eLife assessment:

Autosomal dominant optic atrophy (DOA) in humans is associated with mutations in OPA1, a mitochondrial dynamin like GTPase. This study uses Drosophila as a model to recapitulate some aspects of the disease phenotype, and it supports and extends previously published data to provide valuable findings that have theoretical or practical implications in the field of rare retinal diseases. The approaches used are solid and allow to investigate differences between mutations that are supposed to be loss-of-function or acting as dominant negative with consequences in the optic system or in a version of DOA, in which other tissues are also affected. However, the main claims are only partially supported and additional information in the materials and methods and several figure legends is needed to complete the study.

eLife assessment

This study presents convincing evidence that metabolite levels in Escherichia coli bacteria from a long-term evolution experiment have changed in consistent ways, which in turn can be explained by recurrent mutations in regulatory genes that affect enzyme expression levels. The use of high-resolution mass spectrometry measuring bulk metabolite levels, in combination with existing gene expression and DNA sequencing datasets provides valuable information linking changes in an organism's genome, transcriptome, and metabolome.

eLife assessment

This study presents a computational model to explore how neurostimulation could impact hippocampal theta oscillations. The computational model combines a detailed physiologically realistic hippocampus model and an abstract theta oscillator. If confirmed, the study could be a useful tool that provides useful predictions on pathological changes in this network. The modelling is based on solid approaches that could be significantly improved with experimental validation.

eLife assessment

This important paper provides new insight into how asexual reproduction can arise in interspecific hybrids, an empirical example of the "extended speciation continuum." The molecular cytogenetic evidence supporting the conclusions is solid, but additional replicates within each species would strengthen the overall findings. By highlighting the potential for asexuality to evolve in hybrids during a narrow window of species divergence, this work will be of broad interest to evolutionary biologists.

eLife assessment

This valuable offers insight into the relationship between floral and reproductive phenotypes and gene expression in allopolyploids. This well-reasoned experimental setup uses thorough statistical analyses to provide compelling insights into the mechanisms driving both phenotypic and gene expression evolution in allopolyploids. The work will be of interest to researchers working in plant speciation and genomics, as well as those more broadly in the effects of ploidy on phenotypic and expression evolution.

eLife assessment

This manuscript presents a valuable analysis of allosteric communication in the CFTR protein using a coarse-grained dynamic model and characterized the role of disease-causing mutations. Some of the results are convincing and make a contribution to understanding the mechanism of CFTR, the discussion of the allostery mechanism is incomplete. Further discussion and validation of the computational approach will help strengthen the manuscript.

eLife assessment

This study presents findings on changes in brain network asymmetry in infants with congenital hearing loss. The findings are valuable but the evidence supporting the claims is incomplete and needs more appropriate and strict statistical analyses. The findings will be of interest to psychologists, neuroscientists, and clinicians.

eLife assessment

This paper reports the fundamental discovery of a new function of neutrophil in specifically clearing apoptotic hepatocytes by penetrating the cells rather than engulfing them without causing inflammation as a part of tissue homeostasis. This solid study transforms the way we think about role of neutrophil in pathogenesis of autoimmune liver disease.

eLife assessment

The authors present "MotorNet", a useful software package to train artificial neural networks to control a biomechanical model of an effector. The manuscript provides solid evidence that MotorNet is easy to use and can reproduce past results in the field, both at the neural and behavioural levels. Validation is limited to planar arm-like plants or point-masses, so future work exploring three-dimensional movements and other types of plants would strengthen the impact of the tool.

eLife assessment

This study presents a valuable set of findings on how prior expectations modulate tactile sensory processing. The neuroimaging evidence supporting the main conclusions is solid, although the nature of the experimental task somewhat limits the interpretation of the findings. This work will be of interest to neuroscientists working on sensory processing and perception.

eLife assessment

This useful study investigated the appearance of a "new-type" ultrasonic vocalization around 44 kHz that occurs in response to prolonged fear conditioning in rats. While the descriptive approach applied may be of interest to some researchers, evidence in support of the conclusions is incomplete.

eLife assessment

Using sophisticated reinforcement learning modeling, authors provide a valuable and convincing result that acute ketamine reduces the strength of the impact of losses vs neutral/gains on performance of a token-based matching-pennies task. However, authors provide incomplete evidence that this interesting acute effect may be a mechanism whereby ketamine is a rapid-acting antidepressant.

eLife assessment

This study involves a valuable investigation of habit-learning in obsessive-compulsive disorder versus controls with participants engaging in a month of motor-sequence task practice administered via a smartphone app. Currently the results are inadequate to support the authors' key claims as not all of the criteria were met to establish that habit learning occurred.

eLife assessment

This study provides a valuable contribution to the study of eye-movements in reading, revealing that attention-weights from a deep neural network show a statistically reliable fit to the word-level reading patterns of humans. Its evidence is solid and strengthens a line of research arguing that attention in reading reflects task optimization, although the work may further benefit from a more specific attribution of the predictive power of the models. The work would be of interest to psychologists, neuroscientists, and machine learning researchers.

eLife assessment

This useful study identifies several gain-of-function division protein variants that can suppress the lethality caused by depletion of Aeg1/AdvA in Acinetobacter baumannii, but characterization and description of AdvA in its localization patterns and interactions with other divisome proteins are inadequate. Since a role of AdvA in cell division has been shown before, the claim that a "novel cell division protein" has been identified is incorrect. The evidence provided also does not support the claim that AdvA plays a critical role in the assembly of the A. baumannii divisome.

eLife assessment

This study has uncovered some important initial findings about how certain extracellular vehicles (EVs) from the mother might impact the energy usage of an embryo. While the study's findings are in general solid, some experiments lack statistical power due to small sample sizes. The study's title might be a bit too assertive as the evidence linking maternal mtDNA transmission to changes in embryo energy use is still correlative.

