eLife assessment

This is a valuable study providing solid evidence that the Mediator kinase module mediates an elevated inflammatory response, manifested by heightened cytokine levels, associated with Downs syndrome (DS) via transcriptional changes impacting cell signaling and metabolism, which has significance for the treatment of DS and other chronic inflammatory conditions. Particular strengths of the study include the combined experimental approaches of transcriptomics, untargeted metabolomics, cytokine screens, and the use of sibling-matched cell lines (trisomy 21 vs disomy 21) from various donors. Less certain is that the Mediator kinase plays a meaningful role in regulating mRNA splicing. Further evidence that nuclear receptors are activated by changes in lipid levels and that mitochondrial function is substantially reduced on Mediator kinase inhibition would strengthen the work.

eLife assessment

This manuscript presents valuable findings on two isolates of deep sea Lentisphaerae strains, which further our understanding of deep sea microbial life. The manuscript's primary claim is that phage isolates augment polysaccharide use in Pseudomonas bacteria, with preliminary evidence for the potential auxiliary metabolic genes in chronic phage infection and/or host proliferation. The strength of the evidence is overall solid and there are only minor weaknesses regarding the mechanism of polysaccharide use by the phages and the evidence for chronic infection. Overall, the data on Lentisphaerae strains will deepen our understanding of microbial life in the deep sea.

eLife assessment

This important study provides a new perspective on why preparatory activity occurs before the onset of movement. The authors report that when there is a cost on the inputs, the optimal inputs should start before the desired network output for a wide variety of recurrent networks. The authors present compelling evidence by combining mathematically tractable analyses in linear networks and numerical simulation in nonlinear networks.

eLife assessment

This is a potentially 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. A strategy for minimizing variability across cell lines is used, but the explanation is not complete. The revised manuscript adds RNAseq and qPCR measurements of the expression of the gene SCN1A, however these do not appear to agree, perhaps because of the way the qPCR measurements are normalized, and there is no measurement of Nav1.1, the gene product thought to be responsible for the majority of DS cases. Hence the evidence that there is reduced expression of SCN1A or its gene product is not complete and therefore it is difficult to evaluate whether or not the observed epigenetic changes are causal. The work would potentially be of interest to scientists who study development, developmental disorders, and epigenetic contributions to disease.

eLife assessment

This important study identifies the anti-inflammatory function of PEGylated PDZ peptides that are derived from the ZO-1 protein. Results from cellular and in vivo experiments tracking key inflammatory markers are compelling. Although the present study would benefit from investigating chronic inflammation conditions using microbe and protein data, the work provides a proof of concept for developing novel strategies against acute inflammatory conditions such as sepsis.

eLife assessment

This important study presents a novel pipeline for the large-scale genomic prediction of members of the non-ribosomal peptide group of pyoverdines based on a dataset from nearly 2000 Pseudomonas genomes. The advance presented in this study is based on convincing evidence. This study of bacterial siderophores has broad theoretical and practical implications beyond a singular subfield.

eLife assessment

This valuable study uses neuroanatomical techniques to investigate somatosensory projections from the elephant trunk to the brainstem. Given its unique specializations, understanding how the elephant trunk is represented within the brain is of general interest to evolutionary and comparative neuroscientists. The authors present solid evidence for the existence of a novel isomorphism in which the folds of the trunk are mapped onto the trigeminal nucleus; however, due to their unusual structure, some uncertainty remains about the identification and anatomical organization of nuclei within the elephant brainstem.

eLife assessment

This fundamental study provides insights into how pathogens respond, on a systemic level including several gene targets and clusters, to selected antimicrobial molecules. Compelling evidence is provided, through multi-omics and functional approaches, that very similar molecules originally designed to target the same bacterial protein act differently within the context of the whole set of cellular transcripts, expressed proteins, and pre-lethal metabolic changes. Given the rapid accumulation of omics data and the much slower capacity of extracting biologically relevant insights from big data, this work exemplifies how the development of sensitive data analysis is still a major necessity in modern research.

eLife assessment

This important paper addresses the process by which cryptic splice sites that occur randomly in exons are ignored by the splicing machinery. Integrating state-of- the-art genome-wide approaches such as CLIP-seq with the study of individual examples, this study convincingly implicates members of RBMX family of RNA binding proteins in such cryptic splice site suppression and showcases its importance for the fidelity of expression of genes with very large exons.

eLife assessment

This study presents a valuable finding that the blood-brain barrier functionality changes with age and differs between males and females. The analysis is solid, comprising a large and racially diverse dataset, and utilizes a contrast-agent-free MRI method. Since limited work has been done in the MRI field on the blood-brain barrier using this method, this study is of great interest to neuroimaging researchers and clinicians.

eLife assessment

Peng et al. reported important findings that 36THz high-frequency terahertz stimulation (HFTS) could suppress the activity of pyramidal neurons by enhancing the conductance of voltage-gated potassium channels. The significance of the findings in this paper is that chronic pain remains a significant medical problem, and there is a need to find non-pharmacological interventions for treatment. The authors present convincing evidence that high-frequency stimulation of the anterior cingulate cortex can alter neuronal activity and improve sensory pain behaviors in mice.

eLife assessment

This important research describes the sensory innervation of oral tumors, with potential implications for understanding cancer-induced alterations in motivation and anhedonia in a mouse model. These findings are solid and are supported by anatomical and transcriptional changes in the tumor that suggest sensory innervation, neural tracing, and neural activity measurements. While nerve innervation of the tumor and associated increase in brain activity is well-supported, future studies could enhance specificity by employing more targeted genetic and pharmacological tools to manipulate these circuits selectively.

eLife assessment

This important study reports findings on the GnRH pulse generator's role in androgen-exposed mouse models, providing further insights into PCOS pathophysiology and advancing the field of reproductive endocrinology. The experimental data were collected using cutting-edge methodologies and were solid. However, it is noteworthy that the findings, while interesting, are primarily applicable to mouse models, and their translation to human physiology requires cautious interpretation and further validation. This work will be of interest to endocrinologists and reproductive biologists.

