eLife assessment

This study is of potential interest to readers in human genetics and quantitative genetics, as it presents a new method for homozygosity mapping in population-scale datasets, based on an innovative computational algorithm that efficiently identifies runs-of-homozygosity (ROH) segments shared by many individuals. Although the method is innovative and has the potential to be broadly useful, its power and limitations have not yet been adequately evaluated. The application of this new method to the UK Biobank dataset identifies several interesting associations, but it remains currently unclear under what conditions the new approach can provide additional power over existing genome-wide association study methods.

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 will be of broad interest to vision scientists interested in the interplay of vision, eye movements, and memory.

eLife assessment

This important study provides previously unappreciated insights into the functions of protist eIF4E 5'mRNA cap-binding protein family members, thereby contributing to a better understanding of translation regulation in these organisms. The authors provide solid evidence to support the major conclusions of the article. However, the study may further benefit from establishing whether all of the eIF4E family members are indeed involved in translation and more direct evidence for the selectivity of their binding.

eLife assessment

This study uses ex vivo live imaging of the uterus, uterotubal junction, and oviduct post-mating to test the role of the sperm hook in the house mouse (Mus musculus) in sperm movement which could be interesting to evolutionary biologists. The work is useful as their live imaging revealed sperm behaviors in the female tract that have not been previously reported. However, the strength of evidence is incomplete since the limited quantification of the data is insufficient and the extensive speculation on the functions of these sperm behaviors is not supported by sufficient experimental evidence to support their conclusions.

eLife assessment

This study provides valuable information on the mechanism of PepT2 through enhanced-sampling molecular dynamics, backed by cell-based assays, highlighting the importance of protonation of selected residues for the function of a proton-coupled oligopeptide transporter (hsPepT2). The molecular dynamics approaches are convincing, but with limitations that could be addressed in the manuscript, including lack of incorporation of a protonation coordinate in the free energy landscape, possibility of protonation of the substrate, errors with the chosen constant pH MD method for membrane proteins, dismissal of hysteresis emerging from the MEMENTO method, and the likelihood of other residues being affected by peptide binding. Some changes to the presentation could be considered, including a better description of pKa calculations and the inclusion of error bars in all PMFs. Overall, the findings will appeal to structural biologists, biochemists, and biophysicists studying membrane transporters.

eLife assessment

The manuscript presents a useful model for the field of endosome maturation, providing perspective on the role of the deubiquitinating enzyme UPS-50/USP8 in the process. The evidence presented in the paper is clear, incorporating well-designed experiments that suggest the dual actions of UPS-50 and USP8 in the conversion of early endosomes into late endosomes. Overall, the work is solid and centers on an intriguing subject.

eLife assessment

This important study reports the formation of a new organelle, called giant unilocular vacuole (GUVac), in mammary epithelial cells through a macropinocytosis-like process. The evidence supporting conclusions is solid, using state-of-the-art cell biology techniques. This work will be of interest to cell biologists and contribute to the understanding of cell survival mechanisms against anoikis.

eLife assessment

In this valuable study, Kumar et al., provide evidence suggesting that the p130Cas drives the formation of condensates that sprout from focal adhesions to cytoplasm and suppress translation. Pending further substantiation, this study was found to be likely to provide previously unappreciated insights into the mechanisms linking focal adhesions to the regulation of protein synthesis and was thus considered to be of broad general interest. However, the evidence supporting the proposed model was incomplete; additional evidence is warranted to substantiate the relationship between p130Cas condensates and mRNA translation and establish corresponding functional consequences.

eLife assessment

This fundamental study offers new structural insights into the form and functions of the ribosome-translocon complex. Through a combination of in vitro translation, cryoEM imaging, and comprehensive AlphaFold comparative modeling, the authors offer convincing support for the lateral gate model of co-translational ER protein biogenesis, including the location of RAMP4 near the Sec61 lateral gate and the plausible role of helix 59 of the 28S ribosomal RNA as a determinant of the positive-inside rule. While the reviewers identified minor limitations, such as the need to validate RAMP4 presence with orthogonal measures, these results will be broadly impactful.