eLife assessment

This study presents a valuable finding on variations within the RNA synthesis protein of SARS-CoV-2, the virus that is responsible for COVID 19. The evidence supporting the claims of the authors is solid, although a more in-depth analysis of the structures and simulations would have strengthened the conclusions of the work. This work has implications for drug design and will be of broad interest to the general biophysics and structural biology community.

eLife assessment

In this valuable paper, the authors use an existing theoretical framework relying on information theory and maximum entropy inference in order to quantify how much information single cells can carry, taking into account their internal state. They reanalyze experimental data in this light. Despite some limitations of the data, the study convincingly highlights the difference between single-cell and population channel capacities. This result should be of interest to the quantitative biology community, as it contributes to explaining why channel capacities are apparently low in cells.

eLife assessment

This study presents a novel fluorescence based imaging strategy to investigate the folding status of RNA-binding proteins (RBPs) and their association with molecular chaperones under stress. It provides fundamental findings that will potentially advance our understanding in the folding and aggregation status of RBPs in nuclear stress bodies in a significant manner. However, there is also the concern that the evidence regarding protein fate is incomplete and additional controls are needed to fully support the conclusion. The imaging methodology can be adapted to study many other proteins that undergo liquid-liquid phase separation under specific cellular conditions.

eLife assessment

This study assesses homeostatic plasticity mechanisms driven by inhibitory GABAergic synapses in cultured cortical neurons. The authors report that up- or down-regulation of GABAergic synaptic strength, rather than excitatory glutamatergic synaptic strength, is critical for homeostatic regulation of neuronal firing rates. The reviewers noted that the findings are potentially important, but they also raised questions. In particular, the evidence supporting the findings is currently incomplete and demonstration of independent regulation of mEPSCs and mIPSCs is a necessary experiment to support the major claims of the study.

eLife assessment

The manuscript represents an important study on the pathogenesis of rubella virus tropism and neuropathology in human microglia-containing human stem cell derived organoids and human fetal brain slices. The strength of evidence is compelling, employing two different human-relevant models. The findings will be of broad interest to virologists and infectious disease experts, as well as neurodevelopmental biologists. The findings could also be of interest to pediatrics and obstetrics clinical colleagues.

eLife assessment

This manuscript describes important findings that will impact our understanding of nuclear pore complex (NPC)-genome interactions and how nuclear pore proteins (nucleoporins) impact super enhancer function. The authors develop a clever new approach termed NPC-DamID to map chromatin-NPC interactions that has several important advantages over existing techniques and may be used in contexts that are incompatible with genetic manipulation. The authors provide compelling evidence that nucleoporins interact with super enhancers in multiple cell types and also suggest that the phase separation behavior of nucleoporins contributes to the hierarchical organization of super enhancers, which is exciting and will stimulate additional work.

eLife assessment

This study addresses the long-standing question as to how different functional pools of synaptic vesicles are organized in presynaptic terminals to mediate different modes of neurotransmitter release. Based on imaging of active synapses with recycling synaptic vesicles labeled by FM-styryl dyes, the authors provide data that are compatible with the hypothesis that two separate reserve pools of vesicles - slowly vs. rapidly mobilizing - feed two distinct releasable pools - reluctantly vs. rapidly releasing. Overall, this study represents a valuable contribution to the field of synapse biology, specifically to presynaptic dynamics and plasticity. However, the authors' methodological approach of using bulk FM-styryl dye destaining as a readout of precise vesicle arrangements and pools in a population of functionally very diverse synapses has limitations. Consequently, the evidence that directly supports the authors' two-pool-interpretation of their data is incomplete, and alternative interpretations of the data remain possible.

eLife assessment

This is an important study that demonstrates a role of the murine thalamus in ocular dominance plasticity. The evidence supporting the authors' claims is solid, although the inclusion of a conditional KO in which synaptic inhibition was only interfered with in adulthood could better support the authors' conclusions. This work will interest those in the field of ocular dominance plasticity in the visual system as well as scientists investigating the function of synaptic plasticity in the brain.

eLife assessment

This important study examines whether synaptic cell adhesion molecules neuroligin 1-3 resident on astrocytes, rather than neurons, exert effect on synaptic structure and function. With convincing evidence, the authors report that deletion of neuroligins 1-3 specifically in astrocytes does not alter synapse formation or astrocyte morphology in the hippocampus or visual cortex. This study highlights the specific role of neuronal neuroligins rather than their astrocytic counterparts in synaptogenesis.

eLife assessment

This valuable study investigates how hierarchies are processed in the brain, using a paradigm that intends to bridge disparate domains (e.g., language/music and memory). The main findings are that hippocampus and medial prefrontal cortex are sensitive to hierarchy position, while the response in inferior frontal gyrus seems to vary with amount of experience with the hierarchy. Evidence supporting these claims is solid, and would be strengthened by additional methodological clarifications (e.g., as to why the particular analyses are most appropriate for the research question) and further discussion of limitations related to the study design (e.g., the possibility that the task does not require hierarchical representations).

eLife assessment

This manuscript describes a fundamental strategy for developing isozyme-selective inhibitors of inositol hexakisphosphate kinases. The compelling evidence that subtle changes to the gatekeeper position can sensitize the inositol hexakisphosphate kinase mutant to allosteric inhibitors will undoubtedly inspire other analog-sensitive inhibitor studies. This manuscript will be of interest to researchers focusing on kinase regulation and inhibitor design.

eLife assessment

The paper, which investigates mechanisms regulating the F-actin cytoskeleton in the B cell synapse, is an Important contribution to the study of B cell immunology and cell biology. The evidence provided for a key role of N-WASP regulation of F-actin proximal to the B cell receptor is solid, with parts of it being compelling.

eLife assessment

This study presents valuable findings on the role of transcription readout and intron retention in transposon expression during aging in mammals. While the findings are interesting, the evidence supporting the claims of the authors is incomplete, and additional analysis would be required to strengthen the study. The work will be of interest to scientists studying aging, transcription regulation, and epigenetics.

eLife assessment

The manuscript represents an important study on the pathogenesis of rubella virus tropism and neuropathology in human microglia-containing human stem cell derived organoids and human fetal brain slices. The strength of evidence is compelling, using state-of-the-art multimodal technologies. The findings will be of interest to neuroscientists, virologists, and epidemiologists, presenting novel hypotheses and generally helpful tools.

