eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

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

eLife assessment

This valuable study aims to identify pioneer transcription factors - which are defined as transcription factors that compete with nucleosomes for DNA binding. The authors provide methods for identifying pioneer transcription factors on a cell type basis, using nucleosome positioning and motif information across different cell lines. The evidence to support the claims is largely solid. This work will be of interest to computational and molecular biologists working on transcription factors.

eLife assessment

This manuscript introduces two valuable new metrics - "variant vulnerability" and "drug applicability" - that would be of use to identify candidate drugs for treating infections while considering longer-term, evolution-based treatment outcomes. Despite the intuitive appeal of the metrics and their potential, the study remains incomplete, as it fails to demonstrate the generality of the approach. The work could be improved by analysing a broader range of data in a systematic way and directly tying the metrics to outcomes, which would make it possible to better assess their impact and utility.

eLife assessment

In this valuable study, the discovery and subsequent design of the AF03-NL chimeric antibody yielded a tool for studying filoviruses and provides a possible blueprint for future therapeutics. However, the data are incomplete and not presented clearly, which obscures flaws in the analyses and leaves unexplained phenomena. The work will be of interest to virologists studying antibodies.

eLife assessment

This valuable study employs a diverse array of techniques encompassing cell biological manipulations, biophysical measurements, and mouse models to elucidate the impact of target cell stiffness on CD8+ cytotoxic T cell activation, with a particular focus on the actin nucleator protein WASP. The finding that WASP is essential for the stiffness-dependent phosphorylation of ZAP70 in CD8 T cells is convincing. However, the data regarding the role of WASP in mechanosensing within CD8 T cell-mediated anti-tumor immunity is incomplete and would benefit from a more rigorous study design. This work would be of interest to cell biologists and investigators studying mechanosensing within the immune system.

eLife assessment

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

eLife assessment

Perampalam and colleagues provide solid evidence that Netrin signaling drives survival of non-proliferating ovarian cancer cells and their dissemination. These valuable findings were thought to provide unique insights into the molecular underpinnings of ovarian cancer spread and thus to be of significant interest to cancer biologists. However, the incomplete evidence supporting the role of the described Netrin-dependent mechanism in cancer dormancy was found to be a major shortcoming of the study.

eLife assessment

This important work by Park et al. introduces an open-top two-photon light sheet microscopy (OT-TP-LSM) for lesser invasive evaluation of intraoperative 3D pathology. The authors provide convincing evidence for the effectiveness of this technique in investigating various human cancer cells. The paper needs some minor corrections and has the potential to be of broad interest to biologists and, specifically, pathologists utilizing 3D optical microscopy.

eLife assessment

This manuscript addresses an important question, that in countries endemic for P vivax the need to administer a primaquine (PQ) course adequate to prevent relapse in G6PD deficient persons poses a real dilemma. On one hand PQ will cause haemolysis; on the other hand, without PQ the chance of relapse is very high. As a result, out of fear of severe haemolysis, PQ has been under-used. This manuscript is convincing that regimen (1) can be used successfully to deliver within 3 weeks, under hospital conditions, the dose of PQ required to prevent P vivax relapse.

eLife assessment

This study, utilizing CITE-Seq to explore CML, is considered a useful contribution to our understanding of treatment response. However, the reviewers express concern about the incomplete evidence due to the small sample size and recommend addressing these limitations. Strengthening the study with additional patient samples and validation measures would enhance its significance.

eLife assessment

This work describes a connection between inflammation and metabolism, in which itaconate stabilizes the mitochondrial fatty acid uptake enzyme Cpt1a to enhance fatty acid oxidation. The mechanism for itaconate action may be generalizable to other protein targets. This is an important advance, which is supported by solid experimental data.

eLife assessment

This paper represents important findings when identifying untargeted metabolomics and its differences between metabolomes of different biological samples. GromovMatcher is the fantasy name for the soft development. The main idea behind it is built on the assumption of featuring and matching complex datasets. Although the manuscript reflects a solid analysis, it remains incomplete for validation with putative non-curated datasets.

eLife assessment

This useful study describes a single set of label-chase mass spectrometry experiments to confirm the molecular function of YafK as a peptidoglycan hydrolase, and to describe the timing of its attachment to the peptidoglycan. Confirmation of the molecular function of YafK will be helpful in further studies to examine the function and regulation of the outer membrane-peptidoglycan link in bacteria. The evidence supporting the molecular function of YafK and that lpp molecules are shuffled on and off the peptidoglycan is solid, however, data supporting conclusions relating to the locations of lpp-peptidoglycan attachment are incomplete. The work will be of interest to microbiologists studying the bacterial cell wall.

eLife assessment

This is an important study that investigates the role of commensal microbes and molecules in the antigen presentation pathway affecting the development and phenotype of an unusual population of T lymphocytes. The authors provide compelling evidence to identify a population of unconventional T cells that exist in the small intestinal epithelium, which appear to depend on commensal microbes, and show that a single commensal microbe (that encodes an antigen capable of weakly stimulating these cells) is sufficient to maintain this T cell population.