eLife assessment

This study provides a potentially valuable understanding of the contribution of different striatal subregions, the anterior Dorsal Lateral Striatum (aDLS) and the posterior Ventrolateral Striatum (pVLS), to auditory discrimination learning. The combined methods used to probe this are compelling, yet the data presented are incomplete to support the conclusions. There is insufficient data visualization of learning vs. performance, and missing details about timing of manipulations and microPET imaging.

eLife assessment

This important study compared the brain development trajectories of humans and macaque monkeys to quantify different evolutionary effects of convergent and divergent neural pathways between the two species. The cross-species evidence is solid, based on brain age prediction models that were carefully developed by using public MRI datasets of both humans and macaque monkeys. The findings will be of interest to neuroscientists, developmental biologists, and evolutionary biologists.

eLife assessment

This important work offers an experimental structural characterization of the Tramtrack-like BTB/POZ domains in insects, revealing that these domains form stable hexameric assemblies. The structural evidence is convincing, and validated by fold prediction and evolutionary pathway analyses. This paper would be of interest to structural and evolutionary biologists.

eLife assessment

This important study explores and delineates multivariate mappings between brain structure and functional measures with latent dimensions of psychopathology. This work provides solid evidence for the existence of such mappings and charts the relationship between different neurobiological measures and distinct dimensions of psychopathology. This work will be of broad interest within the neuroscience field.

eLife assessment

This potentially important work presents a tool for performing phylogenetic taxonomic classification of DNA sequences. In terms of methodology, the work is compelling. The authors perform a benchmark experiment against current state-of-the-art tools using real and simulated datasets to demonstrate where the novel tool stands in the context of existing methods. However, the experimentation is still incomplete. It would benefit from a more thorough exploration of existing methods as well as data sets that better represent real-world use cases.

eLife assessment

In this study, Perez-Lopez and colleagues examine an important function of the chemokine CCL28 in mucosal host defenses against the gut bacterial pathogen Salmonella Typhimurium and lung pathogen Acinetobacter baumanii. They find that CCL28-CCR3 axis regulates neutrophil recruitment and function, and promotes bacterial clearance in one infectious context but exacerbates disease against the other pathogen. Therefore, CCL28 plays a critical role in mucosal immunity and neutrophil biology that differentially affects host defenses against pathogens.

Editors Assessment:

RAD-Seq (Restriction-site-associated DNA sequencing) is a cost-effective method for single nucleotide polymorphism (SNP) discovery and genotyping. In this study the authors performed a kinship analysis and pedigree reconstruction for two different cattle breeds (Angus and Xiangxi yellow cattle). A total of 975 cattle, including 923 offspring with 24 known sires and 28 known dams, were sampled and subjected to SNP discovery and genotyping using RAD-Seq. Producing a SNP panel with 7305 SNPs capturing the maximum difference between paternal and maternal genome information, and being able to distinguish between the F1 and F2 generation with 90% accuracy. Peer review helped highlight better the practical applications of this work. The combination of the efficiency of RNA-seq and advances in kinship analysis here can helpfully help improve breed management, local resource utilization, and conservation of livestock.

This evaluation refers to version 1 of the preprint

Editors Assessment: This work is part of a series of papers from the Hong Kong Biodiversity Genomics Consortium sequencing the rich biodiversity of species in Hong Kong (see https://doi.org/10.46471/GIGABYTE_SERIES_0006). This example assembles the genome of the black-faced spoonbill (Platalea minor), an emblematic wading bird from East Asia that is classified as globally endangered by the IUCN. This Data Release reporting a 1.24Gb chromosomal-level genome assembly produced using a combination of PacBio SMRT and Omni-C scaffolding technologies. BUSCO and Merqury validation were carried out, gene models created, and peer reviewers also requested MCscan synteny analysis. This showed the genome assembly had high sequence continuity with scaffold length N50=53 Mb. Presenting data from 14 individuals this will hopefully be a useful and valuable resources for future population genomic studies aimed at better understanding spoonbill species numbers and conservation.

*This evaluation refers to version 1 of the preprint *

eLife assessment

This study provides useful in vitro evidence to support a mechanism whereby dyslipidemia could accelerate renal functional decline through the activation of the AT1R/LOX1 complex by oxLDL and AngII. As such, it improves the knowledge regarding the complex interplay between dyslipidemia and renal disease and provides a solid basis for the discovery of novel therapeutic strategies for patients with lipid disorders. The methods, data, and analyses support the presented findings, although the observed variability and need for further in vivo validation require additional research in this key area.

eLife assessment

The study explored the influence of magnesium on phenotypic antibiotic resistance in two Vibrio model bacteria. This research is fundamental for revealing the phenotypic antibiotic resistance mechanism utilized by the specified model bacteria in elevated levels of magnesium. The study produced solid evidence indicating that in high concentrations of magnesium, the efficacy of selected antibiotics was diminished due to decreased biosynthesis of unsaturated fatty acids and PE, along with an increase in the biosynthesis of PG.

eLife assessment

This valuable study demonstrates how proximity labeling with streptavidin can be used to boost fluorescence signals in otherwise hard-to-label regions of cells. The experimental verification of amplification of fluorescence near epitope tags in phase-separated compartments is solid, demonstrating enhanced signal-to-noise compared to immunofluorescence. This study will be of particular interest to those using correlative light and electron microscopy or expansion microscopy when the signal is limiting or inaccessible.

eLife assessment

The authors made an important finding that CD29+/CD56+ progenitor cells isolated from human muscles have the potential to differentiate to tendons in vitro and in vivo. The author's approach to testing the tenogenesis of the CD29+/CD56+ progenitors is solid, and the conclusion is supported by enough evidence with minor flaws. This work will be of interest to the population who need tendon regeneration from their injury.

eLife assessment

In this potentially important study, the authors conducted atomistic simulations to probe the salt-dependent phase separation of the low-complexity domain of hnRN-PA1 (A1-LCD). The authors have identified both direct and indirect mechanisms of salt modulation, provided explanations for four distinct classes of salt dependence, and proposed a model for predicting protein properties from amino acid composition. There is a range of opinions regarding the strength of evidence, with some considering the evidence as incomplete due to the limitations in the length and complexity of the atomistic MD simulations. The work should be put into a better context in relation to previous studies of salt effects on protein phase separation.