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

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, but the overall support for the major claims remains incomplete. In particular, the authors could have provided stronger support for the combination of technologies and interpretation regarding cancer-associated genomic changes.

eLife assessment

The authors present valuable findings on how to determine the genetic architecture of extreme phenotype values by using data on sibling pairs. While the authors' derivations of the method are correct, the scenarios considered are incomplete, making it difficult to have confidence in the interpretation of the results as demonstrating the influence of de-novo or Mendelian (rare, penetrant-variant) architectures. The method shows nevertheless promise and will be of interest to researchers studying complex trait genetics.

eLife assessment

In this study, the authors discuss the relevance of the tumor mutational burden (TMB) as an appropriate predictive biomarker for the effectiveness of immunotherapy. The study offers important findings that will contribute to current dialogues around the biomarkers used for therapy in cancer (and perhaps, other diseases). This is an area of substantial controversy, and the authors have gone to great lengths to support their claims with convincing evidence.

eLife assessment

This work presents valuable findings on the cellular and ultrastructural organization of the nervous system in the freshwater polyp Hydra. The authors use adequate methods and present outstanding imaging data with solid evidence to support their claims. The manuscript provides a starting point for further functional in vivo studies. The work will be of interest to developmental biologists and neurobiologists.

eLife assessment

This important study reports on a novel read-out methodology and fabrication strategy to mimic nuclear pore complexes, without the drawbacks of usual techniques, revealing a clear correlation between the size of the nuclear pore complex mimic and its transport selectivity. The methods are compelling, and the data, analyses and interpretation with coarse grained simulations and phenomenological models are solid, supporting the claims with minor weaknesses that would benefit from further clarification. This approach has important potential implications for further understanding of transport by the Nuclear Pore Complex.

eLife assessment

This valuable study examines the effects of different co-stimulatory pathways on gene expression and chromatin accessibility in T cells, in order to link the role of co-stimulatory proteins to genetic variants associated with inflammatory bowl disease (IBD). The work provides valuable insight into the role of alternative co-stimulatory proteins in controlling T cell responses. However, the data presented and the analyses performed are still incomplete and inconclusive with regards to IBD risk factors.

eLife assessment

The authors present a useful analysis of the phenotype of sheep in which the muscle developmental regulator myostatin has been mutated in a FGF5 knockout background. The goal was to produce sheep with a "double-muscled" phenotype, yet the genetically engineered sheep exhibited meat with a smaller cross-sectional area and higher number of muscle fibers. The work extends the extensive body of knowledge already published in this area. The authors provide evidence using in vitro experiments that Fosl1 regulates myogenesis, but the strength of evidence relating to the muscle phenotype and underlying cellular and molecular mechanism is inadequate.

eLife assessment

This important work examines hepatic acetate production via ACOT12/18 in starvation and diabetes. The investigators use solid loss of function strategies in cells, including mouse primary hepatocytes, and in vivo mouse experiments to show that ACOTs are necessary for normal acetate production in the context of fasting and type 1 diabetes. Given that acetate is commonly thought to primarily represent a fermentation product, this study is of interest as it describes hepatic pathways converting fatty acids to acetate.

eLife assessment

This paper will be of interest to scientists in the fields of virology, entomology, ecology and epidemiology as the paper explores the drivers of viral and host composition in natural and disturbed ecosystems. The data are of high quality and have been rigorously assessed.However, important additional information on the transmission ecology of these viruses and their relationship with the environment is lacking, making it difficult to interpret the results from a disease ecology perspective.

eLife assessment

The authors compellingly demonstrate that k-fiber length and dynamics are regulated at the level of individual fibers, even in the absence of focused poles, but that unfocused spindles fail to accurately segregate chromosomes, suggesting that coordination of k-fiber length by pole focusing is important for spindle function. This study provides important new information on spindle scaling, extending in an original manner previous work on this topic.

eLife assessment

This valuable paper uses representative samples of micro-census data from Botswana to describe migration rates over four points in time, from 1981 to 2011. The authors use compelling descriptive data to present migration characteristics where roughly 10% of the population moved in the past year - with equal numbers of men and women, and with migration between districts more common than within districts. Preliminary data indicated migration patterns could have supported HIV diffusion, this can be a starting point for more in-depth analyses. The work will be of interest to those studying human movement and its impact on diseases.

eLife assessment

The authors have established a model for studying p38g/d signaling, which is an important accomplishment given that previous models have been compromised by changes in the TPL2/ERK pathway. Compelling evidence is presented to support the conclusions.

eLife assessment

This manuscript provides important findings and would be of interest to specialists and researchers dealing with polycystic ovarian syndrome. Based on the compelling evidence, the authors present significant results on the role of B cells in immune cell activation in PCOS. However, there are some remarks regarding the statistics and data presentation.

eLife assessment

This important study gives novel insight into the folding diversity of the cerebellum compared to the cerebrum among 56 mammalian species. Based on impressive data, the analyses performed for anatomical descriptions and phylogenetic comparisons are solid, although some issues need to be addressed regarding the choice of statistical models, and the sample size versus the number of explanatory variables. This study will be of interest to neuroscientists, evolutionary and developmental biologists, and physicists interested in biomechanics, as these observations provide a basis for models of brain folding mechanisms.

