while repressing the immune response. With the discussion part strengthened this paper would be of broad interest to plant biologists working on cell signaling and plant-microbe interactions.

eLife assessment

This manuscript investigates how chloroplasts are broken down during light-limiting conditions as plants reorganize their energy-producing organelles during carbon limitation. The authors provide convincing live-cell imaging data of plastids, documenting that buds form on the surface of chloroplasts and pinch away, then associate with the vacuole via a mechanism that depends on autophagy machinery, but not plastid division machinery. However, the absence of quantitative analyses makes the work incomplete at the current stage. The manuscript nevertheless provides important groundwork for other scientists studying the regulation and breakdown of energy-producing organelles, including chloroplasts and mitochondria.

eLife assessment

This study provides useful information by identifying the cell type (macrophages) in synovial tissues involved in the pathogenesis of post-traumatic osteoarthritis (OA) and clarifying distinct transcriptomic signatures that may be a good therapeutic target for OA. However, the analysis performed so far is incomplete, with a main weakness being the lack of data to confirm the authors' speculation about the underlying mechanisms.

eLife assessment

This important study presents a new way to selectively activate a cell signaling pathway in a specific cell type by designer ligands that link signaling co-receptors to a marker specific to the target cells. Convincing experimental results demonstrate that the agonist molecules activate Wnt signaling in target cells expressing the marker as intended. More broadly, this concept could be used to induce Wnt signaling or another pathway initiated by co-receptor association in a cell type-specific manner. In vitro results in this study could be further strengthened by assessing the biological consequences of Wnt activation in target cells.

eLife assessment

This important study reports the generation of genetic tools for manipulating several tissues at the same time in Drosophila. The authors provide convincing evidence that this allows the generation of LexA and QF2 driver lines, which will be of great utility for understanding inter-organ communication. Making the tools available through the Drosophila stock center and plasmid depository will ensure that they are easily accessed by many researchers.

eLife assessment

This study represents a valuable mechanistic contribution towards understanding how ribosomal RNA is processed during ribosome biogenesis. The biochemical evidence supporting the major conclusions is convincing. This work will be of interest to cell biologists and biochemists working on ribosome biogenesis.

eLife assessment

This study presents valuable findings on the potential of short-movie viewing fMRI protocol to explore the functional and topographical organization of the visual system in awake infants and toddlers. Although the data are compelling given the difficulty of studying this population, the evidence presented is incomplete and would be strengthened by additional analyses to support the authors' claims. This study will be of interest to cognitive neuroscientists and developmental psychologists, especially those interested in using fMRI to investigate brain organisation in pediatric and clinical populations with limited fMRI tolerance.

eLife assessment

This valuable study draws attention to the importance of a previously overlooked structural motif in kinase regulation. While the data presented are intriguing and mostly solid, further analysis and additional experiments will be needed in the future to support the authors' hypothesis. The work will be of interest to protein biochemists and enzymologists with an interest in kinases and allostery.

eLife assessment

The reviewers were generally enthusiastic about this study, noting that it reports new tools that could be valuable to the community. However, the results in follow-up experiments testing specific tools are often inconsistent with those in the literature, and some conclusions are overstated. More details are needed for both sections, the tool generation and the testing of the CNMa peptide. While the evidence for the tool development was solid, evidence demonstrating the validity of the tools was deemed incomplete.

eLife assessment

This important study combines disease-associated genetic variation with a massively parallel reporter assay and different cellular perturbations to identify context-specific genetic regulatory effects. The methods and analyses are solid and the proposed functional variants will be helpful for experimental and quantitative geneticists studying a wide range of complex traits.

eLife assessment

In this manuscript, the authors investigate whether the effects of the BCG vaccine on immunity to Mtb infection could be improved by inhibiting amidation of the peptidoglycan sidechains to allow for recognition by NOD-1. This is a very important area and an interesting new approach to improve vaccination for TB. The authors find that CRISPRi knockdown of murT-gatD causes rather dramatic cell wall defects, more accessible cell wall labeling, and results in attenuated growth in macrophages and mice. This forms a foundation for further study of whether an approach like that which is presented herein would improve vaccination responses in TB.

eLife assessment

In this study, deep learning methods are deployed in the context of a group hunting scenario wherein two predators pursue a single prey. Through deep learning, the two predators achieve higher predation success than occurs with single predators. Much of the evidence in this important study is solid, with implications for future work on the ethology and simulation of cooperative behaviors.

eLife assessment

This study provides a valuable investigation into whether phenotypic variance due to interactions between genetic variants can be measured using genome-wide association summary statistics. The authors present a method, i-LDSC, that uses statistics on the correlations between genotypes at different loci (linkage disequilibrium) to estimate the phenotypic variance explained by both additive genetic effects and pairwise interactions. While the authors present extensive simulations on the performance of their method and empirical results indicating the presence of epistasis (as they define epistasis) it is unclear how their method and results relate to the traditional definitions of additive and non-additive genetic effects, which are different from the authors' definitions.

eLife assessment

This study presents valuable findings regarding inter-individual variability in the neural and behavioral effects of ketamine. The methodological approach used to characterize this variability is compelling, but the evidence to support the specificity of the changes and their genetic correlates is incomplete. The study would benefit from a more thorough examination of the specificity of the pharmacological and genetic results.