eLife assessment

This manuscript reports important findings on the impact of maternal obesity on oocyte methylation and its transgenerational effects. The evidence presented to substantiate the major claims appears incomplete. This study would be of interest to biologists in the fields of epigenetics and metabolism.

eLife assessment

This study reports the adhesion G-protein-coupled receptor A3 (ADGRA3) as a possible target for activating adaptive thermogenesis in white and brown adipose tissue. The study provides valuable insights for scientists who study metabolism, obesity, and adipose tissue biology. Meanwhile, the experimental evidence supporting the claim is incomplete, and more rigorous approaches are needed to demonstrate the relevance of this receptor in adipose tissue biology.

eLife assessment

In an important fMRI study with an elegant experimental design and rigorous cross-decoding analyses, this work shows a solid dissociation between two parietal regions in visually processing actions. Specifically, aIPL is found to be sensitive to the causal effects of observed actions, while SPL is sensitive to the patterns of body motion involved in those actions. Additional analysis and explanation would help to determine the strength of evidence and the mechanistic underpinnings would benefit from closer consideration. Nevertheless, the work will be of broad interest to cognitive neuroscientists, particularly vision and action researchers.

eLife assessment

The authors have reported an important study in which they use a double-blind design to explore pharmacological manipulations in the context of a behavioral task. Despite a relatively small sample size, the findings are solid and motivate future explanations of the mechanism underlying their observations. The findings could be further strengthened by addressing some remaining concerns that relate to preprocessing, statistical details, and possible ocular artifacts.

eLife assessment

This study identified an innovative molecular mechanism linking diabetes to Alzheimer's disease (AD) risk, with important significance. The finding presents novel insights into AD pathogenesis and provides strong evidence about the mechanistic roles of Kallistatin, and the therapeutic potential of fenofibrate in AD. The experiments are well conducted, and the evidence is convincing.

eLife assessment

This valuable study investigates the selectivity of neuronal responses in the primary visual cortex and the dorsal lateral geniculate nucleus to stimuli presented far outside their receptive fields. The evidence supporting the claims is incomplete, due to lack of clarity. This paper should be of interest to neurophysiologists interested in vision and contextual modulations.

eLife assessment

This work presents important findings regarding the interaction of the monkeypox virus (MPXV) attachment H3 protein with the cellular receptor heparan sulfate and the use of this information to develop antivirals potentially effective against all orthopoxviruses. Using a combination of state-of-the art computational and wet experiments the authors present solid evidence to sustain their claims. These results will interest those working on basic orthopoxviruses biology and antiviral development.

eLife assessment

This study presents valuable framework and findings to our understanding of the brain cortex as a fractal object. Based on detailed methodology, the evidence provided on the stability of its shape property within 11 primate species is convincing, as well as the scale-specific effects of ageing on the human brain. 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

This study presents a valuable report on a machine-learning tool for predicting synergistic drug combinations for cancer treatment. However, the evidence supporting the claims of the authors is incomplete, as the reported model shows some evidence of overfitting, and the claims of the authors could be strengthened if additional validation experiments were performed. The work will be of interest to oncologists and medical biologists working on cancer.

eLife assessment

This study reports a comparative biochemical and structural analysis of two PLP decarboxylase enzymes from plants. The work is useful because of the potential application of these enzymes in industrial theanine production. The structure provides a solid basis for understanding substrate specificity but some aspects of the work are incomplete. The paper will be of interest to enzymologists studying PLP enzymes and those working on enzyme engineering in plants.

eLife assessment

This is a valuable contribution to our understanding of how different cell stressors (ethanol or heat-shock) elicit unique responses at the genomic and topographical level under the regulation of yeast transcription factor Hsf1, providing solid evidence documenting the temporal coupling (or lack thereof) between Hsf1 aggregation and long-range communication among co-regulated heat-shock loci versus chromatin remodeling and transcriptional activation. A particular strength is the combination of genomic and imaging-based experimental approaches applied to genetically engineered in vivo systems.

eLife assessment

Pharmacological induction of physiological slowing combined with organ perfusion systems could provide a novel therapeutic strategy for tissue and organ preservation. Using a Xenopus model, the authors provide important findings on a use of drug to slow down metabolism for the purpose of organ preservation. The authors provide compelling evidence that SNC80 can rapidly and reversibly slow biochemical and metabolic activities while preserving cell and tissue viability. This approach may be beneficial for transplantation, trauma management, and improving organ survival in remote and low-resource settings

eLife assessment

This important study highlights the importance of SLAM-SAP signaling in determining innate gamma-delta T cell sublineages and their T cell receptor repertoires. It uncovers the complex role of the SLAM-SAP pathway in developing specific gamma-delta T cell subsets. The evidence presented is compelling, backed by high-quality data obtained through advanced single cell proteogenomics techniques.This work will be of broad interest to immunologists.

eLife assessment

This valuable study reports that while most plasmacytoid dendritic cells (pDCs) originate from common dendritic cell precursors, approximately 20% are derived from lymphoid progenitors shared with B cells. The methodology used and the evidence are solid, and further demonstrate the distinct transcription factor requirements and activities of this subset of pDCs, although the functional significance of this dendritic cell subset will require further elucidation. The findings will be of great interest for those interested in the developmental and functional biology of the immune system.

eLife assessment

This important study examines E. coli growth and division, suggesting that inhomogeneous organization of ribosomes in the cytoplasm results in cell size-dependent growth rate perturbations. The work is conceptually appealing, but incomplete due to shortcomings in the experiments and modeling.

eLife assessment

Giamundo et al. present valuable data with new insights new insight into the role of Ezrin, a major membrane-actin linker that assembles signaling complexes, in the spatial regulation of EGF signaling mediators. The use of multiple state-of-the-art microscopy techniques, multiple cell lines and inhibitors, and in vivo models provides solid support for the majority of their conclusions. The findings are helpful for our understanding of EGF/mTOR signal transduction and support a critical role for the scaffolding protein Ezrin, in the upstream regulation of EGFR/AKT activity, TSC subcellular localization and mTORC1 signaling, thus contributing to our understanding of the regulation of endo-lysosomal signaling, alterations in which are implicated in many human diseases.