eLife assessment

Sulphur atoms derived from cysteine are thought to play significant roles in maintaining redox homeostasis in Mycobacterium tuberculosis, which encounters stresses associated with immune cell interactions. In this valuable manuscript, the authors provide solid evidence that the genes encoding cysteine biosynthetic enzymes (cysM and cysK2) are required to maintain full viability of M. tuberculosis under in vitro stress conditions, macrophage infections, and within the lung tissues of mice. The manuscript presents transcriptomic and metabolomic evidence to support the hypothesis that CysM and CysK2 play distinct roles in maintaining cysteine-derived metabolite pools under stress conditions. The work will be of interest to microbiologists in general.

eLife assessment

This valuable work develops a new approach to measure imaginal disc growth in Drosophila. With this approach, the roles of two protocadherins (Fat and Dachsous), in late larval development is explored, and there is novel data on the scaling of their protein gradients. The evidence supporting the authors' findings overall are solid, though the genetic analysis of Fat and Dachsous function is incomplete and would benefit from further experiments.

eLife assessment

This valuable contribution studies factors that impact molecular exchange between dense and dilute phases of biomolecular condensates through continuum models and coarse-grained simulations. The authors provide solid evidence that interfacial resistance can cause molecules to bounce off the interface and limit mixing. Results like these can inform how experimental results in the field of biological condensates are interpreted.

eLife assessment

This important study identifies differential Orsay virus infection of C. elegans when animals are fed on different bacteria. The evidence for this is however, incomplete, as experiments to control for feeding rate and bacterial pathogenicity are needed as well as direct quantification of viral load.

eLife assessment

This useful work argues that claims on travelling waves in the cortex must be backed up with more careful experimental and theoretical work. Through simulations and neural recordings, the authors provide solid evidence to show that differences in activation timings can superficially appear as a travelling wave. This work has implications for how the field might need to revisit how travelling waves are methodologically characterised.

• for: IEA 2023 report - exec summary - Fossil Fuel industry, IEA 2023 report - exec summary - Oil and Gas industry

• summary

  • this is the IEA summary of the position of the Oil and Gas industry and what they must do in order to transition to a net zero world by 2050 and avert 1.5 Deg C global mean temperature.
  • it contains a lot of useful information and statistics

eLife assessment

This important work provides a detailed analysis of the population dynamics of an important human bacterial pathogen, Neisseria gonorrhoeae, using a large global collection of genomes with geographic, temporal, and demographic metadata. A unique facet of this work is the focus on both importation and exportation of N. gonorrhoeae; whilst quantifying importation is important to national public health efforts, quantifying exportation is relevant on an international level. However, the evidence supporting the conclusions is incomplete, due to potential inaccuracies in the method used for phylogenetic analysis, which forms the basis of this work. With the phylogenetic analysis strengthened, this paper would be of interest to epidemiologists and public health officials working on N. gonorrhoeae epidemiology and interventions.

eLife assessment

This is an important report that has implications for both the brain stimulation field and beyond. The strength of evidence provided is quite convincing. The major strength of this work is the recognize the importance of participant expectation in brain stimulation studies.

eLife assessment

This study presents a useful method for the extraction of behaviour-related activity from neural population recordings based on a specific deep learning architecture - a variational autoencoder. However, the evidence supporting the scientific claims resulting from the application of this method is incomplete as the results may stem, in part, from its properties. The authors should: (1) improve how they benchmark their method, by comparing against additional relevant techniques, and (2) reframe their results considering what observations may be a byproduct of their method, and which do constitute new scientific observations.

eLife assessment

In this potentially useful study, the authors use deep learning models to provide solid evidence that epithelial wounding triggers bursts of cell division at a characteristic distance away from the wound. The usefulness of the methods to the community will depend on documenting their robustness toward variability in temporal resolution and/or mitotic event duration and demonstrating their overall superiority over existing approaches.

eLife assessment

This paper investigates host and viral factors influencing transmission of alpha and delta SARS-CoV-2 variants in the Syrian hamster model and fundamentally increases knowledge regarding transmission of the virus via the aerosol route. The strength of evidence is solid and could be improved with a clearer presentation of the data.

eLife assessment

This valuable study uses a model to determine when catalytic self-replication of polymers can emerge from a random pool of replicating polymers. The model accounts for the folding and function of polymers in addition to abstract evolutionary dynamics, providing solid evidence for the claims of the authors. The work will be of relevance to those interested in the origin of life, artificial cells, and evolutionary dynamics.

eLife assessment

This is a fundamental resource of snRNA-seq and and chromatin accessibility data from human aortic endothelial cells (ECs), treated with relevant perturbations such as IL1b, TGFB2, or si-EGR. The authors show that ECs can be categorized by distinct subpopulations of differing plasticity. The support for the existence of these subpopulations is compelling, supported also by three publicly available scRNA-seq datasets, and differential enrichment of coronary artery disease associated SNPs in open chromatin in these subpopulations. Inter alia, clarifications of controls and variability among EC responses would strengthen the interpretations of the study.

eLife assessment

This important study provides an unprecedented overview of the subcellular organization of proliferative blood stage malaria parasites using expansion microscopy. The localization of multiple parasite organelles is comprehensively probed using three-dimensional super-resolution microscopy throughout the entire intraerythrocytic development cycle. This work provides a compelling framework to investigate in future more deeply the unconventional cell biology of malaria-causing parasites.

