eLife assessment

This valuable paper examines gene expression differences between male and female individuals over the course of flower development in the dioecious angiosperm Trichosantes pilosa. Male-biased genes evolve faster than female-biased and unbiased genes, which is frequently observed in animals, but this is the first report of such a pattern in plants. In spite of the limited sample size, the evidence is mostly solid and the methods appropriate for a non-model organism. The resources produced will be used by researchers working in the Cucurbitaceae, and the results obtained advance our understanding of the mechanisms of plant sexual reproduction and its evolutionary implications: as such they will broadly appeal to evolutionary biologists and plant biologists.

eLife assessment

This study identifies two new transporters in the apicoplast, a non-photosynthetic organelle of apicomplexan parasites. While this is important work, it only partially reveals how essential these transporters are, as it does not address the metabolic function of the transporters for the parasite. Although the evidence is still incomplete, the results should be of interest to parasitologists and eukaryotic cell biologists.

eLife assessment

This study presents an important conceptual advance of how vitamin A and its derivatives contribute to atherosclerosis. There is solid evidence for the contributions of specialized populations of T cells in atherosclerosis resolution, including use of multiple in vivo models to validate the functional effects. A limitation is the insufficient analysis of lesions, but the manuscript has been improved from the original preprint version and the overarching conclusions have been refined.

eLife assessment

This important study combines state-of-the art proteomics and genetic manipulation of Chlamydia trachomatis to study the function of a chlamydial effector, Cdu1, with deubiquitination and acetylation activities. Solid evidence is provided to show that Cdu1 is able to protect itself and three other chlamydial effectors, which are involved in the control of chlamydial egress from host cells, from ubiquitin-mediated degradation, and that this depends on the acetylation activity of Cdu1, but not on its deubiquitination activity. This work will be of interest to microbiologists and cell biologists studying host cell-pathogen interactions.

eLife assessment

This important study advances our understanding of how different types of communication signals differentially affect mouse behaviors and amygdala cholinergic/dopaminergic neuromodulation. Researchers interested in the complex interaction between prior experience, sex, behavior, hormonal status, and neuromodulation should benefit from this study. Nevertheless, some of the statistical comparisons using baseline normalized data might result in inadequate statistical power at this stage, requiring additional analysis to support the conclusions fully. With a few analytical parts strengthened, this paper will be of interest to neuroscientists and ethologists.

eLife assessment

This study presents important new insights into how best to address common problems encountered in the statistical analysis of neural data, including those related to temporal autocorrelations and unknown variables. The authors show that certain approaches, including those using cross-validation and permutation tests, are better than others at controlling error rates, particularly false negatives. At present, the evidence presented is incomplete, including a lack of more rigorous theoretical justifications for the differences observed between the different approaches tested and a focus on p-values without considering effect sizes, but could be improved with substantial revisions that address these issues.

eLife assessment

The aim of this important study is to functionally characterize neuronal circuits underlying the escape behavior in Drosophila larvae. Upon detection of a noxious stimulus, larvae follow a series of stereotyped movements that include bending their body, rolling, and crawling away. This paper combines quantitative behavioral analyses, cell-type specific manipulations, optogenetics, calcium imaging, immunostaining, and connectomic analysis to provide convincing evidence of an inhibitory descending pathway that controls the switch from rolling to fast crawling behaviors of the larval escape response.

eLife assessment

This study presents a valuable finding on the influence of visual uncertainty and Bayesian cue combination on implicit motor adaptation in young healthy participants. The evidence supporting the claims of the authors is solid, although a better discussion of the link between the model variables and the outcomes of related behavioral experiments would strengthen the conclusions. The work will be of interest to researchers in sensory cue integration and motor learning.

eLife assessment

This study presents useful results on glutamine-rich motifs in relation to protein expression and alternative genetic codes. The solid data are based on bioinformatic approaches that are employed to systematically uncover sequence features associated with proteome-wide amino acid distribution and biological processes.

eLife assessment

The authors have greatly expanded their important hippocampome.org resource about rodent hippocampal cell types, their physiological properties, and their interactions. With version 2.0, they make a significant advance in providing a user-friendly means to make computer models of hippocampal circuits. The work is convincing, and there are only minor reservations that the figures may be too complex.

eLife assessment

This convincing study demonstrates a potentially important role for the factor Numb in skeletal muscle excitation-contraction coupling, since a Numb knockout reduced contractile force. The authors thus demonstrate a novel role for Numb in calcium release in skeletal muscle.

Modula and Oberon should have been codenames rather than independent projects.

eLife assessment

This important study reports jAspSnFR3, a biosensor that enables high spatiotemporal resolution of aspartate levels in living cells. To develop this sensor, the authors used a structurally guided amino acid substitution in a glutamate/aspartate periplasmic binding protein to switch its specificity towards aspartate. The in vitro and in cellulo functional characterization of the biosensor is convincing, but evidence of the sensor's effectiveness in detecting small perturbations of aspartate levels and information on its behavior in response to acute aspartate elevations in the cytosol are still lacking.

eLife assessment

This important study presents convincing evidence for the use of orangutan teeth as terrestrial proxies to reconstruct rainfall regimes, while exploring the potentially conflicting impact of breastfeeding signals. The findings will be of broad interest for those using and developing methods and tools to reconstruct environmental conditions in the historical and archaeological past.

eLife assessment

This study presents useful work comparing different techniques for monitoring insect species in agricultural settings, including a brand new one using optical sensors. That said, the data were analysed using an inadequately-described -- or potentially inadequate -- framework, and more careful thought must be given to the interpretation of the results before the new methodology can be used as a starting point for insect studies in agricultural fields and beyond.

eLife assessment

This valuable manuscript describes a genetic system in yeast used to find mutations in two distinct amino acid transporters that enable the cells to utilize additional amino acids as a nitrogen source. The study provides solid evidence in membrane proteins of a phenomenon that has been previously described in enzymes: that substrate specificity can be altered through the introduction of point mutations to either the ligand binding site or gating helices. This work establishes that amino acid transporters likely evolved specific functionality/specificity from an ancestral transporter that could transport most amino acids.