eLife assessment

This study presents valuable findings that relate the pH pattern along the root surface of the plant Arabidopsis thaliana to the auxin response and gravitropic (changes in growth orientation) response. The evidence supporting the claims of the authors is solid, based on the observation of dynamic responses at a second-to-minute time scale and the systematic correlation between the observed changes in the longitudinal surface pH profile and changes in growth rate. The work will be of interest to a wide range of plant biologists working on plant development and responses to the environment.

eLife assessment

This paper studies color vision in anemonefish. The central conclusion of the paper is that anemonefish use signals from their UV cones to discriminate colors that would not otherwise be distinguishable; this differs from other fish in which UV cones extend the range of wavelengths of sensitivity but do not add a dimension to color vision. The work fits into a rich history of studies investigating how color vision fits into an animal's ecological niche. At the same time, the manuscript needs to more clearly establish and convey the degree to which each conclusion is supported by the data and where the limits of certainty lie.

eLife assessment

This manuscript presents a valuable new microfluidic tool that will allow researchers from different fields to rapidly quantify the chemotactic response of microbes to chemical gradients that have different strengths. Using planktonic bacteria, this paper convincingly shows that a multiplexed microfluidic device produces similar results to previously described microfluidic devices that generate only one gradient at a time. By performing on-chip dilutions, this device allows data for six different gradient strengths to be generated simultaneously, potentially reducing both experimental effort and biological variability.

eLife assessment:

This manuscript uses an innovative combination of spatial profiling with single-cell transcriptomics to define expression profiles of stromal components in proximal tumor regions compared to those in distal regions in pancreatic ductal adenocarcinoma (PDAC). Based on this, the authors claim that the presence of a proximal fibroblast population predicts worse outcomes for PDAC patients than the presence of a distal fibroblast population. While the work provides valuable insight into how different types of tumor stromal fibroblasts may affect PDAC outcomes, the work is currently incomplete and will benefit from more extended use of fibroblast and myeloid cell markers and efforts to better define the transcriptomic data generated.

eLife assessment

This study of human perceptual decision-making provides important insights into the sources of suboptimality in human inference. The authors provide solid evidence by combining psychophysics in an audiovisual causal inference task with detailed modeling of the observed behavior. Additional control analyses should be carried out to validate the identifiability of distinct suboptimalities using the authors' modeling framework, and the generalizability of their findings in other conditions should be tested or discussed more explicitly.

eLife assessment:

This important study convincingly shows that the endopeptidases ECS1 and ECS2 repress the formation of polyspermy-derived triparental offspring and haploid induction by promoting double fertilization. While the underlying mechanisms remain to be further elucidated, the data presented in this study represent a valuable foundation for understanding the regulation of offspring genome size. This study will be of particular interest to the large community of scientists who are interested in plant reproduction and breeding.

eLife assessment

This development of a highly concentrated and potentially clinically valuable antibody formulation for MS-Hu6, a first-in-class FSH-blocking humanized antibody is of potential translational importance in the management of osteoporosis, obesity, and Alzheimer's disease. The meticulous methodology is thorough and compelling in its range of techniques examining the stability and physiochemical properties of the formulated MS-Hu6.

eLife assessment

This study presents valuable structures of a pentameric ligand-gated ion channel from a thermophilic worm that is a homologue of the well-known mammalian nicotinic receptors. Although the function of the worm receptor is unknown, the authors convincingly identify interesting features for this class of receptors including a steroid detergent that is bound in the canonical neurotransmitter site and that induces conformational changes of the extracellular domains. These observations will be of broad interest to the ligand-gated ion channel community, although it is difficult at this moment to relate these observations to channel function as the channel's activating ligand remains unknown.

eLife assessment

This research provides convincing evidence that standard behavioral modeling and EEG-derived signatures of the decision process may not agree on mechanisms underlying changes in decision strategy. The authors make a strong case for the importance of informing behavioral modeling with putative neural signatures of the corresponding decision processes. The assumptions of this neurally-informed modeling approach should be further explored and clarified to highlight not only its benefits but also potential caveats.

eLife assessment

Models of cerebellar function and the coding of inputs in the cerebellum often assume that random stimuli are a reasonable stand-in for real stimuli. However, the important contribution of this paper is that conclusions about optimality and sparseness in these models do not generalize to potentially more realistic sets of stimuli, for example, those drawn from a low-dimensional manifold. While the mathematical modelling and analysis in the paper are convincing, one important limitation of the paper is that the neural dynamics and circuit architecture are not very specific to the cerebellum, and lack important biological detail.

eLife assessment

This manuscript by Combe et al. presents the role of cholinergic modulation in the spike rate adaptation in pyramidal place cells. Using combined electrophysiology, pharmacological, and multi-compartment computational modeling, the authors identify the downstream pathway (e.g. activation of TRPM4 channel) that shapes the firing pattern under the triangular-shaped ramps. The study demonstrates solid evidence, and the findings are important for bridging pyramidal neurons' molecular/channel properties to behavior-level implications (place field firing).

eLife assessment

This important work studies the spontaneous contractions (SC) of the Hydra body wall and presents a mathematical model of nutrient transport to hypothesize the role of SC on maintaining the microbiota. The solid evidence presented yields insights on the functional implications of the SC and the increased nutrient update obtained from mixing the local fluid environment through body wall contractions. The main result represents an important observation about the role of hydrodynamics on organism behavior and its relation to diffusive chemical transport processes.