eLife assessment

This work provides a valuable characterization of the chaotic dynamics of high-dimensional spiking networks in the presence of internally generated oscillations due to synaptic delays or externally generated oscillations due to external input. The authors provide convincing analytical and numerical calculations to support their claims, however, the paper suffers from heavy mathematical jargon that reduces its impact. The paper could be revised to provide interpretations of the results so that it can be accessible to a broader neuroscience audience. In its current form, findings will be of interest mostly to researchers working at the interface between theoretical neuroscience, applied mathematics, and physics.

eLife assessment

This important study advances our understanding of how past and future information is jointly considered in visual working memory by studying gaze biases in a memory task that dissociates the locations during encoding and memory tests. The evidence supporting the conclusions is convincing, with state-of-the-art gaze analyses that build on a recent series of experiments introduced by the authors. This work, with further improvements incorporating the existing literature, will be of broad interest to vision scientists interested in the interplay of vision, eye movements, and memory.

eLife assessment

This is an important study that extends our understanding of how the medial prefrontal cortex regulates goal-directed action during threat. The authors provide convincing evidence that prefrontal cortex parvalbumin neurons suppress conditional freezing responses, permitting the initiation of active controlling responses over shock onset (termed 'avoidance'); also, this cell-type function does not generalize to appetitive situations or general locomotion. These findings are expected to be of great benefit to multiple neuroscience subfields interested in the mechanisms of adaptive behavior.

eLife assessment

This study provides an important contribution to understanding how parafoveal words are neurally processed. The study employs a state-of-the-art frequency tagging paradigm to study the MEG response to words during natural reading. It provides solid evidence that semantic information of parafoveal words can be extracted.

eLife assessment

This study provides a valuable contribution to understanding the neural mechanisms underlying age-related changes in attention and speech understanding. The large dataset (N=105) provides solid evidence for how speech recognition behaviour and neural tracking of speech separately evolve in about 2 years. The work would be of interest to psychologists, neuroscientists, and audiologists.

eLife assessment

The aim of this valuable study is to uncover developmental roles of the neuropeptide prothoracicotropic hormone (PTTH) and ecdysone, which later regulate female receptivity of Drosophila melanogaster. The work combines spatially and temporally restricted genetic manipulation with behavior quantification to explore these molecular pathways and the neuronal substrates participating in the control of female sexual receptivity. At present, the implication of both signaling pathways in this process is convincing but the strength of the evidence is incomplete to support the main claim that PTTH pathway controls female sexual receptivity through the function of ecdysone in pC1 neurons.

eLife assessment

This important and elegant study makes a significant step towards harmonisation of two perspectives on synaptic plasticity in the brain: Bayesian inference and energy efficiency. Through a combination of analytical derivations and numerical simulations, the authors make a compelling case that the two perspectives, which on the surface seem very different, are in fact closely related. In addition, they provide moderate experimental evidence that corroborates predictions of their synaptic plasticity models.

eLife assessment

Winter months with short days are commonly associated with seasonal depression and hypersomnolence; the mechanisms behind this hypersomnolence however remain unclear. Chen and colleagues identify a genetic basis for this phenomenon in the fly Drosophila - mutations in the circadian photoreceptor cryptochrome resulted in increased sleep under short photoperiods. These findings are potentially valuable insights into the genetic mechanisms regulating sleep under short days. The data supporting the neurobiological basis of these effects is however incomplete.

eLife assessment

This study reports valuable findings that corticostriatal projections (specifically, from M1 and MCC ) target direct and indirect pathway striatal projection neurons in partially segregated ways. Moreover, this partial segregation is biased, implying that specific engagement of the direct pathway may be achieved through the selective activation of unique cortical neurons. The evidence for this conclusion is solid, though the key experiments (rabies tracing controls, etc.) are incomplete. Otherwise, the experiments are rigorously designed, and the results are solid. This work will be of interest to those interested in brain anatomy and/or circuitry, cortical and/or basal ganglia function, locomotor activity, reinforcement learning, or diseases related to these.

eLife assessment

This MEG study reports valuable new findings regarding the nature of memory reactivation during cued recall. It replicates previous work showing that such reactivation can be sequential or clustered, with sequential reactivation being more prevalent in low performers. It adds solid evidence, even though based on limited data, that item strengths during clustered reactivation vary with item distance in the learned graph structure. The study will be of interest to human and rodent neuroscientists working on memory replay.

eLife assessment

This valuable study provides molecular-level insights into the functional mechanism of bacterial ice-nucleating proteins, detailing electrostatic interactions in the domain architecture of multimeric assemblies. The evidence supporting the claims of the authors is solid, with results from protein engineering experiments, functional assays, and cryo-electron tomography, while the proposed structural model of protein self-assembly remains hypothetical. The work is of broad interest to researchers in the fields of protein structural biology, biochemistry, and biophysics, with implications in microbial ecology and atmospheric glaciation.

eLife assessment

This manuscript presents a useful analysis of allosteric communication in the CFTR protein using a coarse-grained dynamic model and characterized the role of disease-causing mutations. The results and analyses are generally solid and validated with available experimental observations. The findings provide comprehensive insights into the allosteric mechanism of this protein.

eLife assessment

This important paper reports major technical advances for in vivo intramuscular electrical recording from multiple motor units in behaving animals. The paper includes compelling demonstrations of the efficacy of this new technique in multiple animal species. This new muscle recording method has the potential to provide new insight into a wide range of questions in motor neuroscience.