eLife assessment

By taking advantage of noise in gene expression, this important study introduces a new approach for detecting directed causal interactions between two genes without perturbing either. The main theoretical result is supported by a proof, although clearer statements are needed to ensure that there are no edge cases that can violate the theorem. Preliminary simulations and experiments on small circuits are presented, but the evidence remains incomplete because further investigations are needed to demonstrate the broad applicability and scalability of the method.

eLife assessment

This study presents important findings on long-lived proteins in the mouse ovary and oocytes. Convincing evidence using two-generation stable isotope-based metabolic labelling of mice in combination with mass spectrometry analysis describes a resource of enriched long-lived macromolecules in oocytes and somatic cells. Mitochondrial, cytoskeletal, and myosin proteins were identified as long-lived. While this is a unique resource with significant value in the understanding of female reproductive aging, the results would be strengthened if supported by an orthogonal validation and a more in-depth mechanistic explanation of the relationship between mitochondrial and cytoskeletal protein stability and aging.

eLife assessment

This important paper examined how attention affects temporal binding. Through a combination of careful experimental designs and computational modelling, this study provides solid evidence highlighting the role of attention in shaping temporal binding. Overall, the present findings will be of interest to cognitive scientists studying phenomena related to time perception, temporal binding, and spatial attention.

eLife assessment

In an important study that will be of interest to the mechanistic membrane transport community, the authors capture the first cryo-EM structure of the inward facing melbiose transporter MelB, a well-studied model transporter from the major facilitator (MFS) superfamily. Cryo-EM experiments and supporting biophysical experiments provide solid evidence for transporter conformational changes.

eLife assessment

This study presents a useful inventory of immune signatures that are correlated with cancer treatment-related pneumonitis. The data were collected and analysed using solid and validated methodology and can be used as a starting point for further functional studies.

eLife assessment

This useful manuscript focuses on understanding how an Eklf mutation confers anticancer and longevity advantages in vivo. The data demonstrate that Eklf (K74R) imparts such advantages in a background and age independent manner in both female and male mice, and that the benefits are transferable by bone marrow transplantation. Despite added data since a previous version, the paper unfortunately remains incomplete, as it is still unclear whether Eklf affects resistance to malignant progression/metastasis by modulating Pd1 or Pdl1, or by increasing NK cells. The authors provide evidence that supports in principle both mechanisms, and they do not resolve which mechanism is primarily involved.

eLife assessment

This study provides useful insights into inter- and intra-site B cell receptor repertoire heterogeneity, noting that B cell clones from the tumour interact more with their draining lymph node than with the blood and that there is less mutation/expansion/activation of B cell clones in tumours. Unfortunately, the main claims are incomplete and only partially supported. This work could be of interest to an audience including medical biologists/immunologists and computational biologists across cancer specialities.

eLife assessment

This paper provides an important assessment of competition dynamics allowing coexistence of the carnivore guild within a large national park. A solid dataset and multiple surveying techniques (camera traps and DNA metabarcoding) provide convincing evidence that spatial segregation represents the main strategy of coexistence, while species have a certain degree of temporal and dietary overlap. Altogether, the manuscript provides important information critical to the conservation and management agenda of the park.

eLife assessment

This important study identifies the gene mamo as a new regulator of pigmentation in the silkworm Bombyx mori, a function that was previously unsuspected based on extensive work on Drosophila where the mamo gene is involved in gamete production. The evidence supporting the role of Bm-nano in pigmentation is convincing, including high-resolution linkage mapping of two mutant strains, expression profiling, and reproduction of the mutant phenotypes with state-of-the-art RNAi and CRISPR knock-out assays. While the discussion about genetic changes being guided or accelerated by the environment is extremely speculative and has little relevance for the findings presented, the work will be of interest to evolutionary biologists and geneticists studying color patterns and evolution of gene networks.

eLife assessment

This study presents a valuable dissection on how functional HSCs are expanded in PVA cultures. The functional and multi-omic analyses provided are convincing, although the additional data and their analysis provided during revision could have been included in the test to assist readers and to strengthen the published manuscript. Nevertheless, the present work will be of value for stem cell biologists interested in HSC regulation.

eLife assessment

This study presents valuable findings on the mechanism of glucocorticoid-induced osteonecrosis of the femoral head. The data were collected and analyzed using solid, validated methodology and can be used as a starting point for functional studies of development of glucocorticoid-induced osteonecrosis. This paper would be of interest to cell biologists and biophysicists working on potential pharmacological treatments for glucocorticoid-induced osteonecrosis.

eLife assessment

This valuable paper explores the idea that transient modulations of neural gain promote switches between distinct perceptual interpretations of ambiguous stimuli. Evidence for this idea is provided by pupillometry (an indirect proxy of neuromodulatory activity), fMRI, neural network modeling, and dynamical systems analyses. While this integrative approach is intriguing, the data analysis, as well as computational modeling, are incomplete, especially for supporting the many causal statements in the paper.

eLife assessment

This important paper uses a genome-wide, massively parallel reporter assay to determine how CpG methylation affects regulatory sequences that control the expression of human genes. The authors provide compelling evidence that methylation not only influences baseline activity of regulatory sequences but also the magnitude of acute responses to environmental stimuli. The findings are of broad interest, and the extensive data set will likely become a key resource for the community.

eLife assessment

This study investigates the role of the bile acid receptor TGR5 in adult hematopoiesis of the mouse model. The findings are potentially useful because the loss of TGR5 leads to dysregulation of bone marrow adipose tissue (BMAT) that has emerging regulatory functions. However, the study is still incomplete because the mechanism of TGR5 is not clear, the stromal cells expressing TGR5 have not been well defined, and there is not strong evidence for the role of TGR5 in recovery from transplant stress.

eLife assessment

This study presents valuable information that demonstrates CCDC146 as a novel cause of male infertility that play key role in microtubule-associated structures. The evidence supporting the claims of the authors is solid using combination of human and mouse genetics, biochemical and imaging approaches. This paper would be of interest to cell and developmental biologists working on genes involved in spermatogenesis and male infertility.