eLife assessment

This important work shows compelling data that significantly advances our understanding of the regulation of neurotransmitter and hormone secretion by exploring the mechanisms of how the protein complexin 2 (Cplx2) interacts with the calcium sensor synaptotagmin. The function of mammalian Cplx2 is studied using chromaffin cells derived from Cplx2 knock out mice as a system to overexpress and functionally characterize mutant Cplx2 forms and the interaction between Cplx2 and synaptotagmin. The authors identify structural requirements within the protein for Cplx's dual role in preventing premature vesicle exocytosis and enhancing evoked exocytosis. The findings are of broad interest to neuroscientists and cell biologists.

eLife assessment

Shore et al. report important effects of a heterozygous mutation in the KCNT1 potassium channel on ion currents and firing behavior of excitatory and inhibitory neurons in the cortex of KCNT1-Y777H mice. The authors provide solid evidence of physiological differences between this heterozygous mutation and their previous work with homozygotes. The reviewers appreciated the inclusion of recordings in ex vivo slices and dissociated cortical neurons, as well as the additional evidence showing an increase in persistent sodium currents (INaP) in parvalbumin-positive interneurons in heterozygotes. However, they were unclear regarding the likelihood of the increased sodium influx through INaP channels increasing sodium-activated potassium currents in these neurons.

eLife assessment

This important work proposes a neural network model of interactions between the prefrontal cortex and basal ganglia to implement adaptive resource allocation in working memory, where the gating strategies for storage are adjusted by reinforcement learning. Numerical simulations provide convincing evidence for the superiority of the model in improving effective capacity, optimizing resource management, and reducing error rates, as well as solid evidence for its human-like performance. The paper could be strengthened further by a more thorough comparison of model predictions with human behavior and by improved clarity in presentation. This work will be of broad interest to computational and cognitive neuroscientists, and may also interest machine-learning researchers who seek to develop brain-inspired machine-learning algorithms for memory.

eLife assessment

Rachubinski and colleagues provide an important manuscript that includes two major advances in understanding immune dysregulation in a large cohort of individuals with Down syndrome. The work comprises compelling, comprehensive, and state-of-the-art clinical, immunological, and autoantibody assessment of autoimmune/inflammatory manifestations. Additionally, the authors report promising results from a clinical trial with the JAK inhibitor tofacitinib for individuals with dermatological autoimmune disease.

eLife assessment

Based on analyses of retinae from genetically modified mice, and from wild-type ground squirrel and macaque, employing microscopic imaging, electrophysiology, and pharmacological manipulations, this valuable study on the role of Cav1.4 calcium channels in cone photoreceptor cells (i) shows that the expression of a Cav1.4 variant lacking calcium conductivity supports the development of cone synapses beyond what is observed in the complete absence of Cav1.4, and (ii) indicates that the cone pathway can partially operate even without calcium flux through Cav1.4 channels, thus preserving behavioral responses under bright light. The evidence for the function of Cav1.4 protein in synapse development is convincing and in agreement with a closely related earlier study by the same authors on rod photoreceptors. The mechanism of compensation of Cav1.4 loss by Cav3 remains unclear but appears to involve post-transcriptional processes. As congenital Cav1.4 dysfunction can cause stationary night blindness, this work relates to a wide range of neuroscience topics, from synapse biology to neuro-ophthalmology.

eLife assessment

The authors have presented an interesting set of results showing that female sex peptide signaling adversely affects late-life neurodegeneration after early-life exposure to repetitive mild head injury in Drosophila. This fundamental work substantially advances our understanding of how sex-dependent response to TBI occurs by identifying the Sex Peptide and the immune system as modulators of sex differences. The evidence supporting the conclusions is compelling with rigorous inclusion of controls and appropriate statistics.

eLife assessment

These valuable findings develop a mouse model with trackable fusion Fshr protein, which will be of use to the field. The animal model helps to elucidate the expression and function of the FSH receptor in extra-gonadal tissues. The strength of the evidence is solid in most parts, although additional validation of the localization data would strengthen the study considerably.

eLife assessment

This important study identifies a novel gastrointestinal enhancer of Ctnnb1. The authors present convincing evidence to support their claim that the dosage of Wnt/β-catenin signaling controlled by this enhancer is critical to intestinal epithelia homeostasis and the progression of colorectal cancers. The study will be of interest to biomedical researchers interested in Wnt signaling, tissue-specific enhancers, intestinal homeostasis, and colon cancer.

eLife assessment

The valuable work by authors improves our understanding on the effects of tree diversity on host-parasitoid communities of insects in forests in an experimental setting. Most of the analyses used are solid, but some of the conclusions seem a bit too strong and stretched.

eLife assessment

The manuscript presents a machine-learning method to predict protein hotspot residues. The validation is incomplete, along with the misinterpretation of the results with other current methods like FTMap.

eLife assessment

This useful study examines the neural activity in the motor cortex as a monkey reaches to intercept moving targets, focusing on how tuned single neurons contribute to an interesting overall population geometry. The presented results and analyses are solid, though the investigation of this novel task could be strengthened by clarifying the assumptions behind the single neuron analyses, and further analyses of the neural population activity and its relation to different features of behaviour.

eLife assessment

Semenova et al. have studied a large cross-sectional cohort of people living with HIV on suppressive antiretroviral therapy and performed high dimensional flow-cytometry for analysis with data science/machine learning approaches to investigate associations of immunological and clinical parameters and intact/total HIV DNA levels (and categorizations). The study is useful in introducing these new methods and large data set and appears mostly solid, though some of the claims were incompletely supported by the modeling results. The authors have revised the text to fairly reflect their results, yet open questions remain about utility, particularly as to the value of categorical classification (vs continuous measurement) of reservoir size.

eLife assessment

The present work provides new insights into detailed brain morphology. Using state-of-the-art methods, it provides compelling evidence for the relevance of sucal morphology for the precise localization of brain function. The fundamental findings have great relevance for the fields of imaging neuroscience and individualized medicine as ever-improving techniques improve precision to the point where individual brain anatomy is taking centre stage.

eLife assessment

This is an important study that connects the polymerase-associated factor 1 complex (Paf1C) with Histone 2B monoubiquitination and the expression of genes key to virulence in Cryptococcus neoformans. The provided information is convincing and has the potential to open several opportunities to further understand the basic biology of this significant human fungal pathogen.