eLife assessment

This is a valuable computational study that applies the machine learning method of bilinear modeling to the problem of relating gene expression to connectivity. Specifically, the author attempts to use transcriptomic data from mouse retinal neurons to predict their known connectivity. The results are promising, although the reviewers felt that demonstration of the general applicability of the approach required testing it against a second data set. Hence the present results were felt to provide borderline incomplete support for a key premise of the paper.

eLife assessment

In this paper, the authors introduce fundamental work on mathematical methods for inferring evolutionary parameters of interest from RNA data in healthy tissue and during hematopoiesis. By combining single cell and bulk sequencing analyses, the authors use a stochastic process to inform different aspects of genetic heterogeneity; the strength of evidence in support of the authors' claim is exceptional. The work will be of broad interest to cell biologists and theoretical biologists.

eLife assessment

This review examines seasonal dormancy in various species, including hibernating mammals (excluding bats and bears) and ectotherms. It tests hypotheses on dormancy timing, considering energetic constraints and life history as alternative drivers. While the review is valuable, ecological differences between males and females can drive differences in energy balance, hence the idea that sex differences in dormancy timing are associated with non-energy constraints. Evidence supporting a life-history hypothesis is therefore somewhat incomplete. Nonetheless, examining these alternative hypotheses is of interest to evolutionary biologists, and including a diverse range of species, population-level traits, and some ecological context would enhance the value of the review.

eLife assessment

This study presents fundamental findings on the evolution of extremely elongated mandibular symphysis and tusks in longirostrine gomphotheres from the Early and Middle Miocene of northern China. The integration of multiple methods provides compelling results in the eco-morphology, behavioral ecology, and co-evolutionary biology of these taxa. In doing so, the authors elucidate the diversification of fossil proboscideans and their likely evolutionary responses to late Cenozoic global climatic changes.

eLife assessment

This valuable manuscript reports on the relationship between GTP hydrolysis parameters and kinase activity of LRRK2, which is associated with Parkinson's disease. The authors provide a detailed accounting of the catalytic efficiency of the ROC GTPase domain of pathogenic variants of LRRK2, in comparison with the wild-type enzyme. The authors propose that phosphorylation of T1343 inhibits kinase activity and influences monomer-dimer transitions, but the experimental evidence is currently incomplete.

eLife assessment

This is a theoretical analysis that gives compelling evidence that length control of bundles of actin filaments undergoing assembly and disassembly emerges even in the absence of a length control mechanism at the individual filament level. Furthermore, the length distribution should exhibit a variance that grows quadratically with the average bundle length. The experimental data are compatible with these fundamental theoretical findings, but further investigations are necessary to make the work conclusive concerning the validity of the inferences for filamentous actin structures in cells.

eLife assessment

The authors present 16 new well-preserved specimens from the early Cambrian Chengjiang biota. These specimens potentially represent a new taxon which could be useful in sorting out the problematic topology of artiopodan arthropods - a topic of interest to specialists in Cambrian arthropods. Because the anatomic features in the new specimens were neither properly revealed nor correctly interpreted, the evidence for several conclusions is inadequate.

eLife assessment

This is a useful study examining the determinants and mechanisms of LRMP inhibition of cAMP regulation of HCN4 channel gating. The evidence provided to support the main conclusions is unfortunately incomplete, with discrepancies in the work that reduce the strength of mechanistic insights.

eLife assessment

This important study provides proof of the principle that C. elegans models can be used to accelerate the discovery of candidate treatments for human Mendelian diseases by detailed high-throughput phenotyping of strains harboring mutations in orthologs of human disease genes. The data presented are solid and would potentially be convincing if complete data sets were to be made available to the scientific community. This approach enables the potential rapid repurposing of FDA-approved drugs to treat rare diseases for which there are currently no effective treatments.

eLife assessment

This valuable study presents presents solid evidence that an anti-CTLA-4 antibody drug conjugate transiently depletes circulating B cells in a mouse model, showing how dysregulation of the T cell immune system can impact B cell homeostasis. The work will be of broad interest to immunologists and medical biologists, but a major limitation is that the mechanism of B-cell reduction remains unclear, as evidence of killing of B-cells by T-cells is not presented.

eLife assessment

This study presents valuable information that an anti-CTLA-4 antibody drug conjugate transiently depletes circulating B-lymphocytes in a mouse model. It shows how dysregulation of the T cell immune system can impact B cell homeostasis. The work will be of broad interest to immunologists and medical biologists, but the strength of evidence is incomplete at this time mainly because they only analyzed circulating B cells.

eLife assessment

This important study offers new and convincing support for the idea that about a third of mouse liver DNAse hypersensitivity sites (DHS) showing male-biased chromatin opening are sex-biased because of the male-specific cyclic action of growth hormone pulses to alter chromatin accessibility, as compared to the relative ineffectiveness of the more static pattern of growth hormone secretion in females. Supporting evidence is found in the impact of hypophysectomy and growth hormone treatment on chromatin accessibility, and the binding of specific transcription factors and epigenetic marks at STAT5-sensitive sites. This work uncovers mechanisms underlying sex differences in liver function and will be of broad interest to endocrinologists and hepatologists.