eLife assessment

This important study advances our understanding of why diabetes is a risk factor for more severe Covid-19 disease. The authors offer solid evidence that cathepsin L is more active in diabetic individuals, that this higher activity is recapitulated at the cellular level in the presence of high glucose, and that high glucose leads to higher cathepsin L maturation. While not all aspects of the relationship between diabetes and cathepsin L (e.g., effects of metabolic acidosis) have been investigated, the work should be of interest to researchers in diabetes, virology, and immunology.

eLife assessment

This useful study uses a mouse model of pancreatic cancer to examine mitochondrial mass and structure in atrophying muscle along with aspects of mitochondrial metabolism in the same tissue. Most relevant are the solid transcriptomics and proteomics approaches to map out related changes in gene expression networks in muscle during cancer cachexia.

eLife assessment

This important study explores the physicochemical properties of SARS-CoV-2 N proteins with mutations that have been found in variants of concern but for which there is limited knowledge of their contribution to the biological activity of such variants. The evidence presented is solid; however, this study could be considerably improved by a more extensive analysis of LLPS in R203K/G204R and in the P31L mutants, as well as a more quantitative analysis of the LLPS droplets.

eLife assessment

The authors present evidence suggesting that MDA5 can substitute as a sensor for triphosphate RNA in a species that naturally lacks RIG-I. The key findings are potentially important for our understanding of the evolution of innate immune responses, but the evidence is incomplete, as additional biochemical and functional experiments are needed to unambiguously assign MDA5 as a bona fide sensor of triphosphate RNA in this model. This also leaves the title as overstating its case.

eLife assessment

This important study addresses the mechanisms by which mutations in the PURA protein, a regulator of gene transcription and mRNA transport and translation, cause the neurodevelopmental PURA syndrome. Based on convincing evidence from structural biology, molecular dynamics simulation, biochemical, and cell biological analyses, the authors show that the PURA structure is very dynamic, rendering it generally sensitive to structure-altering mutations that affect its folding, DNA-unwinding activity, RNA binding, dimerization, and partitioning into processing bodies. These findings are of substantial importance to cell biology, neurogenetics, and neurology alike, because they provide first insights into how very diverse PURA mutations can cause similar and penetrant molecular, cellular, and clinical defects.

eLife assessment

This important study investigates the molecular mechanisms underpinning how the tumor necrosis factor alpha-induced protein, TIPE, regulates aerobic glycolysis to promote tumor growth in melanoma. Data using multiple independent approaches provide new insights into the molecular mechanisms underpinning aerobic glycolysis, also known as the Warburg Effect, in melanoma cells. The claims of the authors are solid, although more in-depth metabolic assays as well as the inclusion of melanoma patient survival analysis in TIPE high and low tumors would strengthen the study. The work will be of interest to biomedical researchers working in cancer and metabolism.

eLife assessment

This study presents a cellular automaton model to study the dynamics of virus-induced signalling and innate host defense against viruses such as SARS-CoV-2 in epithelial tissue. The data presented are convincing and represent a valuable contribution that would be of interest to researchers studying the dynamics of viral propogation. The significance of the study might be further elevated with more details on the reduction of expression data to the model rules discussed.

eLife assessment

This study presents a valuable finding that a testis-enriched gene is essential for normal formation and function of the sperm flagellum, motility, and male fertility in mice. The data on phenotypic characterization are solid, but the evidence supporting the direct role of this protein in preventing RNP granule formation in the sperm flagellum appears insufficient. This work will be of interest to biomedical researchers who work on testicular biology and male fertility.

eLife assessment

This study provides a detailed evaluation of how HIV evades nascent immune pressure from people living with HIV followed nearly immediately after infection. There is convincing evidence that H173 mutations in the V2 loop was a key determinant of selection pressure and escape. These data are congruent with protection in the RV144 clinical trial, the only trial that showed protection from infection. Overall, this study is valuable to the field.

eLife assessment

In this valuable study, the authors investigate the transcriptional landscape of tuberculous meningitis, revealing key molecular differences contributed by HIV co-infection. Whilst some of the evidence presented is compelling, the bioinformatics analysis is limited to a descriptive narrative of gene-level functional annotations, which are somewhat basic and fail to define aspects of biology very precisely. Whilst the work will be of broad interest to the infectious disease community, validation of the data is critical for future utility.

eLife assessment

This current revision builds on observations in validated conditional double KO (cDKO) mice for LRRK1 and LRRK2 that will be useful for the field, given that LRRK2 is widely expressed in the brain and periphery, and many divergent phenotypes have been attributed previously to LRRK2 expression. The manuscript presents solid data demonstrating that it is the loss of LRRK1 and LRRK2 expression within the SNpc DA cells that is not well tolerated, as it was previously unclear from past work whether neurodegeneration in the LRRK double Knock Out (DKO) was cell autonomous or the result of loss of LRRK1/LRRK2 expression in other types of cells. Future studies may pursue the biochemical mechanisms underlying the reason for the apoptotic cells noted in this study, as here, the LRRK1/LRRK2 KO mice did not replicate the dramatic increase in the number of autophagic vacuoles previously noted in germline global LRRK1/LRRK2 KO mice.

eLife assessment

This important study presents interesting findings that suggest that the UPR and immune regulators can act as evaluators of nutritional quality in C. elegans. Convincing evidence expands our understanding both of physiological food evaluation systems and of the known roles of stress response pathways in organismal physiology. However, there is limited mechanistic exploration in the study, and in some cases, the effect size is small and statistical significance questionable.

eLife assessment

This valuable paper presents a thoroughly detailed methodology for mesoscale-imaging of extensive areas of the cortex, either from a top or lateral perspective, in behaving mice. While the examples of scientific results to be derived with this method are in the preliminary stages, they offer promising and stimulating insights. Overall, the method and results presented are convincing and will be of interest to neuroscientists focused on cortical processing in rodents.

eLife assessment

This study reports a valuable new mechanism through which the TGF-beta signaling pathway promotes contacts between oocytes and their surrounding somatic cells via regulating the number of transzonal projections (TZPs) in mice. The evidence supporting the major conclusions is solid, although further assessments of the physiological significance of SMAD4-dependent formation of transzonal projection networks would have strengthened the study. The work will be of interest to biomedical researchers who work on ovarian biology and female fertility.