eLife assessment

The manuscript by Brunetti et al. represents an important contribution where SARS-CoV-2 infection of T-helper cells is implicated and found to be mediated by CD4. The work progressed through a computationally driven hypothesis, by analyzing the interaction partners of SARS-CoV-2 spike glycoprotein (as initially modelled through similar SARS-CoV-1), followed by experimental validations, and further computational and experimental insights on the mechanism of binding. The study identifies the interaction between spike RBD domain and N Terminal domain of CD4 molecule as the specific viral attachment strategy. The evidence supporting the claims of the authors is solid, the results look significant and the data is clear and enough for understanding the manuscript. It also provides a potential usefulness of their approach in future work in understanding how viruses mediate infection of T cells. The work will be of interest to medical biologists working on SARS-CoV-2.

eLife assessment

This fundamental work advances our understanding of the effects of metformin on bone healing in hyperglycemic conditions. The evidence supporting the conclusion is convincing, using three different types of bone fracture models in type-2 diabetes (T2D) mice. This paper is of potential interest to skeletal biologists, orthopaedic surgeons, and endocrinologists who study the effects of metformin on fracture healing.

eLife assessment

In their current study, Detraux D and colleagues provide some evidence suggesting a role for heme biosynthesis on FGF-ERK and TGF beta signalling and exit from naïve pluripotency, and in controlling the 2-cell-like cell state. The observations provided by the authors are interesting and potentially relevant in the field of pluripotent cell state transitions.

eLife assessment

Dhekne et al report a novel pathway for activation of the multi-domain LRRK2 protein kinase by Rab12 GTPase. LRRK2, which is mutated in Parkinson's Disease phosphorylates a subset of Rab proteins involved in intracellular trafficking, and Parkinson's disease-linked mutations increase this phosphorylation. This work adds an important new layer of understanding of this highly complex pathway by revealing that LRRK2's binding to Rab12 enhances its ability to phosphorylate Rab10. This conclusion is supported by compelling evidence from a wide array of rigorous approaches.

eLife assessment

This valuable study reports on the role of transposable elements in gene expression variation in rice and how TE-associated expression changes could have been selected during domestication. The combination of evidence from linkage studies and selection scans for a subset of insertions is convincing, although it is difficult to know in how many cases linkage of TE insertions to other regulatory variants is responsible for altered gene expression and in how many cases the TE insertions themselves are the bona fide cause of altered gene expression. The work will be of interest to colleagues working on the role of transposable elements in adaptation and to biologists working on domestication.

eLife assessment

This manuscript describes a valuable method to study the mechanism of action of essential genes and novel putative drug targets. Evidence for the effectiveness of the system, which is based on engineering pre-validated targets for RNA-mediated knockdown into genes of interest, is compelling, and the method should find use as an orthogonal method for generating gene specific knockdowns.

eLife assessment

This important study demonstrates that the human FUS protein, which is implicated in ALS and related conditions, interacts with RNAs containing GGGGCC repeats and can regulate their translation by altering three-dimensional structures caused by these repeats. The study is carefully executed and the data provide convincing evidence for its major claims. This work will likely be of interest to researchers studying RNA binding proteins, and to those working on ALS and related diseases.

eLife assessment

This important work provides evidence that artificial recurrent neural networks can be used to investigate neural mechanisms underlying reversible remapping of spatial representations. Authors perform convincing state of the art analyses showing how population activity preserves the encoding of spatial position despite remappings due to the tracking of an internal variable. This paper will be of interest to neuroscientists studying contextual computations, neural representation of space and links between artificial neural networks and the brain.

eLife assessment

In this valuable study, the authors report a structural model of full-length kinesin-1, describing its autoinhibitory mechanism using cryo-EM, AlphaFold structural predictions, cross-linking, and mass spectrometry, which together indicate that the previous model for kinesin-1 auto-inhibition using a small motif in the kinesin tail was not adequate. The data offer a convincing model for how kinesin-1 is autoinhibited, although the evidence is in some places still incomplete and would thus benefit from additional analyses. The work will be of significant interest to the research community working on cytoplasmic transport and microtubule motors.

eLife assessment

This important study makes use of AlphaFold2 to predict the models of tens of cohesin subcomplexes from different species. The models are in most cases consistent with published cohesin mutants with defects in cohesin function in vitro and in vivo. The models provide solid evidence that leads to testable hypotheses of cohesin dynamics and regulation. More broadly, this study serves as an example of how to use AlphaFold2 to build models of protein complexes that involve the docking of flexible regions to globular domains.

eLife assessment

This study offers a model that is used to interrogate how microscopic epistasis and factors like clonal interference affect evolutionary dynamics. The study offers several important insights that can aid in our understanding of the forces that operate in adaptation. The evidence provided is solid, in the form of models and analytical descriptions that describe how these forces manifest themselves.

eLife assessment

The manuscript provides valuable insights into the regulatory role and mechanisms of the spectrin cytoskeleton in mechanotransduction in Drosophila. The data are compelling in establishing that alpha and beta spectrin regulate the Hippo signaling pathway independently via their effect on cytoskeletal tension. The work will be of interest to cell and developmental biologists, particularly those who focus on mechanotransduction and the cytoskeleton.

eLife assessment

This paper presents a valuable advance in the ability to manipulate the integrity of the barrier between endothelial cells. A wide range of data are presented, offering convincing support for the effectiveness of the method. This work is likely to attract a diverse audience of both cell biologists and researchers developing tools to manipulate cell and tissue function.

eLife assessment

This paper presents important computational modeling work that provides a mechanistic account for how memory representations become integrated or differentiated (i.e., having distinct neural representations despite being similar in content). The authors provide convincing evidence that simple unsupervised learning in a neural network model, which critically weakens connections of units that are moderately activated by multiple memories, can account for three empirical findings of differentiation in the literature. The paper also provides insightful discussion on the factors contributing to differentiation as opposed to integration, and makes new predictions for future empirical work.