eLife assessment

This study presents an important computational tool for the quantification of the cellular composition of human tissues profiled with ATAC-seq. The methodology is solid and its application results on breast cancer tumor tissues are convincing. It advances existing methods by utilizing a comprehensive reference profile for major cancer-relevant cell types, compatible with a widely-used cell type deconvolution tool.

eLife assessment

This is a useful paper regarding the roles of brown adipose tissue and skeletal muscle in thermogenesis in mice, with potential significance for the field. The overall approach is innovative but on balance the evidence for the claim is incomplete, as cast immobilization, while innovative, is likely stressful, may impact muscle and BAT directly, and imposes an energetic cost of motion on the animal that is not accounted for. Further experiments are also needed to directly assess the role of adipose-derived BCAAs in thermogenesis.

eLife assessment

This important study combines experiment and theory to examine how the intrinsic physiological properties of neurons involved in orchestrating birdsong are related to the temporal structure of song. Intrinsic properties determine how neurons respond to inputs, and in this manuscript, the authors describe rules that connect these intrinsic properties to a learned behaviour, the learned song of an adult songbird. The experimental data are convincing and the computational model builds on a robust and well-validated biophysical framework. Although some key points of the model could be established more strongly, the evidence supporting the idea that song temporal structure is related to intrinsic physiology is solid and this research will be of general interest to researchers in the field and neurophysiologists.

eLife assessment

This preprint explores the involvement of cyclic di-GMP in genome stability and antibiotic persistence regulation in bacterial biofilms. The authors proposed a novel mechanism that, due to bacterial adhesion, increases c-di-GMP levels and influences persister formation through interaction with HipH. While the work may provide useful insights that could attract researchers in biofilm studies and persistence mechanisms, the main findings are inadequately supported and require further validation and refinement in experimental design.

eLife assessment

This study retrospectively analyzed clinical data to develop a risk prediction model for pulmonary hypertension in high-altitude populations. The evidence is solid and the findings are useful and hold clinical significance as the model can be used for intuitive and individualized prediction of pulmonary hypertension risk in these populations.

eLife assessment

This manuscript provides valuable evidence comparing the performance of mathematical models and opinions from experts engaged in outbreak response in forecasting the spatial spread of an Ebola epidemic. The evidence supporting the conclusions is convincing though the work might have benefited from the use of more than two models in the ensemble predictions. It will be of interest to disease modellers, infectious disease epidemiologists, policy-makers, and those who need to inform policy-makers during an outbreak.

eLife assessment

The authors report that chemogenetic methods targeting the ventral cervical spinal cord can be used to increase phrenic inspiratory motor output and subsequent diaphragm EMG activity and ventilation in rodents. These findings are important because they are a necessary first step towards using chemogenetic methods to drive inspiratory activity in disorders in which motor neurons are compromised, such as spinal injury and degenerative disease. The data are convincing, with rigorous assessments of phrenic inspiratory activity and its ability to drive the diaphragm and subsequent ventilation, as well as assessments of DREADD expression.

eLife assessment

This valuable study by Cui et al. investigates mechanisms generating sighs, which are crucial for respiratory function and linked to emotional states. Utilizing advanced methods in mice, they provide solid evidence that increased excitability in specific preBötzinger complex neuronal subpopulations expressing Neuromedin B receptors, gastrin-releasing peptide receptors, or somatostatin, can induce sigh-like large-amplitude inspirations. With additional technical clarifications and further supporting evidence for the implied capability of the neuron subpopulations studied to intrinsically generate the normal slow sigh rhythm, the study will interest neuroscientists studying respiratory neurobiology and rhythmic motor systems.

eLife assessment

This study reports a fundamental observation concerning cell death regulation by the anti-apoptotic BCL2 family NOXA. The authors convincingly demonstrate that NOXA is destabilized through the interaction with WSB2, a substrate receptor in CRL5 ubiquitin ligase complex, sensitizing the cells to treatments. These are key findings for cell biologists and cancer researchers as they identified a new target impacting drug responsiveness in cancer therapies.

eLife assessment

This study reports a valuable finding for the treatment of colorectal cancer (CRC), as the authors demonstrated that the enzyme CPT1A plays a significant role in the response to radiotherapy in CRC patients. The methodology and results presented by the authors are solid, supporting the role of CPT1A in CRC radiosensitivity, as the authors determined the expression of CPT1A in CRC tumors and non-tumor tissue, and they validated these findings with in vitro experiments.

eLife assessment

The authors provide useful data to support the existence of a regulatory pathway starting with SPI1-driven ZFP36L1 expression, that goes on to downregulate HDAC3 expression at the transcript level, leading to PD-L1 upregulation due to implied enhanced acetylation of its promoter region. This is therefore an interesting pathway that adds to our understanding of how PD-L1 expression is controlled in gastric cancer. However, this is likely one of many possible pathways that impact PD-L1 expression, and the data are currently incomplete to support the claims made.

eLife assessment

Early-life adversity or stress can enhance stress susceptibility by causing changes in emotion, cognition, and reward-seeking behaviors. This important manuscript highlights the involvement of lateral amygdala astrocytes in fear generalization and the associated synaptic plasticity, which are parallel to the effects of early life stress. With an elegant combination of behavioral models, morphological and functional assessments using immunostaining, electrophysiology, and viral-mediated loss-of-function approaches, the authors provide solid correlational and causal evidence that is consistent with the hypothesis that early life stress produces neural and behavioral dysfunction via perturbing lateral amygdala astrocytic function.

eLife assessment

This manuscript provides convincing evidence derived from diverse state-of-the-art approaches to suggest that non-dopaminergic projection neurons in the ventral tegmental area (VTA) make local synapses. These important findings challenge the prevailing wisdom that VTA interneurons exclusively form local synaptic contacts and instead reveal that VTA neurons expressing interneuron markers also form long-range projections to forebrain targets such as the cortex, ventral pallidum, and nucleus accumbens. Given the importance of VTA interneurons to many models of VTA-linked behavioral functions, these findings have significant implications for our understanding of the neural circuits underlying reward, motivation, and addiction.