eLife assessment

In this manuscript, the authors investigate the properties of prokaryotic NADPH oxidases (NOX) and discuss the implications for NOX regulation and function. The structure of the S. pneumoniae Nox protein is an important step forward in our understanding of procaryotic NOX enzymes and the characterization and interpretation are convincing. The results will be of interest to structural biologists as well as biochemists focusing on enzymatic functions.

eLife assessment

This paper presents an important finding: that Styxl2, a poorly characterized pseudo-phosphatase, plays a role in the sarcomere assembly by promoting the degradation of non-muscle myosins. The genetic evidence supporting the conclusions is compelling, although future work will be needed to elucidate the functional role and biochemical mechanism of autophagic degradation of non-muscle myosins. This work will be of interest to biologists studying muscle development, cell biology, and proteolysis.

eLife assessment

CCL2 is a chemokine known to have relevant immune cell chemoattractant properties, and it is believed to play a role in several chronic inflammatory diseases. The RNA-binding protein HuR controls the stability and translation of CCL2 mRNA. This paper presents solid evidence that a relatively common genetic variant tied to several disease phenotypes affects the interaction between the mRNA of CCL2 and the RNA-binding protein HuR. As CCL2 is believed to be relevant for leukocyte migration in various conditions, including chronic inflammation and cancer, this is an important finding that may be relevant to a broad audience.

eLife assessment

This study addresses how protein synthesis in activated lymphocytes keeps up with their rapid division, with important findings that are of significance to cell biologists and immunologists endeavouring to understand the 'economy' of the immune system. The work is supported by solid data. Because it proposes non-conventional mechanisms, the study sets the scene for further work in this area.

eLife assessment

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

eLife assessment

This manuscript utilizes a Drosophila explant system and modeling to provide important insights into the mechanism of microtubule aster positioning. Although the intellectual framework of aster positioning has been worked out by the same authors in their previous work, this study provides additional solid evidence to solidify their model.

eLife assessment

This important report studies the recovery of genome-reduced bacterial cells in laboratory evolution experiments to understand how they regain their fitness. Through the analysis of gene expression and a series of tests, the authors discover distinct molecular changes in the evolved bacterial strains and propose that various mechanisms are employed to offset the effects of a reduced genome. While the findings have intriguing implications for understanding genome evolution, it is crucial to note that the evidence supporting these claims is incomplete due to insufficient experimental tests and statistical analysis.

eLife assessment

This important work by Hann et al. advances our understanding of the role of the survival motor neuron (SMN) protein in coordinating pathogenesis of the spinal muscular atrophy (SMA). The authors addressed many concerns raised by the reviewers, providing convincing evidence in terms of skeletal analyses not being able to satisfactorily elucidate SMN regulation of bone development.

eLife assessment

This important work combines DNA contact analysis and controlled genome rearrangements to investigate the processes that organize the E. coli chromosome, with a particular focus on how the SMC-related complex MukBEF is regulated. The evidence supporting the conclusions is compelling, with time-resolved experiments and analysis of mutant strains. The work will be of broad interest to chromosome biologists and bacterial cell biologists.

eLife assessment

This manuscript describes an important web resource for kinases connected to cytokines. The compelling information will be used by researchers across a number of fields including analysts, modelers, wet lab experimentalists and clinician-researchers, who are looking to improve our understanding of pathologies and means to correct them through modulating the immune response.

eLife assessment

This is a methodologically state-of-the-art systematic review and meta-analysis of studies that addressed the question of whether the administration of multiple antibiotics simultaneously prevents antibiotic resistance development in individuals. The findings are solid. Rather than providing a precise answer, the synthesis of studies eligible for analysis leads to the conclusion that "our analysis could not identify any benefit or harm of using a higher or a lower number of antibiotics regarding within-patient resistance development." This article is important as it articulates the existing knowledge gap, but also serves as an example to careful future use of the meta-analysis methodology, when existing data just don't allow conclusions.

eLife assessment

This very interesting study by Vuond and colleagues reports on the kinetics of viremia in a large set of individuals from Vietnam. In the large cohort, all 4 dengue serotypes are represented and the authors try to correlate viraemia measured at various days from illness onset with thrombocytopaenia and severe dengue, according to the WHO 2009 classification scheme. These are fundamental findings and provide compelling evidence of the importance of measuring viremia early in the phase of the disease. These data will help to inform the design of studies of antiviral drugs against dengue.

eLife assessment

This solid study investigates the transdifferentiation of chicken embryonic fibroblasts into muscle and fat cells in 3D to create whole-cut meat mimics. The study is important and provides a method to control muscle, fat, and collagen content within the 3D meat mimics and thus provides a new avenue for customized cultured meat production. Limitations of this study include the use of transgene for transdifferentiation and thus the creation of GMO food.

eLife assessment

The study provides useful data supporting prior findings that mitochondria in cultured cells maintain a temperature that is up to 15°C above the external temperature at which cultured cells are maintained. The evidence supporting the hypothesis is solid, although direct measures of temperature in isolated mitochondria or comparison with other cellular compartments would have strengthened the ability to interpret the relevance of the findings. Nevertheless, the bioenergetic implications of the work will be of interest to cell biologists, biochemists, and physiologists.

eLife assessment

The study provides valuable data supporting prior findings that mitochondria in cultured cells maintain a temperature that is up to 15°C above the external temperature at which cells are cultured. The evidence supporting the hypothesis is incomplete at this stage, and additional benchmarking of temperature probes and inclusion of outcome measures beyond mitochondrial temperature will strengthen the ability to interpret the relevance of the findings. Nevertheless, the bioenergetic implications of the work will be of interest to cell biologists, biochemists, and physiologists.

eLife assessment

This study presents the useful observation that repetitive Transcranial Magnetic Stimulation (rTMS) over the medial prefrontal cortex (mPFC) is associated with immediate dampening effects of conditioned responses and generalization of these responses to similar cues. Additionally, the effects were still present one week later, in the absence of any stimulation. However, the evidence supporting the claims of the authors is incomplete. The main outcome data (skin conductance response) have been normalized and standardized in suboptimal ways and, most critically, no comparisons are being made with the strength of conditioned responses during acquisition. If the observations hold, when based on within-subject comparisons, the work will be of interest to psychologists and neuroscientists working on interventions into aberrant emotional memories.