eLife assessment

This important study shows that two methods of sleep induction in the fly, optogenetically activation of the dorsal fan-shaped body (which is rapidly reversible and maintains a neuronal activity signature similar to wakefulness), and Gaboxadol-induced sleep (which shuts down neuronal activity), produce distinct forms of sleep and have different effects on brain-wide neural activity. The majority of the conclusions of the paper are supported by compelling data, but the evidence supporting the claim that the two interventions trigger distinct transcriptional responses is incomplete.

eLife assessment

This is a potentially important study that contributes to our understanding of the role of beta-arrestins in endosomal activation of the vasopressin type 2 receptors. While the methodology is innovative, the evidence provided is still incomplete, which precludes drawing strong conclusions from the current data.

eLife assessment

This important study advances our understanding of how historical human activities have driven changes in freshwater biodiversity and ecosystem functioning. The authors highlight the value of including not only spatiotemporal scales in biodiversity assessments but also some of the possible drivers of biodiversity loss. Analyzing their joint contribution as environmental stressors, the authors provide compelling evidence that ecosystem assessment methods currently used by environmental regulators throughout Europe are not fit-for-purpose, and they identify several alternatives, more robust indicators of freshwater ecosystem health. The work will be of broad interest to anyone studying changes in biodiversity and their drivers.

eLife assessment

In this Tools and Resources article, the authors overcome the challenge of low Borrelia burgdorferi numbers during infection for analyses such as RNA-sequencing or mass spectrometry. They do so by physically enriching for spirochetes, which is important, as it provides technical advances for the study of global transcriptomic changes of B. burgdorferi during tick feeding, helping to build on the knowledge already collected by the field. The evidence presented is compelling, and the strategy described here could benefit researchers in the field and possibly also support broader applications.

eLife assessment

The authors provide a fundamental resource, detailing genetic variation of nutrient-responsive islet calcium regulation in mice through the lens of proteomics. The evidence for the mechanisms identified using this resource is compelling and strongly supported by integration with results from genome-wide association studies in humans. The construction of a streamlined and searchable web interface for the data maximizes their accessibility and utilization by the community.

eLife assessment

In this valuable study, the authors investigate the mechanism of amyloid nucleation in a cellular system using their novel ratiometric measurements and uncover interesting insights regarding the role of polyglutamine length and the sequence features of glutamine-rich regions on amyloid formation. Overall, the problem is significant and being able to assess nucleation in cells is of considerable relevance. The data, as presented and analyzed, are currently still incomplete. The specific claims would be stronger if based on in vitro measurements that avoid the intricacies of specific cellular systems and that are more suitable for assessing sequence-intrinsic properties.

eLife assessment

Secondary cell walls support vascular plants and conduct water throughout the plant body, and are important resources for lignocellulosic feedstocks. Here the authors present convincing genetic and biochemical evidence that secondary cell wall synthesis, known already to be under complex transcriptional control, is also controlled post-transcriptionally by MUSASHI-like RNA-binding proteins. These important results point to a new mechanism for control of secondary cell wall synthesis, which will be interesting to cell biologists and biochemists studying and attempting to manipulate plant biomass.

eLife assessment

Overall, this manuscript presents an intriguing potential refinement of models for adult SVZ neurogenesis, and highlights the role of RNA splicing at specific stages in the lineage. As such, the findings are valuable to the field of adult neurogenesis. Yet, the reviewers found the strength of the evidence to be incomplete and in some areas inadequate to support the claims. Thus, the conclusions require additional experimental support.

eLife assessment

This study presents a useful inventory of the joint effects of genetic and environmental factors on psychotic-like experiences, and identifies cognitive ability as a potential underlying mediating pathway. The data were analyzed using solid and validated methodology based on a large, multi-center dataset. However, the claim that these findings are of relevance to psychosis risk and have implications for policy changes are only partially supported by the results.

eLife assessment

This important paper reveals how cells in adjacent tissues use the extracellular matrix to establish mechanical connections. Through a series of crisp genetic manipulations and quantitative image analyses, the authors provide compelling evidence to show how an essential adhesion between the uterus and the seam cells in the nematode C. elegans is formed. The assembly of type IV collagen triggers internalization of a cell surface receptor, which then signals from endocytic vesicles to strengthen the connection.

eLife assessment

This study reports valuable findings on the influence of acute stress on prosocial behavior and its neural correlates. Though the evidence is generally solid, concerns about confounding and sampling bias detract from the potential impact.

eLife assessment

This valuable study examined the mechanisms underlying reduced excitability of ventral tegmental area dopamine neurons in mice that underwent a chronic mild unpredictable stress treatment. The authors identify NALCN and TRPC6 channels as key mechanisms that regulate spontaneous firing of ventral tegmental area dopamine neurons and examined their roles in reduced firing in mice that underwent a chronic mild unpredictable stress treatment. The evidence supporting the authors' conclusions are solid yet the reviewers pointed out some limitations in the study including statistics, specificity in pharmacological and gene knockdown experiments, and the relevance to depressions.

eLife assessment

This study represents a valuable finding on the neuron-glia communication and glial responses to traumatic brain injury (TBI). The data supporting the authors' conclusions on TBI analysis, RNA-seq on FACS sorted astrocytes, genetic analyses on Pvr-JNK/MMP1 are solid. However, astrocyte proliferation upon TBI and some of the quantitative methods are incomplete, which could be further strengthened by more rigorous analyses.

eLife assessment

This important work advances our understanding of TLR7 signaling at epithelial surfaces that drives monocytes expansion and its impact on viral responses. The evidence supporting this conclusion is solid, particularly data demonstrating TLR7 stimulation and the requirement for TLR7 in the monocyte expansion. The work will be of interest to immunologists and virologists.