eLife assessment

Franke et al. explore and characterize color response properties of neurons in mouse primary visual cortex (V1), revealing specific color opponent encoding strategies across the visual field. The paper provides evidence for the existence of color opponency in a subset of neurons within V1 and shows that these color opponent neurons are more numerous in the upper visual field. Support for the main conclusions is convincing and the dataset that forms the basis of the paper is impressive. The paper will make an important contribution to understanding how color is coded in mouse V1.

eLife assessment

This valuable work uses unbiased approaches to discover critical molecules in C. elegans and its bacterial food for nutrition sensing and food choice, providing a framework for other studies. The data convincingly support their model that C. elegans uses UPRER and immune response pathways to evaluate sugar contents in the bacteria to change their behaviors.

eLife assessment

The findings presented by the authors are useful within the focused scope of endometriosis treatment, providing a potential new therapeutic approach. The strength of the evidence is, however, incomplete, as the main claims are only partially supported by the authors' data. The research nevertheless offers promising initial evidence for KMO inhibition as a novel non-hormonal therapy for endometriosis, but further studies are needed to confirm efficacy and address any potential side effects.

eLife assessment

This study presents a useful computational data preprocessing methodology for de-biasing/denoising high-throughput genomic signals using optimal transport techniques. The evidence supporting the claims of the authors is, however, in parts incomplete, with a partially insufficient experimental setup for validation. The method needs to be be compared with other algorithms, using datasets that demonstrate broad applicability of the algorithm presented. The work could be of interest to scientists in the field of computational genomics.

eLife assessment

This important study presents genome-wide high-resolution chromatin-based 3D genomic interaction maps for over 50 diverse human cell types and integrates these data with pediatric obesity GWAS. The work provides convincing evidence that multiple pancreatic islet cell types are key effector cell types. The authors also perform variant-to-gene mapping to nominate genes underlying several GWAS hits. Overall, the results will be of interest to bth the fields of 3D genome architecture and pediatric obesity.

eLife assessment

This study presents valuable insights into the involvement of miR-26b in the progression of metabolic dysfunction-associated steatohepatitis (MASH). The delivery of microRNA-containing nanoparticles to reduce MASH severity has practical implications as a therapeutic strategy. Whereas convincing evidence is provided on the phenotypic changes produced by miR-26, the analyses of its precise role and function are incomplete and need more comprehensive evaluation including mechanistic studies.

eLife assessment

This study presents an important finding on the metabolism-independent role of IDH1 in regulating nuclear chromatin during terminal erythropoiesis. The evidence supporting IDH1's role on chromatin regulation is solid, but the analysis of its proposed non-metabolic activity is incomplete. The mechanistic perspective of this work, along with other intriguing observations, such as the connection between NAD+-dependent deacetylase SIRT1 and IDH1, should be of great interest to researchers working on erythropoiesis and erythroid disorders.

eLife assessment

This study provides a valuable examination of the social recognition abilities of a jumping spider, Phippidus regius. Behavioral essays yielded solid evidence that these spiders discriminate between familiar and unfamiliar individuals on the basis of visual cues, but the experimental support for individual recognition and long-term memory is incomplete.

eLife assessment

This study is potentially valuable, however currently its findings are incomplete, in that the paper's promise to deliver multiscale models that further our understanding of striatal function remains largely unfulfilled. A major weakness is that the findings are not integrated well within the rich landscape of existing striatal network modeling literature. Another major weakness is that the model is explored only in overly simplified scenarios and with limited comparison to data.

eLife assessment

This important study sheds light on how poison frogs gain their toxins, with surprising new data on low levels of toxins in previously non-toxic frogs. The authors propose a new theory for evolution of toxicity based on convincing evidence, but the manuscript needs restructuring to be clearer. While the manuscript will benefit from improved presentation, this research has the potential to greatly impact our understanding of animal defense mechanisms.

eLife assessment

This valuable study examines whether the BMP signaling pathway has a role in H3.3K27M DMG tumors, regardless of the presence of ACRVR1 activating mutations. The authors provide solid evidence that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. Although this work could be further enhanced by the inclusion of additional models, the study overall points to BMP2/7 as a potential target for future therapies in this deadly cancer.

eLife assessment

This important study extends existing sequentially Markovian coalescent approaches to include the combined use of SNPs and hypervariable loci such as epimutations. This is an intriguing addition to infer population size history in the recent past, and the authors provide solid validation of their methods via simulation and analysis of empirical data in Arabidopsis thaliana. Given the increasing availability of such data, this work is a timely contribution and represents a foundation for further developments to explore when and where these methods will be best used.

eLife assessment

This study presents a valuable finding on the heterogeneity of tumour metabolism using fluorescence lifetime imaging, measured across 4 cell lines, 4 tumour types of in vivo mouse models, and 29 patient samples. The indication is that the level of heterogeneity of cellular metabolism increases with model complexity and demonstrates high heterogeneity at a clinical level. The evidence supporting the claims of the authors is solid, and at the revision stage, the authors have included additional samples from 8 patients in the data pool, which is helpful for the conclusions that the authors are trying to draw. The work will be of interest to medical biologists developing methods for quantifying metabolic heterogeneity.

eLife assessment

This work presents valuable information on the structure of the spirosome's native extended conformation as the active form of the aldehyde-alcohol dehydrogenase (AdhE) enzyme. The evidence is solid, although the work does not provide a mechanistic understanding of the function and dynamics of AdhE.

eLife assessment

In this important manuscript, the authors used unbiased approaches to identify somatic mutations in publicly available databases that would disrupt clinically approved antibodies targeting HER2. Using a solid combination of both computational and experimental approaches they identify mutations that could restore therapeutic antibody sensitivity in a series of disease-relevant model systems. Additional cell-based and in vivo assays would strengthen the work and increase the translational and potential clinical relevance of the proposed work.

eLife assessment

This important study demonstrates that combining AlphaFold2 with the author's sampling method AF2-RAVE improves protein-ligand docking for three protein kinases and their inhibitors. The evidence is compelling and the results will be of interest to researchers who work on computer-aided drug design.