eLife assessment

Large populations of neurons are capable of entering pathological synchronous oscillations under a variety of conditions and work over many decades has found ways to disrupt such oscillations using stimulation in both open loop and closed loop configurations. This study adds useful results and methodology to this line of research, by providing solid evidence that delayed feedback control via electrical stimulation can, under certain conditions, terminate network level oscillations in cultured cortical neurons. The study provides analyses and simulation results that shed light on why some networks respond to such feedback control while others do not.

eLife assessment

This important study demonstrates that the transcription factor TEAD1 is required for the function of Yap/Taz in Schwann cells, with conditional mouse mutants having very similar dysmyelinated phenotypes. Convincing histological evidence is shown for the role of TEAD1 itself, leaving open the function of other TEAD proteins in this system. This study will nevertheless be of great interest to researchers in the field of peripheral nerve development.

eLife assessment

This study examines an interplay between synaptic mitochondria and glutamate receptor exocytosis in C. elegans. Collectively, the solid results support the idea that mitochondrial function influences receptor dynamics at postsynaptic sites. This is important because tight control of synaptic function likely integrates several mitochondrial functions: energy production, calcium buffering, and (here) reactive oxygen species signaling.

eLife assessment

This convincing manuscript represents a valuable advance in understanding the role of MCT1 – a transporter for lactate and other organic anions – in hepatocytes and hepatic stellate cells in the liver. The authors also generate exciting new tools to investigate hepatic stellate cell biology, and these may have much broader applications, but future studies are required to validate these new tools.

eLife assessment

This important study extends insights on NAFLD and NASH regarding the role of plasma lactate levels using mice haplo-insufficient for the gene encoding lactate transporter MCT-1. While the evidence is largely convincing and the work significantly advances our understanding of the roles of distinct hepatic cell types in steatosis, a number of issues require attention and would best be solved by further experimentation.

eLife assessment

Payne et al. present a novel model that predicts the sites and directions of plasticity within the vestibular cerebellum to explain the basis for learned adjustments to reflexive eye movements in monkeys. The work is solid; the model is well constrained by prior biological observations and makes an important prediction about the level of feedback available to the cerebellar cortex post-learning. Overall, a number of exciting and testable experiments will likely be motivated by this study.

eLife assessment

This study presents a useful characterization of the biochemical consequences of a disease-associated point mutation in a nonmuscle actin. The study uses solid and well-characterized in vitro assays to explore function. In some cases the statistical analyses are inadequate and several key in vitro assays are not employed.

eLife assessment

This study presents an advance in efforts to use histone post-translational modification (PTM) data to model gene expression and predict epigenetic editing activity. Such models are broadly useful to the research community, especially ones that can model epigenetic editing activity, which is novel. However, whereas the authors have nicely integrated datasets across cell types into their model, the work is incomplete in two key areas: (1) a lack of comparisons to existing models that predict gene expression from PTM data makes it unclear what advantages the current model offers, and (2) more rigorous experimental evidence for dCas9-based perturbations is needed to rigorously assess how well the model predicts epigenetic editing outcomes.

eLife assessment

This valuable study uses population and functional genomics to examine long non-coding RNAs (lncRNAs) in the context of human evolution. Computational prediction of human-specific lncRNAs and their DNA binding sites and analyses of these loci lead to the development of hypotheses regarding the potential roles of these genetic elements in human biology. The evidence supporting the conclusions is, however, still incomplete, as key details regarding the methodology and analyses are lacking.

eLife assessment

This important study addresses two questions: (i) how danger signaling is altered for people with childhood adversities, and (ii) how this differs across different operationalizations of adversity. The latter is of particularly broad interest to multiple fields, given that childhood adversity is operationalized very differently across the literature, but the strength of evidence is incomplete because the statistical techniques used do not sufficiently account for between-subjects covariates. These data will be of interest to scientists and clinicians interested in early life adversity, statistical approaches for quantifying stress exposure, or aversive learning.

eLife assessment

This important study poses a provocative mechanism of channel activation of the mechanically activated ion channel TREK-1. The data provide solid evidence that the application of shear to cells causes a redistribution of both TREK-1 and an associated enzyme, PhospholipaseD2 in the membrane that increases the enzyme activity. The work offers a new mechanism, but note that this is only one possible method of channel activation, and mechanisms independent of PLD2 are also probable.

eLife assessment

Miyano et al. study the impact of RIM-BP2 deletion at mossy fiber synapses, using direct electrophysiological recordings from mossy terminals and STED super-resolution microscopy. The paper addresses an important question in the field of synaptic transmission and provides compelling evidence demonstrating reduced calcium channel abundance in mossy terminals upon RIM-BP2 removal.

eLife assessment

This study represents a useful description of a third interaction site between melanophilin and myosin-5a which has a role in regulating the distribution of pigment granules in melanocytes. While much of the data forms a solid case for this interaction, the inclusion of key controls for the cellular studies and measurement of interaction affinities would have been helpful.

eLife assessment

This study presents fundamental findings on the role of transcription readout and intron retention in transposon expression during aging in mammals. The evidence supporting the claims of the authors is compelling, strongly supporting the authors' claims. The work will be of interest to scientists studying aging, transcription regulation, and epigenetics.

eLife assessment

Receptor tyrosine kinases such as ALK play critical roles during appropriate development and behaviour and are nodal in many disease conditions, through molecular mechanisms that weren't completely understood. This manuscript identifies a previously unknown neuropeptide precursor as a downstream transcriptional target of Alk signalling in Clock neurons in the Drosophila brain. The experiments are well designed with attention to detail, the data are solid, and the findings will be useful to those interested in events downstream of signalling by receptor tyrosine kinases.

eLife assessment

This valuable study reports novel active learning batch selection methods that have been applied to optimization tasks related to ADMET and affinity properties relevant within the drug discovery field. While the evidence is solid, the paper could have benefited from a clearer and deeper description of methods as well as interpretation of the obtained models, and a wider comparison to existing methods. The article will be of general interest to scientist working in the field of drug discovery and, in general, to researchers within the fields of machine learning and data analysis.