eLife assessment

In this work, the authors provide important mechanistic insights into how the intracellular effector protein Calcineurin B homologous protein 3 (CHP3) can be regulated in a calcium-independent manner to expose its lipid binding site. Compelling evidence demonstrates a binding partner protein (NHE1) triggers a conformation change and exposure of the myristoyl group in CHP3 resulting in membrane association. This provides mechanistic insight into the signalling mechanisms achieved by CHP3 in a target-dependent manner, which will be of broad scientific interest.

eLife assessment

Although largely descriptive, this meta-analysis of 13,000 published Typhi genomes is hugely important to public health. The dataset and presented analysis represents the first wholesale analysis of all available Typhi genomes from the last 21 years. The findings are of great significance to tracking the emergence and maintenance of AMR in Typhi and include novel insights into XDR strain emergence in Pakistan as well as the relationship between MDR maintenance and chromosomal integration.

eLife assessment

The authors describe a sophisticated method to follow enhancer activity in both live embryos and fixed embryos in Tribolium and present important data about the function of a number of enhancers in early development. They show that some of the enhancers are "dynamic" and others are "static" and use this to provide support for the "enhancer-switching" model of gene regulation suggested by some of these authors in the past. However, the evidence they provide is incomplete and although it is consistent with the model, it does not directly support it.

eLife assessment

This study presents findings that are important for understanding plant-soil feedbacks in agriculture. The authors use a large-scale agricultural field experiment to demonstrate the role of root-emitted secondary metabolites in enhancing the yield of the next crop. By using a benzoxazinoid-deficient maize genotype, the authors provide compelling evidence that biomass production and grain yield of several wheat varieties can be increased when grown in soil conditioned by maize plants able to release benzoxazinoids.

eLife assessment

This valuable work investigates the fundamental concept of how the energy of agonist binding is converted into the energy of the conformational change that opens the pore of a ligand-gated ion channel. The conclusions are based on analysis of solid data in terms of a mechanistic model, but adequate statistical analysis is lacking and the uniqueness of the proposed model is not discussed. The findings will be interesting to biophysicists working on ligand-gated ion channels and, more generally, to enzymologists focused on allosteric enzyme regulation.

eLife assessment

This valuable study examines the distribution of four states of brain activity across a variety of cognitive conditions, linking systems neuroscience with cognition and behavior. The work is convincing, using null models and replication in independent datasets to support their findings.

eLife assessment

This important work shows how a transcription factor, fruitless isoform C, fine-tunes the expression of stemness genes to maintain proper stem-cell identity during neurogenesis in Drosophila. The rationale of the work is well-thought-out, conclusions are supported by compelling evidence, and experiments are performed in a rigorous manner, although additional statistics would improve the conclusions. Overall, this work will be of interest to those working on chromatin regulation, transcription regulation, and stem-cell biology.

eLife assessment

This study presents a fundamental meta-analysis on the causes of glucocorticoid variation in birds and mammals. It provides convincing evidence that an increase in metabolic rates also increases glucocorticoid concentrations. As such, the work will be of broad interest to animal physiologists.

eLife assessment

This valuable study provides insights into the IDA peptide with dual functions in development and immunity. The approach used is solid and helps to define the role of IDA in a two-step process, cell separation followed by activation of innate defenses. The main limitation of the study is the lack of direct evidence linking signaling by IDA and its HAE receptors to immunity. As such the work remains descriptive but it will nevertheless be of interest to a wide range of plant cell biologists.

eLife assessment

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

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 solid, allowing for the first time to discriminate among proposed ejection mechanisms. More details about the model, regarding both the actual topology of the system and the pressure, would be, however, helpful for the reader. The approach implemented here, 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 important study used a battery of cutting-edge technologies including whole exosome sequencing, knockout/knockdown animal models and comparative proteomics to define the physiological roles of ZMYND21 in the regulation of sperm flagellar development and male fertility. The data supporting the conclusion are solid, although inclusion of more patients and ultrastructural studies would have further strengthened the study. This work will be of interest to clinicians and researchers who work on male fertility, but also those working on organs/systems containing motile cilia (e.g., trachea, oviduct, ventricular ependymal cells).

elife assessment:

This small-sized clinical trial comparing nebulized dornase-alfa to best available care in patients hospitalized with COVID-19 pneumonia is valuable, but in its present form the paper is incomplete: the number of randomized participants is small, investigators describe also a contemporary cohort of controls and the study concludes about decrease of inflammation (reflected by CRP levels) after 7 days of treatment but no other statistically significant clinical benefit.

eLife assessment

This manuscript represents a valuable study showing that microplastics indeed accumulate in both bovine and human ovarian follicular fluid. It also presented data that direct exposure of bovine eggs to polystyrene, a microplastic commonly found in follicular fluid, negatively affects oocyte maturation, probably through the downregulation of key proteins involved in oxidative stress, DNA damage, apoptosis, and oocyte maturation. Despite the solid supporting evidence, inclusion of the demographics and reasons for assisted reproduction of the human subjects used, as well as the details on quality control for proteomic analyses would further strengthen the study. The work will be of interest to reproductive toxicologists, regulatory scientists and reproductive health care professionals.

eLife assessment

This paper presents an important effort to develop an open source software framework for monitoring trends and variations in healthcare over time in England. They demonstrate a compelling example of how this system can track key health care indicators over the course of the COVID-19 pandemic. The paper will likely be mainly of interest to stakeholders in England, but could inspire the creation of similar systems in other countries.