eLife assessment

This valuable manuscript describes a novel role of Vangl2, a core planar cell polarity protein, in linking the NF-kB pathway to selective autophagic protein degradation in myeloid cells. The mechanistic studies provide convincing evidence that Vangl2 targets p65 for NDP52-mediated autophagic degradation, limiting inflammatory NF-kB response, with functional significance of the proposed mechanism in sepsis. Additional future studies dissecting autophagic Vangl2 functions in various myeloid subsets in the context of inflammation could be informative, and additional Vangl2 targets in the inflammatory pathway, including IKK2, could also be explored. Overall, this exciting study can advance our understanding of NF-kB control, particularly in the context of inflammatory diseases.

eLife assessment

This study provides an important, original framework to study locomotion on the ground with physics-based simulations. Through numerical simulations, the authors propose that intermediate numbers of body modules and high body symmetry enhance speed. The current way discussions and conclusions are written is overly broad: evidence that evolution may favour bilateral symmetry and modularity for efficient directed locomotion is still incomplete as further performance metrics and a more accurate description of the dynamics in water are needed.

eLife assessment

This valuable study presents a new framework (ASBAR) that combines open-source toolboxes for pose estimation and behavior recognition to automate the process of categorizing behaviors in wild apes from video data. The authors present compelling evidence that this pipeline can categorize simple wild ape behaviors from out-of-context video at a similar level of accuracy as previous models, while simultaneously vastly reducing the size of the model. The study's results should be of particular interest to primatologists and other behavioral biologists working with natural populations.

eLife assessment

This important study shows that in teleost fish, the RIG-I-like protein MDA5 can compensate for the absence of RIG-I by detecting 5'-triphosphorylated RNA. A fish virus containing such RNA can nevertheless evade MDA5 detection through a mechanism involving m6A methylation-induced silencing. The conclusions, which are supported by solid data, advance our understanding of antiviral immunity and virus-host conflicts in vertebrates.

eLife assessment

This fundamental study provides a modeling regime that provides new insight into the energy-preservation parameters among schooling fish. The strength of the evidence supporting observations such as distilled dynamics between leading and lagging schooling fish which are derived from emergent properties is compelling. Overall, the study provides exciting insights into energetic coupling with respect to group swimming dynamics.

eLife assessment

This study presents valuable findings describing how the midbrain periaqueductal gray matter and basolateral amygdala communicate when a predator threat is detected. Though the periaqueductal gray is usually viewed as a downstream effector, this work contributes to a growing body of literature from this lab showing that the periaqueductal gray produces effects by acting on the basolateral amygdala, the experimental design, data collection and analysis methods provide solid evidence for the main claims. The anatomical and immediately early gene evidence that the paraventricular nucleus of the thalamus may serve as a mediator of dorsolateral periaqueductal gray to basolateral amygdala neurotransmission provides and impetus for future functional assessment of this possibility. This study will appeal to a broad audience, including basic scientists interested in neural circuits, basic and clinical researchers interested in fear, and behavioral ecologists interested in foraging.

eLife assessment

This study explores the role of calcyphosine-like (CAPSL) in Familial Exudative Vitreoretinopathy (FEVR) via the MYC pathway, offering valuable insights into disease mechanisms that are supported by a solid, multi-pronged approach. The manuscript, which presents the phenotype of an interesting new mouse model, provides convincing evidence that CAPSL variants cause disease.

eLife assessment

This study provides important new insights into the contribution of local DNA features to the molecular mechanisms and dynamics of copy number variation (CNV) formation during adaptive evolution. While limited to a single CNV, the experiments are carefully controlled and present convincing evidence that supports the conclusions. This work will be of general interest to those studying genome architecture and evolution from yeast biologists to cancer researchers.

eLife assessment

This solid and innovative study explores the uptake of fixed nitrogen in maize chloroplasts facilitated by symbiotic Gluconacetobacter diazotrophicus bacteria. The findings provide valuable insights into plant-microbe interactions, particularly highlighting a symbiotic mechanism of nitrogen delivery independent nodule formation. Additional controls would help to substantiate the findings and enhance the overall strength of the evidence.

eLife assessment

This important study offers insights into the function and connectivity patterns of a relatively unknown afferent input from the endopiriform to the CA1 subfield of the ventral hippocampus, suggesting a neural mechanism that suppresses the processing of familiar stimuli in favor of detecting novelty. The strength of evidence is solid, with careful anatomical and electrophysiological circuit characterization, although the functional role of this pathway in behavior is not firmly established. The work will be of broad interest to researchers studying the neural circuitry of behavior.

eLife assessment

The study by Asabuki et al. is a valuable contribution to understanding how cortical neural networks encode internal models into spontaneous activity. It uses a recurrent network of spiking neurons subject to predictive learning principles and provides a novel mechanism to learn the spontaneous replay of probabilistic sensory experiences. While promising in its ability to explain spontaneous network dynamics, the manuscript is incomplete in terms of the strength of support for its main findings. The difference of the proposed sampling dynamics from Markovian types of sampling is unclear and the use of non-negative synaptic strengths is applied in a non-biological manner.

eLife assessment

This study is a valuable observation that deals with the toxic effects of an intermediary in lipid degradation [trans-2-hexadecenal (t-2-hex)] in yeast through modification of mitochondrial protein import via the TOM complex. However, we find that the claim that the TOM complex is a main target of t-2-hex are supported by incomplete evidence, thus allowing multiple various interpretation. Despite the shortcomings, this study is inspiring for researchers from the organellar, protein trafficking and lipid field and serves as a starting point to further precise and mechanistic analyses of the phenomenon.