eLife assessment

The authors provide an important series of metabolic measurements characterizing group dynamics in fish, rationalizing that schooling behavior presents several benefits. The strength of evidence supporting this conclusion is solid, but the specific methodological and analytical approaches taken should be considered for further interpretation.

eLife assessment

This solid manuscript describes a preclinical model to assess different methods of infusion of organoids for clinical applications. This is an important and timely study with practical implications beyond a single subfield. The methods described, including the analysis, broadly support the claims although there are some areas for improvement.

eLife assessment

This important study reports a new mutant mouse line with compromised function of a DNA damage response protein. The evidence supporting the conclusion that the mutants display defective maintenance of meiotic sex chromosome inactivation is solid. This work is of interest to biomedical researchers working on meiosis and meiotic sex chromosome inactivation.

eLife assessment

In this important study, a mathematical model to predict biological age by leveraging physiological traits across multiple organ systems is developed. The results presented are convincing, utilizing comprehensive data-driven approaches, although additional external validation would further strengthen its generalizability. The model provides a way to identify environmental and genetic factors impacting aging and lifespan, revealing new factors potentially affecting aging and it also shows promise for evaluating therapeutics aimed at prolonging a healthy lifespan.

eLife assessment

This study documents important findings on three variants in SNAP25 that are associated with developmental and epileptic encephalopathy. The thorough characterization of synaptic release and in vitro vesicle fusion phenotypes provides interesting information about the nature of the SNAP25 variants. The evidence supporting the claims is compelling, and this work will be of interest to neuroscientists working on SNAP25, SNAP25-associated encephalopathy, and synaptic vesicle exocytosis.

eLife assessment

The authors use human intracranial recordings to investigate the relationship between the power of brain oscillations and the latency and strength of cortico-cortical couplings. In the current version, the authors provide a valuable finding that the delay between nearby electrodes in ECoG data is correlated with the amplitude of power, differently so for high and low frequencies. The findings of this study will interest investigators in the wider field of systems neurophysiology; however, editors and reviewers perceived headroom for improving clarity in the presentation of analyses and results, and the strength of evidence for some of the claims as currently presented was viewed as incomplete.

eLife assessment

This important study examines the relationship between expiratory airflow and vocal pitch in adult mice during the production of ultrasonic vocalizations and also identifies a molecularly defined population of brainstem neurons that regulates mouse vocal production across development. The evidence supporting the study's conclusions that expiratory airflow shapes vocal pitch and that these brainstem neurons preferentially regulate expiratory airflow is incomplete and would benefit from the inclusion of additional analyses and discussion. This work will be of interest to neuroscientists working on mechanisms and brainstem circuits that regulate vocal production and vocal-respiratory coordination.

eLife assessment

This study presents a valuable exploration of the complex relationship between structure and function in the developing human brain using a large-scale imaging dataset from the Human Connectome Project in Development and gene expression profiles from the Allen Brain Atlas. The evidence supporting the claims of the authors is convincing, although the inclusion of more systematic analyses of structural and functional connectivity with respect to myelin measures and oligodendrocyte-related genes, and also more details regarding the imaging analyses, cognitive scores, and design and validation strategies, would have strengthened the paper. The work will be of interest to developmental biologists and neuroscientists seeking to elucidate structure-function relationships in the human brain.

eLife assessment

The authors investigated the requirement and function of Blimp1/Prdm1 in murine natural killer (NK) cells and the ILC1 lineage of innate lymphoid cells, using a conditional knockout model. The single-cell mRNA-seq data provided here represent a valuable resource for the community, but the lack of mechanistic investigations leaves the study incomplete. The work will be of interest to the fields of innate lymphoid cell biology and tissue immunology.

eLife assessment

This fundamental study evaluates the evolutionary significance of variations in the accuracy of the intron-splicing process across vertebrates and insects. Using a powerful combination of comparative and population genomics approaches, the authors present convincing evidence that species with lower effective population size tend to exhibit higher rates of alternative splicing, a key prediction of the drift-barrier hypothesis. The analysis is carefully conducted and all observations fit with this hypothesis, but focusing on a greater diversity of metazoan lineages would make these results even more broadly relevant. This study will strongly appeal to anyone interested in the evolution of genome architecture and the optimisation of genetic systems.

eLife assessment

This important study advances our understanding of sperm motility regulation during fertilization by uncovering the midpiece/mitochondria contraction associated with motility cessation and structural changes in the midpiece actin network as its mode of action by using various advanced microscopic techniques. The evidence supporting the association is solid, but the evidence to support the causality of contraction and motility cessation is incomplete and would benefit from time-resolved imaging monitoring contraction, motility, and cell viability simultaneously. With the causality part strengthened, the work will be significant and of broad interest to cell biologists working on the cytoskeleton, mitochondria, cell fusion, and fertilization.

eLife assessment

This important study provides solid evidence for a non-genomic action of progesterone in Xenopus oocyte activation. The findings demonstrate that two non-genomic progesterone receptors, ABHD2 and mPRb, function as a novel progesterone-stimulated phospholipase A2. However, the findings are reliant on high concentrations of inhibitor drugs, and mechanistic details about the molecular interaction and respective functions of ABHD2 and mPRb are incomplete. The findings will be of broad interest to reproductive endocrinologists and physiologists.

eLife assessment

The authors present a valuable observation that challenges existing knowledge about DNA methylation dynamics in pre-implantation mammalian development. Their findings suggest a novel role for a well-studied epigenetic mark, with potential implications for gene expression regulation in early embryonic stages. However, the evidence provided is incomplete and only partially supports the main claims.

eLife assessment

The manuscript describes important findings regarding the significance of CHD2 in ovarian folliculogenesis. Overall, the results lead to convincing conclusions, with minimal concerns raised by the reviewers. Both the results and conclusions are well discussed. This work will be of interest to ovarian biologists and physicians working on female fertility.

eLife assessment

Using state-of-the-art fate-mapping models and genetic and pharmacological targeting approaches, this study provides valuable findings on the distinct functions exerted by resident and recruited macrophages during cardiac healing after myocardial ischemia. The evidence supporting the conclusions is solid with the use of the FIRE mouse model in combination with fate-mapping to target fetal-derived macrophages. This study will be of interest for the macrophage biologists working in the heart but also in other tissues in the context of inflammation.