eLife assessment

This study presents a useful deep learning-based inter-protein contact prediction method named PLMGraph-Inter which combines protein language models and geometric graphs. The evidence supporting the claims of the authors is solid, although it could have information leakage between training and test sets, and although more emphasis should be given to predictions starting from unbound monomer structures. The authors show that their approach may be useful in some cases where AlphaFold-Multimer performs poorly. This work will be of interest to researchers working on protein complex structure prediction, particularly when accurate experimental structures are available for one or both of the monomers in isolation.

eLife assessment

The bacterial neurotransmitter:sodium symporter homoglogue LeuT is an well-established model system for understanding the fundamental basis for how human monoamine transporters, such as the dopamine and serotonin, couple ions with neurotransmitter uptake. Here the authors provide convincing data to show that K+ binding on the intraceullular side catalyses the return step of the transport cycle in LeuT by binding to one of the two sodium sites. The mechansitic consequences of K+ binding could either facilitate LeuT re-setting and/or prevent the rebinding and possible efflux of Na+ and substrate.

eLife assessment

This paper reports the fundamental discovery of adrenergic modulation of spontaneous firing through the inhibition of the Na+ leak channel NALCN in cartwheel cells in the dorsal cochlear nucleus. This study provides unequivocal evidence that the activation of alpha-2 adrenergic or GABA-B receptors inhibit NALCN currents to reduce neuronal excitability. The evidence supporting the conclusions is exceptional, the electrophysiological data is high quality and the experimental design is rigorous.

eLife assessment

The authors pair single-cell sequencing technology with the LoopSeq synthetic long-read method to examine samples of hepatocellular carcinoma and benign liver, with the goal of identifying mutations and fusion transcripts specific to cancer cells. The authors present a valuable resource and the overall support for the major claims is solid.

eLife assessment

This important study explores infants' attention patterns in real-world settings using advanced protocols and cutting-edge methods. The presented evidence for the role of EEG theta power in infants' attention is currently incomplete. The study will be of interest to researchers working on the development and control of attention.

eLife assessment

In this important study, chromatin is simulated as a polymer at the scale of genes, and the 3D organization of chromatin is analyzed at nucleosome resolution. There is convincing evidence for the emergence of chromatin 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 considering how the 3D organization of chromatin results from bending and looping of DNA. The work greatly improves our understanding 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, offering insights into the mechanisms of neuronal cell type diversification, provides important findings that have theoretical or practical implications beyond a single subfield. The data are compelling and provide evidence that features methods, data and analyses that are more rigorous than the current state-of-the-art.

eLife assessment

This paper explores how Notch activity acts together with homeodomain transcription Bsh factors to establish distinct cell fates (L4 vs L5) in the visual system of Drosophila. The findings are important and have theoretical or practical implications beyond a single subfield. The methods, data, and analyses are compelling and support the claims with only minor weaknesses.

eLife assessment

This useful study presents a possible solution for a significant problem - that of draining vein sensitivity in functional MRI, which complicates the interpretability of laminar-fMRI results. The addition of a low diffusion-weighted gradient is presented to remove the draining vein signal and obtain functional responses with higher spatial fidelity. However, the strength of the evidence is inadequate, most tests appear to have been done only in a single subject. Significance thresholds in presented maps are very low and most cortical depth-dependent response profiles do not differ from baseline, even in the BOLD data shown as reference. Curiously, even BOLD group data fails to replicate the well-known pattern of draining towards the cortical surface.

eLife assessment

This important study combines psychophysics, fMRI, and TMS to reveal a causal role of FEF in generating an attention-induced ocular dominance shift, with potential relevance for clinical applications. The evidence supporting the claims of the authors is solid, but the theoretical and mechanistic interpretation of results and experimental approaches need to be strengthened. The work will be of broad interest to perceptual and cognitive neuroscience.

eLife assessment

This important study presents a detailed investigation of the early development of cardiac and respiratory interoceptive sensitivity in infants aged 3, 9, and 18 months. The evidence supporting the conclusions are solid and based on convincing statistical analyses, despite the limited sample size for the younger and older age groups. This study will be of significant interest to developmental psychologists and neuroscientists working on interoception and its influence on socio-cognitive development.

eLife assessment

This study presents a valuable framework and findings for our understanding of the brain as a fractal object, by observing the stability of its shape property within 11 primate species. Although the framework is well-detailed, the evidence presented is incomplete and would be strengthened by additional analyses to support the authors' claims, particularly on the effects of aging and on the interpretation of links between brain shape and the underlying anatomy. This study will be of interest to neuroscientists interested in brain morphology, and to physicists and mathematicians interested in modeling the shapes of complex objects.

eLife assessment

In the last 15 years, large-scale association studies (GWAS) have served to estimate the association between genome-wide common variants and a large number of disparate traits and diseases in humans. This valuable method provides a new way to find correlations between the genetic component of a phenotype of interest, and all this wealth of genetic information. This software adds as a new tool to investigate genetic correlation between traits, and to generate new mechanistic hypotheses and dissect the role of the observed associations in disease heterogeneity. The results of the application of their method are solid and generally agree with what others have seen using similar AD and UKB data.

eLife assessment

This study presents important findings on the different polymorphs of alpha-synuclein filaments that form at various pH's during in vitro assembly reactions with purified recombinant protein. Of particular note is the discovery of two new polymorphs (1M and 5A) that form in PBS buffer at pH 7. The strength of the evidence presented is solid, but the addition of replicate experiments with re-purified proteins at pH 5.8 and pH 7 would further strengthen the conclusions. The work will be of interest to biochemists and biophysicists working on protein aggregation and amyloids.

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.