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. Notably, the model matches observed rank-abundance curves in several natural ecosystems.

eLife assessment

This valuable paper presents findings showing that different brain regions were best described by a distinct accumulation model, which all differed from the model that best described the rat's choices. These findings are solid because the authors present a very strong methodological approach. This work will be of interest to a wide neuroscientific audience.

eLife assessment

This study provides valuable new insights into the trade-offs associated with the evolution of drug resistance in the yeast S. cerevisiae, based on a solid approach to evolving and phenotyping hundreds of independent strains. The authors identify distinct phenotypic clusters, defined by their growth across defined conditions, which suggest that tradeoffs are diverse but at the same time could be limited to a few classes according to the underlying resistance mechanisms. The methodologies used align with the current state-of-the-art, and the data and analysis are solid as they broadly support the claims, with only a few minor weaknesses remaining after revision. This work will interest molecular biologists working on the evolution of new phenotypes and microbiologists studying multi-drug therapy.

eLife assessment

This paper describes an important advance in an in vitro neural culture system to generate mature, functional, diverse, and geometrically consistent cultures, in a 384-well format with defined dimensions and the absence of the necrotic core, which persists for up to 300 days. The well-based format and conserved geometry make it a promising tool for arrayed screening studies. Some of the evidence is incomplete and could benefit from a more direct head-to-head comparison with more standard culture methods and standardization of cell seeding density as well as further data on reproducibility in each well and for each cell line.

eLife assessment

This study presents an important set of results illuminating how movement sequences are planned. Using several different behavioural manipulations and analysis methods, the authors present compelling evidence that multiple future movements are planned simultaneously with execution, and that these future movement plans influence each other. The work will be of great interest to those studying motor control.

eLife assessment

This valuable research identifies Smim32 as a new genetic marker for the claustrum and generates transgenic mouse lines aimed at enhancing specificity when studying this brain region. However, the evidence supporting the increased specificity of this marker and its associated transgenic lines is inadequate, as Smim32's specificity to the claustrum is limited. Nevertheless, this work will be of interest to researchers studying the molecular organization of the claustrum.

eLife assessment

This study presents valuable new insights into a HIV-associated nephropathy (HIVAN) kidney phenotype in the Tg26 transgenic mouse model, and delineates the kidney cell types that express HIV genes and are injured in these HIV-transgenic mice. A series of compelling experiments demonstrated that PKR inhibition can ameliorate HIVAN with reversal of mitochondrial dysfunction (mainly confined to endothelial cells), a prominent feature shared in other kidney diseases. The data support that inhibition of PKR and mitochondrial dysfunction has potential clinical significance for HIVAN.

eLife assessment

Chang et al. have investigated the catalytic mechanism of I-PpoI nuclease, a one-metal-ion dependent nuclease, by time-resolved X-ray crystallography using soaking of crystals with metal ions under different pH conditions. This convincing study revealed that I-PpoI catalyzes the reaction process through a single divalent cation. The study uncovers important details of the roles of the metal ion and the active site histidine in catalysis.

eLife assessment

The study answers the important question of whether the conformational dynamics of proteins are slaved by the motion of solvent water or are intrinsic to the polypeptide. The results from neutron scattering experiments, involving isotopic labelling, carried out on a set of four structurally different proteins are convincing, showing that protein motions are not coupled to the solvent. A strength of this work is the study of a set of proteins using spectroscopy covering a range of resolutions. The work is of broad interest to researchers in the fields of protein biophysics and biochemistry.

eLife assessment

Zhu, et al. present convincing data that details the function of the infertile crescent gene (ifc) in fly development with implications on human neurodegenerative disease. The authors unveil interesting and novel phenotypes of ifc loss-of-function in glia. The experiments are well planned and executed, and the data support the conclusions. These important findings have theoretical and practical implications beyond a single subfield and the methods are in line with current state-of-the-art.

eLife assessment

This study presents a useful modification of a standard model of genetic drift by incorporating variance in offspring numbers, claiming to address several paradoxes in molecular evolution. It is unfortunate that the study fails to engage prior literature that has extensively examined the impact of variance in offspring number, implying that some of the paradoxes presented might be resolved within existing frameworks. In addition, while the modified model yields intriguing theoretical predictions, the simulations and empirical analyses are incomplete to support the authors' claims.

eLife assessment

The manuscript describes human intracranial neural recordings in the auditory cortex during speech production, showing that the effects of delayed auditory feedback correlate with the degree of underlying speech-induced suppression. This is an important finding, as previous work has suggested that speech suppression and feedback sensitivity often do not co-localize and may be distinct processes, in contrast with findings in non-human primates where there is a strong correlation. The strength of the evidence is convincing, with appropriate experimental methods, data, and analysis.

eLife assessment

This important study demonstrates that the Pseudomonas aeruginosa-derived quorum sensing signal, 2-aminoacetophenone, induces immune tolerization in macrophages by perturbing metabolism, particularly in the context of mitochondrial respiration and bioenergetics. The authors present convincing evidence for 2-aminoacetophenone-mediated reduction of pyruvate transport into mitochondria, with downstream effects that result in reduced ATP production in tolerized macrophages. The work will be of interest to those studying host-pathogen interactions.

eLife assessment

This manuscript is a valuable study of the responses of GPi neurons to deep brain stimulation (DBS) in human Parkinson disease and dystonia patients and it finds convincing evidence for altered short-term and long-term plasticity in response to DBS between the two patient populations. This dataset is of interest to both basic and clinical researchers working in the field of DBS and movement disorders.

eLife assessment

This study provides useful findings on how phonetic properties of words, i.e., their difficulty and prior knowledge, influence the outcome of targeted memory reactivation (TMR) during sleep. While these findings are supported by solid evidence, they are based on a small sample size warranting future work to shed further light on the impact of TMR in language learning.

eLife assessment

This important study explores the potential influence of physiologically relevant mechanical forces on the extrusion of vesicles from C. elegans neurons. The authors provide compelling evidence to support the idea that uterine distension per se can induce vesicular extrusion from adjacent neurons. Overall, this work will be of interest to neuroscientists and investigators in the extracellular vesicle and proteostasis fields.

eLife assessment

How neural circuits represent sensory signals during and after stimulus presentation is a central question in neuroscience. Here, a model of the insect mushroom body, constructed from simple, known synaptic connectivity rules, is shown to convincingly explain stimulus discrimination and associative memory, even in the presence of variability in the input signals as experimentally measured from the antennal lobe of the honeybee. This important study makes testable predictions for the role of specific neurons in a neural circuit for associative memory, of relevance to any study of neural network design and operation.

eLife assessment

In this valuable contribution, the authors present a novel and versatile probabilistic tool for classifying tracking behaviors and understanding parameters for different types of single-particle motion. The tool will be broadly applicable to single-particle tracking studies. While some reviewers feel that the methodology has been convincingly tested by computational comparisons and experimental data, others feel that the mathematical foundation needs to be strengthened and clearly defined.

eLife assessment

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