eLife assessment

This study provides a useful strategy for treating mouse cutaneous squamous cell carcinoma (mCSCC) with serum derived from mCSCC-exposed mice. The exploration of serum-derived antibodies as a potential therapy for curing cancer is particularly promising but the study provides inadequate evidence for specific effects of mCSCC-binding serum antibodies. This study will be of interest to scientists seeking a novel immunotherapic strategy in cancer therapy.

eLife assessment

This work describes a novel affinity interactomics approach that allows investigators to identify networks of protein-protein interactions in cells. The important findings presented here describe the application of this technique to the SH3 domain of the membrane remodeling Bridging Integrator 1 (BIN1), the truncation of which leads to centronuclear myopathy. The authors present solid evidence that BIN1 SH3 engages with an unexpectedly high number of cellular proteins, many of which are linked to skeletal muscle disease, and evidence is presented to suggest that BIN1 may play a role in mitosis creating the potential for new avenues in drug development efforts. Some of the findings, however, remain rather preliminary, lack sufficient replicates and may require additional experiments to definitively support the conclusions.

eLife assessment

This manuscript presents valuable findings on the identification of epigenetically mediated control for the recognition of dihydropyrimidine dehydrogenase (DPYD) gene expression that is linked with cancer treatment resistance using 5-fluorouracil. The evidence is compelling, supported by data from patient-derived specimens and direct assessment of 5-fluorouracil sensitivity, which provides confidence in the proposed mechanisms. The model is additionally supported by genome data from a population with high "compromised allele frequency". This work will interest those studying drug resistance in cancer therapy.

eLife assessment

This study presents valuable new structures of a carbamylation-mimetic K125E mutant of the Cx26 gap junction channel uncovering the cytoplasmic loop structure and information about the closed state of the channel. The cryo-EM maps are in high quality and serve as strong foundations for dissecting the gating mechanism by CO2, providing convincing evidence in support of a mechanism where CO2-mediated carbamylation of Lys125 shifts the conformational equilibrium towards a state where the N-terminus occludes the pore of the channel. This information will be of interest to biochemists, cell biologists and biophysicists interested in the function of gap-junction channels in health and disease.

eLife assessment

This is a valuable study that develops a new model of the way muscle responds to perturbations, synthesizing models of how it responds to small and large perturbations, both of which are used to predict how muscles function for stability but also how they can be injured, and which tend to be predicted poorly by classic Hill-type models. The evidence presented to support the model is solid, since it outperforms Hill-type models in a variety of conditions. Although the combination of phenomenological and mechanistic aspects of the model may sometimes make it challenging to interpret the output, the work will be of interest to those developing realistic models of the stability and control of movement in humans or other animals.

eLife assessment

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

eLife assessment

BMP signaling plays a vital role in skeletal tissues, and the importance of its role in microtia prevention is novel and promising. This important study sheds light on the role of BMP signaling in preventing microtia in the ear, with solid data broadly supporting the claims of the authors.

eLife assessment

This study presents useful findings on an unresolved question of cerebellar physiology: Do synapses between Purkinje cells and granule cells, made by the ascending part of the granule cells' axon, have different properties than those made by parallel fibers? The authors conducted patch-clamp recordings on rat cerebellar slices and found a new type of plasticity in the synapses of the ascending part of granule cell axons. While the finding may contribute to a better understanding of cerebellar function, the results are still incomplete because the shift in the baseline recording may have influenced the readout of long-term plasticity.

eLife assessment

This paper presents a valuable automated method to track individual mammalian cells as they progress through the cell cycle using the FUCCI system. The authors have developed a technique for analyzing cells that grow in suspension and used their method to look at different tumor cell lines that grow in suspension and determine the effect of drugs that directly affect the cell cycle. They show solid evidence that the method can be applied to both adherent and non-adherent cell lines. This paper will be of interest to cell biologists investigating cell cycle effects.