eLife assessment

This study defines the roles for two different missense mutations observed in patients in the Trabid/ZRANB1 gene associated in children with a range of congenital disorders including reduced brain size. The study is important because the findings have theoretical or practical implications beyond a single subfield, as the study of DUB and cytoskeletal alterations have implications for neurodevelopment broadly. The methods are convincing as they utilize appropriate and validated methodology in line with current state-of-the-art by incorporating knock-in mice of the patient mutations. Many of the reviewer comments were focused on potential next experiments, rather than on evaluation of the data at hand, and the authors have considered these as future studies. The work as presented suggests critical roles for Trabid in the STRIPAK complex mediating APC deubiquitylation.

eLife assessment

This work presents important findings regarding the use of soil environmental DNA for non-invasive monitoring of the endangered kākāpō parrot population in New Zealand. The approach based on sequence analysis is convincing but comparisons to established methods are lacking. The tools presented in this study are innovative and will be relevant to those working with environmental DNA and the conservation of biodiversity.

eLife assessment

This valuable data study presents convincing data that expression of the C. elegans transcription factor NHR-67 is sufficient to drive an invasive fate, and that the alternative proliferative fate is associated with NHR-67 transcriptional down-regulation. While the observation that NHR-67 forms punctae associated with transcriptional repressors in non-invasive cells is intriguing, the work does not yet established a clear link between the formation and dissolution of NHR-67 condensates with the activation of downstream genes that NHR-67 is actively repressing. The work will be of interest to developmental biologists studying transcriptional control of cell fate specification in animals, especially once issues around the functional significance of the NHR-67 contiaining punctae are resolved.

eLife assessment

This important study identifies the role of Caveolin1 and Cavin1 as regulators of TransEndothelial Macroaperture (TEM). The methodology used is rigorous and compelling, and further research can point to a more mechanistic understanding of the process.

eLife assessment

This fundamental work proposes a novel mechanism for memory consolidation where short-term memory provides a gating signal for memories to be consolidated into long-term storage. The work combines extensive analytical and numerical work applied to three different scenarios and provides a convincing analysis of the benefits of the proposed model, although some of the analyses are limited to the type of memory consolidation the authors consider (and don't consider), which limits the impact. The work could be revised to include a more thorough comparison to existing models of memory consolidation and a discussion of its limitations, and the revision could also streamline the technical terminology. The work will be of interest to neuroscientists and many other researchers interested in the mechanistic underpinnings of memory.

eLife assessment

This is a potentially important study that integrates QM/MM free energy simulations and experimental kinetic analyses to probe the nature of phosphoryl transfer transition state in adenylate kinase. The idea that the transition state ensemble encompasses conformations with substantially different structural features (including the breaking/forming bonds) is interesting and potentially applicable to many other enzyme systems. In the current form, however, the study is considered incomplete since the connection between the putative transition state ensemble from the computations and key experimental observables, such as the activation entropy, is not well established.

eLife assessment

This manuscript describes structures of HER4 homo- and HER4/HER2 hetero-dimer complexes using single particle cryo-EM. This important work describes convincingly new structural details of these complexes that expand our understanding of their function. This work will be of interest to researchers working on cell surface signalling and kinase activity.

eLife assessment

The work is a useful contribution towards understanding the role of archaeal and plant D-aminoacyl-tRNA deacylase 2 (DTD2) in deacylation and detoxification of D-Tyr-tRNATyr modified by various aldehydes produced as metabolic byproducts in plants. It integrates convincing results from both in vitro and in vivo experiments to address the long-standing puzzle of why plants outperform bacteria in handling reactive aldehydes and suggests a new strategy for stress-tolerant crops. The impact of the paper is limited by the fact that only one modified D-aminoacyl tRNA was examined, in lack of evidence that plant eEF1A mimics EF-Tu in protecting L-aminoacyl tRNAs from modification, and in failure to measure accumulation of toxic D-aminoacyl tRNAs or impairment of translation in plant cells lacking DTD2.

eLife assessment

The work by Johnson and co-workers has identified an important role of 2-Hydroxybutyrate in skeletal muscle oxidative capacity in the early stages of exercise. Mechanistically, they show convincing data to support a role of 2-Hydroxybutyrate in the regulation of BCAA metabolism via SIRT4, ADP-Ribosylation, and CEBP. However, whether this is the sole mechanism and if these translate to longer exercise training regimes requires future experiments.

eLife assessment

The manuscript "Structure Guided mutatgensis of OSCAs reveals differential activation to mechanical stimuli" seeks to dissect the molecular underpinnings of poke and stretch activation in OSCA channels. While the structural and functional experiments are well done, and the authors present some important data, the reviewers identified weaknesses in experimental design and interpretation that render the data incomplete in supporting some of the main conclusions of the paper. Nevertheless, this work will be of interest to those working in the fields of mechanosensation, sensory biology, and ion channels.

eLife assessment

This study reports valuable findings on the correlation between the positions of dendritic mitochondria and the orientation preference of calcium responses of individual spines. The conclusion about the biased localization of dendritic mitochondria near functional diverse spines is informative to understand the functions of dendritic mitochondria. The experimental evidence supporting the conclusion is compelling.