eLife assessment

Toll like receptor 2 (TLR2) signaling has traditionally been viewed a surface protein that induces innate immune responses and improves acquired immunity. Here, the authors suggest a different role for TLR2 in the hair cycle. By using a Cre reporter that is largely, but not solely active in hair follicle stem cells, the authors conditionally delete Tlr2 in mice and report that BMP signaling is sustained and hair cycle entry is delayed. Delving further, the authors identify CEP (2-ω-carboxyethyl pyrrole) as an endogenous ligand of TLR2 in hair follicle stem cell regulation. Although a role for TLR2 signaling in hair follicle stem cells is potentially novel and important, the reviewers remain in consensus that evidence presented in two significant areas continues to be incomplete: 1) where TLR2 and CEP are expressed and how specific is their expression to the hair follicle stem cells; 2) whether as the authors suggest, TLR2 functions by regulating BMP signaling in the stem cell niche of the hair follicle.

eLife assessment:

The authors report a novel hepatic lncRNA FincoR regulating FXR with therapeutic implications in the treatment of MASH. The findings are important and use an appropriate methodology in line with the current state-of-the-art, with convincing support for the claims.

eLife assessment

This study presents a valuable finding that serum androstenedione levels may provide a new biomarker for early detection and progression of glaucoma, although a single biomarker is unlikely to be singularly predictive due to the etiological heterogeneity of the disease. The strength of the evidence presented is solid, supported by multiple lines of evidence.

eLife assessment

This fundamental study examines the effects of herbivory-induced maize volatiles on neighbouring plants and their responses over time. Measurements of volatile compound classes and gene expression in receiver plants exposed to these volatiles led to the conclusion that the delayed emission of certain terpenes in receiver plants after the onset of light may be a result of stress memory, highlighting the role of priming and induction in plant defences triggered by herbivore-induced plant volatiles. The evidence supporting the conclusions is compelling, with rigorous chemical assays of and state-of-the-art high throughput real time mass spectrometry. The work will be of broad interest to plant biologists and chemical ecologists.

eLife assessment

This useful study asks how the architecture of gene expression differences relates to the development of two alternative morphs in a marine annelid species. The dataset will be of value to the field and the work has the potential to substantially advance our understanding of life history evolution. However, in its current form, the lack of details for some methods and analyses makes the strength of the evidence incomplete. If suitably improved, the work would be of interest to anyone studying the evolution of development and life histories.

eLife assessment

This is an important paper as it is the first to use a reconstituted translation system to study competition among mRNAs for the initiation machinery. Understanding the principles of the biochemistry of mRNA competition for initiation factors cannot be achieved without such a system. The authors provide compelling evidence that Ded1 is required for efficient initiation in highly structured RNAs. A highly significant finding that validates the in vitro reconstituted system indeed recapitulates the effects of in-vivo perturbations of translation initiation.

eLife assessment

The study presents valuable findings on how the hypoxia response pathway senses and responds to changes in the homeostasis of the amino acid cysteine and other sulfur-containing molecules. By providing a compelling, rigorous genetic analysis of the pathway, the study adds to a growing body of literature showing that prolyl hydroxylation is not the only mechanism by which the hypoxia response pathway can act. Although the paper does not reveal new biochemical insight into the mechanism, it opens up new areas of investigation that will be of interest to cell biologists and biomedical researchers studying the many pathologies involving hypoxia and/or cysteine metabolism.

eLife assessment

This useful study aimed to examine the relationship of spatial frequency selectivity of single macaque inferotemporal (IT) neurons to category selectivity. There are some interesting findings in this report but some of these findings were difficult to evaluate because several critical details of the analysis are incomplete. The conclusion that single-unit spatial frequency selectivity can predict object coding needs further evidence to confirm.

eLife assessment

This fundamental study reveals the major role of calcium-binding proteins (CaBP1 and CaBP2) in sustained exocytosis from mouse inner hair cell ribbon synapses. Compelling data and analysis from CaBP1/2 double-knockout mice show enhanced calcium channel (CaV1.3) inactivation, slowed recovery from inactivation, and reduced synaptic vesicle exocytosis as assayed by membrane capacitance measurements, as well as greatly reduced in vivo spontaneous and sound-evoked spikes from the postsynaptic spiral ganglion neurons. Importantly, transgenic expression of CaBP2 led to the rescue of hearing capabilities. The continuous transmission of sound-evoked signals from auditory hair cells thus depends on the expression of both CaBP1 and CaBP2 and their suppression of CaV1.3 inactivation.

eLife assessment

Given a great need for novel human model systems to study small cell lung cancer (SCLC), the authors describe an important pre-clinical model with broad potential for the study of how genetic perturbations or drug treatments alter SCLC tumor growth, metastasis, and response to therapy. For the major finding, the authors provide convincing evidence that RB/TP53 suppression coupled with MYC overexpression in an ES cell-derived model system results in aggressive and metastatic SCLC. However, comparisons of the RB/TP53-suppressed, MYC overexpressing model with RB/TP53-suppressed cells in supporting the minor conclusion that MYC overexpression increases the neuroendocrine compartment are incomplete, and the impact of the work would have been increased with the inclusion of a broader set of genetic perturbations, such as over-expression of MYCL, to better model major SCLC phenotypes. The new model described will be of significant interest to researchers studying lung cancer.

eLife assessment

This study presents valuable insights into the potential role of a general transcription factor in MYCN-dependent regulation of transcription. The study presents solid evidence that TFIIIC and MYCN interact to control transcription. The methods, data, and analyses broadly support the claims with minor weaknesses, yet the logic can be improved, and several specific issues should be addressed. The paper would be of interest to molecular biologists working on MYCN-dependent regulation of gene expression.

eLife assessment

This important work substantially advances our understanding of osteoblast migration to the sites of bone formation and regeneration. The evidence supporting the conclusion is convincing, with rigorous in vitro assays for cellular and biochemical aspects and with appropriate in vivo models. The work will be of broad interest to developmental biologists and bone biologists.