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, though certain modeling choices could benefit from justification or further exploration of alternatives. Overall, this is a well-presented study that explores the question of how changes in intrinsic excitability can influence memory representations.

eLife assessment

This useful study investigates the role of mechanotransduction channels in controlling food ingestion in Drosophila and localizes the role of some of these genes to sensory neurons in the fly pharynx. The evidence supporting several of the authors claims is incomplete and would benefit from additional investigation. With additional evidence, this paper would be of interest to biologists interested in mechanosensation and feeding behavior.

eLife assessment

This important study combines genetically barcoded rabies viruses with spatial transcriptomics in vivo in the mouse brain to decode connectivity of neural circuits. The data generated by the combination of these approaches in this new way is mostly convincing as the authors provide validation and proof-of-concept that the approach can be successful. While this new combination of established techniques has promise for elucidating brain connectivity, there are still some nuances and caveats to the interpretations of the results that are lacking especially with regards to noting unexpected barcodes either due to unexpected/novel connections or unexpected rabies spread.

eLife assessment

This valuable work proposes a new model of basal ganglia function termed the "Triple Control Model" consisting of one direct pathway and two indirect pathways. The study provides evidence that the firing dynamics of substantia nigra reflect action selection but not interval time or reward and makes a case for the need for the Triple Control Model to explain the results of their manipulations of D1 and D2 receptor-expressing cells in the striatum. Although this work may be of interest to neuroscientists who study basal ganglia, without additional analyses of the relationship of neural activity to movements, and direct experimental evidence of two indirect pathways, the evidence for this model is somewhat incomplete.

eLife assessment

The formation of the place cell map in the hippocampus is foundational to many models and is thought to form a substrate onto which memories can be structured. This paper presents an important new observation to our understanding of place cell formation - namely that task learning changes or interferes with the process of place cell map stabilization. Reviewers found that there was incomplete evidence for this result, however, in this version of the manuscript because of a confound between the duration of experience in an environment and task-specific learning.

eLife assessment

This study presents a valuable and comprehensive mutagenesis map of the AAV2 rep gene, which will undoubtedly capture the interest of scientists working with adeno-associated viruses and those engaged in the field of gene therapy. The thorough characterization of massive rep variants across multiple AAV production systems bolsters the claims made in the study, highlighting its utility in enhancing our understanding of Rep protein function and advancing gene therapy applications. Despite some limitations, such as the lack of measurements on AAV transduction efficiency, the evidence presented is solid and establishes a strong foundation that will stimulate and inform future research in the field.

eLife assessment

This study presents valuable findings on the organization of respiratory chain complexes in mitochondria, but the evidence supporting the main claims is currently incomplete, as the structural reasons for and significance of supercomplex formation are unclear. The work will be of interest to the community working on mitochondrial bioenergetics.

eLife assessment

This study presents a useful set of experiments to test how a salivary protein might facilitate planthopper-transmitted rice stripe virus infection by interfering with callose deposition. If the conclusions can be confirmed, the study will enhance our understanding of the mechanisms mediating tripartite virus-insect vector-plant interactions and would be of general interest in plant science research. Whereas most experimental data is compelling, the conclusions rely on inadequate evidence for the salivary protein carbonic anhydrase being present two weeks post injection in the plant, which seems unlikely.

eLife assessment

The full role of small RNAs, often key global regulators of gene expression in connection with environmental adaptation, in flagella regulation has not been determined. This study presents important findings regarding the function of small RNAs in bacterial motility and regulation of flagella biosynthesis regulation and number. The authors combine multiple methods, including RIL-seq, structural probing, RNA blots and reporter assays, to provide convincing biochemical evidence for direct effects of specific small RNAs, whose expression is dependent on flagella sigma 28 (FliA), on transcriptional attenuation of flagella operons via regulation of ribosomal proteins.

eLife assessment

This study presents a valuable finding on the immunophenotypes of cancer treatment-related pneumonitis. The evidence supporting the claims of the authors is solid, although the inclusion of controls, as suggested by one of the reviewers, strengthened the study. The work will be of interest to cancer immunologists

eLife assessment:

This important study represents a comprehensive computational analysis of Plasmodium falciparum gene expression, with a focus on var gene expression, in parasites isolated from patients; it assesses changes that occur as the parasites adapt to short-term in vitro culture conditions. The work provides technical advances to update a previously developed computational pipeline. Although the findings of the shifts in the expression of particular var genes have theoretical or practical implications beyond a single subfield, the results are incomplete and the main claims are only partially supported.

eLife assessment

This study presents important findings regarding the quantification of dynamics in fish communities in changing ecosystems by combining a large-scale environmental DNA metabarcoding time series with novel statistical approaches. The methods are convincing, with controlled experiments, thorough statistical analyses, and a substantial dataset covering two years of detailed observation, which can provide sufficient power to detect fine-scale ecological interactions. This work is relevant for informing future research on assessing community stability under climate change.

eLife assessment

This study makes valuable observations about the representation of "value" in the mouse brain, by using a nice task design and recording from an impressive number of brain regions. The combination of state-of-the-art imaging and electrophysiology data offer solid support for the authors' conclusions. The paper will be of interest to a broad audience of neuroscientists interested in reward processing in the brain.

eLife assessment

This manuscript provides a description of an approach for efficiently integrating diverse libraries into the C. elegans genome and tools that enable researchers to use the method. It is a valuable contribution for researchers carrying out experiments that would benefit from easy generation of such libraries, and the data for the effectiveness of the method is solid. The advantages of this approach in terms of ease and effectiveness relative to others with similar aims will emerge as they are put to more general use in addressing biological problems.

eLife assessment

This study makes a fundamental observation about the role of activity in the mouse thalamus on scalp recorded voltage fluctuations. The novel approach and sophisticated analysis of neural signals provides compelling support for the authors' observations. This work will likely be of broad interest to neuroscientists.

eLife assessment

This study presents a valuable examination into the role Notch-RBP-J signaling in regulating monocyte subset homeostasis. The data were collected and analyzed using solid and validated methodology and can be used as a starting point for exploring the mechanisms involved in RBP-J signaling in non-classical monocytes.