eLife assessment

This important paper exploits new cryo-EM tomography tools to examine the state of chromatin in situ. The experimental work is meticulously performed, with a vast amount of data collected, with convincing interpretation of possible nucleosomal structures in yeast. The majority of these nucleosomes appear not to possess stable octameric configurations. Although it cannot be excluded that there could be an unknown bias in class detection, we agree that the authors have gone as far as is possible, given constraints in current technology and analysis, to support their model. Despite the provocative nature of this report, it is our hope that such work will spark debate, and further the development of exciting new tools that can interrogate the dynamic nature of the nucleosome, and its associated functions in situ.

eLife assessment

This important paper exploits new cryo-EM tomography tools to examine the state of chromatin in situ. The experimental work is meticulously performed and convincing, with a vast amount of data collected. The main findings are interpreted by the authors to suggest that the majority of yeast nucleosomes lack a stable octameric conformation. Despite the possibly controversial nature of this report, it is our hope that such work will spark thought-provoking debate, and further the development of exciting new tools that can interrogate native chromatin shape and associated function in vivo.

eLife assessment

This important study evaluates the outcomes of a single-institution pilot program designed to provide graduate students and postdoctoral fellows with internship opportunities in areas representing diverse career paths in the life sciences. The data convincingly show the benefit of internships to students and postdocs, their research advisors, and potential employers, without adverse impacts on scientific productivity. This work will be of interest to multiple stakeholders in graduate and postgraduate life sciences education and should stimulate further research into how such programs can best be broadly implemented.

eLife assessment

This study presents a valuable new approach for efficient computation of statistics on correlations between genetic variants (linkage disequilibrium, or LD), which the authors apply to quantify the extent of LD across chromosomes. The method appears solid, although the presentation of equations needs clarification and improvement. The authors document that cross-chromosome LD can be substantial, which has implications for geneticists who are interested in population structure and its impact on genetic association studies.

eLife assessment

This study presents important findings regarding the local dynamics at the anion binding site in the SLC26 transporter prestin that is responsible for electromotility in outer hair cells. The authors reveal critical differences to homologous proteins and thereby provide insight into prestin's unique function. The evidence is generally convincing, although orthogonal evidence would be required to fully support the claims concerning the mechanistic basis for voltage sensitivity.

eLife assessment

This study presents important findings regarding the local dynamics at the anion binding site in the SLC26 transporter prestin that is responsible for electromotility in outer hair cells. The authors reveal critical differences to homologous proteins and thereby provide insight into prestin's unique function. The evidence is generally convincing, although the interpretations concerning the mechanistic basis for voltage sensitivity would benefit from orthogonal evidence.

eLife assessment

This study presents valuable observations on a potential role of creatine (Cr) as a novel neurotransmitter. While the data provide compelling evidence that Cr is present in synaptic vesicles, the evidence that Cr is synaptically released and binds to a post-synaptic receptor is incomplete, as no receptor is described. With further evidence, these results will be of wide interest to the field of neuroscience.

eLife assessment

This study presents valuable observations on a potential role of creatine (Cr) as a novel neurotransmitter. The data provide solid evidence that Cr is present in synaptic vesicles. If, in the future, a receptor can be described, it will support the claim that Cr is synaptically released and binds to a post-synaptic receptor. This would be of wide interest to the field of neuroscience.

eLife assessment

This study presents valuable observations on the role of creatine (Cr) in the context of synaptic transmission. Overall, the data are solid in support of the conclusion that Cr is present in synaptic vesicles, although the evidence for Cr release and Cr-dependent modulation of neuronal function was considered incomplete. The work will be of general interest to the field of neuroscience.

eLife assessment

This is a valuable comparative study of local adaptation using gene-by-environment and gene-by-phenotype correlations. The analyses seemed still incomplete, as the biological take-home messages were obscured by the statistical approaches used, and it remains unclear how to best interpret the level of genome-wide convergence and in inversions. The repeatability of local adaptation across species, and the role of inversions in local adaptation, are questions of considerable empirical interest.

eLife assessment

This is a valuable information-theoretic re-analysis of human intracranial recordings during reward and punishment learning. It provides solid evidence that reward and punishment learning is represented in overlapping regions of the brain while relying on specific inter-regional interactions. However, there are weaknesses in the analysis approach that raise concerns about the consistency of the effects across participants and the interpretation of the findings. This preprint will be interesting to researchers in systems and cognitive neuroscience.

eLife assessment

This fundamental study addresses the earliest events that enable plant roots to reorient growth in response to gravity. Compelling molecular and cell biological data establish that plasma membrane localization of the LAZY or NEGATIVE GRAVITROPIC RESPONSE OF ROOTS (NGR) protein family is required for rapid and polar redirection of D6 protein kinase, an activator of the PIN3 auxin transporter. This work complements recent publications on the NGR family in gravity sensing (Chen et al., PMID: 37741279 and Nishimura et al., PMID: 37561884). Collectively these papers advance our understanding of rapid plant gravity sensing and response.

eLife assessment

This manuscript provides a fundamental contribution to the understanding of the role of intrinsically disordered proteins in circadian clocks and the potential involvement of phase separation mechanisms. The authors convincingly report on the structural and biochemical aspects and the molecular interactions of the intrinsically disordered protein FRQ. This paper will be of interest to scientists focusing on circadian clock regulation, liquid-liquid phase separation, and phosphorylation.