eLife assessment

To investigate the evolutionary relationship between the RNAi pathway and innate immunity, this study uses biochemistry and structural biology to investigate the trimeric complex of Dicer-1, DRH-1 (a RIGI homologue), and RDE-4, which exists in C. elegans. The results described include rigorous kinetic analysis of the enzymatic activity of the complex and a moderate resolution cryo-EM structure. The results are convincing and valuable to the broader understanding of the evolution of antiviral defense.

eLife assessment

This valuable study shows that eliminating a large portion of the principal neurons in the mammalian olfactory bulb does not affect the initial establishment of the circuit but has an impact on its maintenance. The strength of the paper is that the anatomical changes induced by genetic ablation of neurons are clear-cut. There is a solid description of the structural and behavioral effects of ablating the majority of M/T neurons; however, the conclusions are incompletely supported by the findings.

eLife assessment

This paper describes valuable results from studies investigating circuits in the brain that underlie behavioral responses in fearful situations. The authors identified a role for a class of neurons that are sufficient to cause these stereotyped behaviors including freezing behaviors. These solid studies increase our understanding of brain pathways regulating these types of behaviors.

eLife assessment

This important work provides a robust yet simple protocol to isolate small extracellular vesicles from small volumes of plasma. The evidence supporting the conclusions is convincing, although a more thorough statistical comparison of the different techniques and technique combinations explored in the study would have been appreciated. The work will be of broad interest to cell biologists and biochemists.

eLife assessment

This useful study compares gene expression patterns among different autonomic ganglia and will be of interest to developmental neuroscientists and neurophysiologists. The study expands the database of genes expressed by subpopulations of autonomic neurons in ganglia, a key step in decoding their developmental origins and physiological functions. The evidence supporting the alternative view that the pelvic ganglionic neurons are actually modified sympathetic neurons is incomplete and may cause confusion, given the enrichment of cholinergic neurons, as well as the large number of molecular and functional differences known to be present between cranial and sacral neurons.

eLife assessment

This useful study compares gene expression patterns among different autonomic ganglia and will be of interest to developmental neuroscientists and neurophysiologists. The study expands the database of genes expressed by subpopulations of autonomic neurons in ganglia, a key step in decoding their developmental origins and physiological functions. The alternative view that the pelvic ganglionic neurons are actually modified sympathetic neurons is incompletely demonstrated given the large number of molecular and functional differences known to be present between cranial and sacral neurons.

eLife assessment

This study explores how Ebola virus evades human immune responses. The study reports a potential new mechanism wherein Ebola virus traps human IRF3, a key transcription factor involved in immune signaling, into virus-produced "inclusion bodies". The topic is important, the paper has many merits, and the biochemical assays are solid. However, the current data do not clearly explain the relationship between the VP35 protein and IRF3.

eLife assessment

This study presents a potentially valuable discovery which indicates that activation of the P2RX7 pathway by the small molecule HEI3090 can reduce lung fibrosis after its establishment by inflammatory damage. If confirmed, the study could clarify the role of specific immune networks in the establishment and progression of lung fibrosis. The presented data and analyses showing the efficacy of HEI3090 small molecule acting via the P2RX7 pathway in reducing lung fibrosis are solid. The studies also show that genetic deletion of P2RX7 itself can reduce the extent of fibrosis. P2RX7 can thus have distinct effects in various phases of the development of lung fibrosis. There is a need for additional definitive studies that specifically identify the discrete phases of when inflammasome activation via P2RX7 signaling can worsen fibrosis versus when the same signaling can be beneficial. It also needs to be established whether distinct immune cell populations mediate the detrimental and beneficial effects of P2RX7 activation in lung fibrosis.

eLife assessment

The authors develop a novel genetic strategy for specific and comprehensive labeling of axo-axonic cells, also referred to as Chandelier cells, in the mouse brain. The approach and analysis are rigorous such that the data convincingly support the key conclusions, including the expanded distribution of axo-axonic cells throughout the brain. This study provides valuable new information about the distribution of this neuronal cell type, as well as new tools for future studies. This work will be of broad interest to neuroscientists who work on the anatomical and functional organization of neural circuits.

eLife assessment

The manuscript addresses a fundamental question: are IDRs responsible for subnuclear clustering of transcription factors? A screen of 75 IDRs yielded convincing evidence that IDRs are rarely sufficient for subnuclear clustering, while the experimental design and data analysis provided limited evidence for the authors' claims regarding transcription factor clustering.

eLife assessment

This is an important paper that combines methods ranging from agronomy and plant breeding to Arabidopsis functional genetics, to argue that polymorphism in a single gene affects crop yield in pearl millet by affecting root cell elongation and drought stress resilience in a poorly studied crop. The overall argument is plausible but whether the solid evidence generated with Arabidopsis experiments can be extended to pearl millet itself is unclear.

eLife assessment

In this valuable contribution, the authors demonstrate that the infusion of NAD+ may prevent death and reduce disease severity from lethal experimental bacterial sepsis, possibly through inflammasome inhibition, without reducing bacterial load. They provide solid evidence for these protective effects of NAD+, though the precise mechanisms involved remain unclear and need further support and elucidation. The core findings may well have clinical implications but, in addition to mechanistic clarifications, contextualised interpretation as metabolic adaptation to sepsis would create wider interest.

eLife assessment

This detailed and well powered manuscript explores auditory perception of modulated noise in the presence of transcranial alternating-current stimulation (tACS) and shows valuable results suggesting that there are subject-specific effects when the phase of 2-Hz tACS varies relative to the phase of the noise modulation. The strength of the evidence is mixed. There is convincing evidence that tACS alters perception significantly in individuals; however, the effects are inconsistent across subjects and even across sessions, frustrating attempts to draw conclusions about the underlying mechanisms of the idiosyncratic effects. Despite these limitations, the paper will be of great interest to researchers interested in determining when and how tACS influences neural processes, especially those interested in neural entrainment and its relationship to perception.

eLife assessment

The study is an important advancement to the consideration of antimalarial drug resistance: the authors make use of both modelling results and supporting empirical evidence to demonstrate the role of malaria strain diversity in explaining biogeographic patterns of drug resistance. The theoretical methods and the corresponding results are compelling, with the novel model presented moving beyond existing models to incorporate malaria strain diversity and antigen-specific immunity. This work is likely to be interesting to malaria researchers and others working with antigenically diverse infectious diseases.