eLife assessment

This manuscript describes fundamental single-molecule correlative force and fluorescence microscopy experiments to visualize the 1D diffusion dynamics and long-range nucleosome sliding activity of the yeast chromatin remodelers, RSC and ISW2. Compelling evidence shows that both remodelers exhibit 1D diffusion on bare DNA but utilize different mechanisms, with RSC primarily hopping and ISW2 mainly sliding on DNA. These results will be of interest to researchers working on chromatin remodeling.

eLife assessment

This manuscript describes useful information on the interactions of the BRAF N-terminal regulatory regions (CRD, RBD and BSR) with the C-terminal kinase domain and with the upstream regulators HRAS and KRAS. The authors provide solid evidence that the BRAF BSR domain may negatively regulate RAS binding and propose that the presence of the BSR domain in BRAF provides an additional layer of autoinhibitory constraints. The data will be of interest for researchers in the RAS/RAF and general kinase regulation fields.

eLife assessment

This important study examined whether the BMP signaling pathway has a role in H3.3K27M DMG tumors, regardless of the presence of ACRVR1 activating mutations. The authors show compelling 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 as well as further consideration of elements, such as the location of the tumor, in the datasets used, overall this work suggests that BMP2/7 could be considered as a target for future therapies in this deadly cancer.

eLife assessment

This study presents a useful finding on the role of GABRD and its downstream target CDK1 in the progression of breast cancer. The evidence supporting the claims of the authors is somewhat incomplete and the elaboration of the mechanistic details on GABARD/CDK1 regulation would have strengthened the study. The work will be of interest to clinicians and biologists working on breast cancer.

eLife assessment

This important study substantially advances our understanding of pediatric Crohn's disease, mapping the cellular make-up of this disease and how patients respond to treatment. The evidence supporting the conclusions is compelling, with thorough bioinformatic analyses, underpinned by rigorous methodology and data integration. The work will be of broad interest to pediatric clinicians, immunologists and bioinformaticians.

eLife assessment

The authors analyzed the causative association between circulating immune cells and periodontitis, and reported three risk immune cells related to periodontitis. The significance of the findings is fundamental, which substantially advances our understanding of periodontitis. The strength of evidence is convincing.

eLife assessment

This manuscript reports important in vitro biochemical and in planta experiments to study the receptor activation mechanism of plant membrane receptor kinase complexes with non-catalytic intracellular kinase domains. Several lines of evidence convincingly show that one such putative pseudokinase, the immune receptor EFR achieves an active conformation following phosphorylation by a co-receptor kinase, and then in turn activates the co-receptor kinase allosterically to enable it to phosphorylate down-stream signaling components. This manuscript will be of interest to scientists focusing on cell signalling and allosteric regulation.

eLife assessment

This useful manuscript reports mechanisms behind the increase in fecundity in response to sub-lethal doses of pesticides in the crop pest, the brown plant hopper. The authors hypothesize that the pesticide works by inducing the JH titer, which through the JH signaling pathway induces egg development. Evidence for this is, however, inadequate.

eLife assessment

This study describes important results from cardiac-specific overexpression of adenylyl cyclase type 8 (TGAC8) mice that was integrated with transcriptomic and proteomic evidence. The paper convincingly provides new insights into how one can interpret signals from visceral organs.

eLife assessment:

This valuable manuscript provides solid methodologies for utilizing SMALP nanodisks for oligomer characterization. The authors present a platform for capturing and studying native membrane protein oligomerization and subsequent cryoEM analysis. The specific application of the method to WbaP, a membrane-bound phosphoglycosyl transferase, adds to our understanding of glycoconjugate production in bacteria. This manuscript would be of interest to those focusing on native membrane protein studies and antimicrobial resistance.

eLife assessment

This important paper addresses the challenging problem of dating the origin of several groups of marine microorganisms. However, while much of the analyses are solid, the lack of robustness analysis in molecular dating component such as using alternative time calibrations, clock models, and input gene sets makes the study incomplete. Despite some concerns, this work is a commendable attempt at an extremely difficult problem and will be of broad interest to microbiologists, geologists, and evolutionary biologists.

eLife assessment

This important paper addresses the challenging problem of dating the origin of several groups of marine microorganisms. The analyses are solid, with various test of clock models and time calibrations used, however given the uncertainty of many of the dates used to anchor ancient geological events, further studies are needed to support or refute the hypotheses put forth in this paper. Despite some methodological concerns, this work is a commendable attempt at an extremely difficult problem and will be of broad interest to microbiologists, geologists, and evolutionary biologists.

eLife assessment

This paper identifies a subset of neurons within adult mouse myenteric ganglia that are not labeled via canonical neural-crest labeling, and argues, based on extensive lineage tracing, imaging and genomic data that these neurons are derived from mesoderm. There is convincing evidence for the existence of an unusual cell type in the gut that expresses neuronal markers, but which is derived from cells expressing markers of the mesoderm rather than the expected neural crest, which is an intriguing and important observation. While the data do not definitively establish the molecular taxonomy of this lineage, there is sufficient evidence to support the provocative and paradigm-shifting hypothesis of the non-ectodermal origin for enteric neurons to warrant further deeper investigation.

eLife assessment

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

eLife assessment

This important study sheds light on the role of sphingolipids on the maturation of Parkinson's disease-associated Synphilin-1 inclusion bodies (SY1 IBs) on the mitochondrial surface in a yeast model using Synthetic Genetic Array (SGA) and state-of-the-art imaging techniques. The authors provide solid evidence that downregulating the sphingolipid biosynthesis pathway leads to defective maturation and enhanced toxicity of SY1 IBs in both yeast and mammalian cells. However, these data neither explain the role of mitochondrial surface sphingolipids in SY1 IB maturation (the cellular site of maturation of smaller toxic aggregates to bigger less toxic IBs), nor the requirement of mitochondrial activity in IB maturation.

eLife assessment

This study presents a valuable finding on the cell composition in mouse spleen depleted for the CD47 receptor and its signaling ligand Thrombospondin in hematopoietic differentiation. The supporting evidence is convincing with analytical improvements on the individual contributions of the signaling components and with functional studies. This work has implications for the role of CD47/Thsp in extramedullary erythropoiesis in mouse spleen and will be of interest to researchers in cell signaling, transfusion medicine, and cell therapy.

eLife assessment

This valuable work deals with mathematical modeling of centrosome maturation, building on the insight that autocatalytic assembly of the centrosome leads to size inequality. To remedy this, the authors propose a catalytic growth model with a shared enzyme pool that is able to reproduce various experimental results such as centrosome size scaling with cell size and centrosome growth curves in C. elegans. While finding the work of interest, the strength of the evidence presented in favor of the model is incomplete.

eLife assessment

These important findings will be of interest for the study of dystroglycanopathies and in the general area of axon migration and synapse formation. This work provides convincing conclusions about how a range of dystroglycan mutations alter CCK interneuron axonal targeting and synaptic connectivity in the forebrain, and seizure susceptibility.

eLife assessment

This study provides a valuable finding on the mechanistic connections between epithelial-mesenchymal transition (EMT) and lipid metabolism. The authors identified the ZEB2/ACSL4 axis as a newly discovered metastatic metabolic pathway that promotes both lipogenesis and fatty acid oxidation. The evidence supporting the claims of the authors is solid. The work will be of interest to medical biologists working on cancer.

eLife assessment

This paper reports important findings on a potent activator of the YAP pathway, demonstrating its mechanism through alternative splicing changes. The authors provide convincing evidence to support their claims. This research is of interest to biologists studying alternative splicing or the Hippo pathway, with significant implications for medical research.

eLife assessment

This valuable study advances our understanding of the evolution of protein complexes and their functions. Through convincing experimental and computational methodologies, the authors show that the specialization of protein function following gene duplication can be reversible. The work will be of interest to investigators working in biochemical evolution and those working on heat shock proteins.

eLife assessment

This valuable paper characterizes a murine model for congenital cystic airway abnormalities (CPAM). In contrast to previous assumptions that only epithelial cells are involved in the formation of pulmonary cysts, the authors provide compelling new evidence that defective BMP signaling in lung mesenchymal cells can disrupt airway development. Knowing that proper BMP signaling in mesenchymal cells is required for normal cyst-free lungs could potentially pave the way to understanding and preventing CPAM in infants at risk for this common disorder, which can be fatal if untreated. The relevance of the murine model could be enhanced by providing further histological details in comparison with human cysts, as well as interrogation of datasets such as GWAS whether genetic changes in human cysts are related to abnormal BMP signaling.

eLife assessment

This valuable study identifies an uncharacterized yeast gene regulating chronological lifespan in a mitochondrial-dependent pathway. The approach to identify and characterise this new gene is compelling, but the evidence is incomplete in supporting the major conclusions. With a stronger focus on the relevance of replicative in addition to chronological lifespan, and stronger data linking to mitochondrial function, this paper would be interesting to the yeast biologists working in metabolism and aging.

eLife assessment

This is a useful contribution to our understanding of how different cell stressors (ethanol or heat-shock) might elicit unique responses at the genomic and topographical level under the regulation of yeast transcription factor Hsf1, and of 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. While much of the data is convincing, the work is incomplete in not providing strong evidence supporting (i) a similar rate and extent of proteotoxic stress under the two chosen stress conditions, (ii) relatively greater bulk chromatin compaction elicited by ethanol, (iii) reproducible levels of interactions between chromosomal loci, and (iv) phase-separated condensates versus other types of Hsf1 clusters.

eLife assessment

This important work shows compelling evidence that Chandelier cells in the visual cortex receive inputs most prominently from local layer 5 pyramidal neurons, only mildly inhibit L2/3 pyramidal neurons, and respond massively to visuomotor mismatch. It also indicates that visual experience in the virtual tunnel activates a plasticity mechanism in Chandelier cells which could be due to the particular visuo-motor coupling experienced in this setting, although a specific control is lacking for this conclusion. This study will be of interest to neuroscientists involved in cortical circuits, visual processing, and predictive coding research.

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• summary

  • Horizon Canada still makes the biggest assumption of all, an intact modernity

eLife assessment

This study reports useful information on the limits of the organotypic culture of neonatal mouse testes, which has been regarded as an experimental strategy that can be extended to humans in the clinical setting for the conservation and subsequent re-use of testicular tissue. The evidence that the culture of testicular fragments of 6.5-day-old mouse testes does not allow optimal differentiation of steroidogenic cells is compelling and should enable further optimizations in the future.