eLife assessment

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

eLife assessment

This study reports useful data suggesting the critical roles of two ancient proteins, XAP5 and XAP5L, in controlling the transcriptional program of ciliogenesis during mouse spermatogenesis. However, this study is considered incomplete because the data only partially support the conclusion. This work will be of interest to biomedical researchers who work on ciliogenesis and reproduction.

eLife assessment

This important study by Lu et al aimed to determine the key factors of T cell responses associated with durable antibody responses following the initial two shots of COVID-19 mRNA vaccinations. By comparing the SARS-CoV-2 spike protein (S)-specific T cell subsets between "Ab sustainers" and "Ab decliners" that were present post-vaccination, the authors concluded that S-specific CD4+ T cells in "Ab sustainers" were enriched with Tfh cells. There is solid evidence as the authors applied multiple methods and approaches to address the key questions, and the presented data are robust.

eLife assessment

In this paper, the male sex-lethal (MSL) complex of proteins and RNA is studied through a domain analysis of one of its components, MSL1, and its interaction with others. While these results could be useful to researchers in the field, several studies have shown that the view that the MSL complex mediates dosage compensation is no longer considered tenable. Since there are many ways to alter viability, claims based on sex-specific viability as a reflection of dosage compensation should be viewed with much caution, and the evidence is currently considered inadequate to support the claims.

eLife assessment

This study characterizes how a point mutation in the TALK-1 potassium channel, encoded by the KCNK16 gene, causes MODY diabetes. The mutation, L114P, causes a gain-of-function to increase K+ currents and inhibit glucose-stimulated insulin secretion. Increased glucagon likely results from paracrine effects in the islets. The data are convincing and the work will be valuable for understanding islet function.

eLife assessment

This important study demonstrated that ablation of astrocytes in the lumbar spinal cord not only reduced neuropathic pain but also caused microglia activation. The findings presented add considerable value to the current understanding of the role of astrocyte elimination in neuropathic pain, offering convincing evidence that supports existing hypotheses and insights into the interactions between astrocytes and microglial cells, likely through IFN-mediated mechanisms. This study may also offer a new therapeutic strategy for the treatment of debilitating neuropathic pain in patients with SCI.

eLife assessment

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

eLife assessment

This work substantially advances our understanding of pharmacological inhibition of SWI/SNF as a therapeutic approach for cancer. The study is well-written and provides compelling evidence, including comprehensive datasets, compound screens, gene expression analysis, epigenetics, as well as animal studies. This study provides a fundamental advance for the uveal melanoma research field that might be exploited to target this deadly cancer and more generally for targeting transcriptional dependency in cancers.

eLife assessment

In this useful study, the authors report the efficacy, hematological effects, and inflammatory response of the BPaL regimen (containing bedaquiline, pretomanid, and linezolid) compared to a variation in which Linezolid is replaced with the preclinical development candidate spectinamide 1599, administered by inhalation in tuberculosis-infected mice. The authors provide convincing evidence that supports the replacement of Linezolid in the current standard of care for drug-resistant tuberculosis. However, a limitation of the work is the lack of control experiments with bedaquiline and pretomanid only, to further dissect the relevant contributions of linezolid and spectinamide in efficacy and adverse effects. Although the manuscript is well written overall, a re-formulation of some of the stated hypotheses and conclusions, as well as the addition of text to contextualize translatability, would improve its value.

eLife assessment

This important study identifies the anti-inflammatory function of PEGylated PDZ peptides that are derived from the ZO-1 protein. Results from cellular and in vivo experiments tracking key inflammatory markers are compelling. Although the mechanism of action remains largely unknown, this study provides a proof of concept for developing novel strategies against acute inflammatory conditions such as sepsis.

eLife assessment

This useful study investigates the impact of disrupting the interaction of RAS with the PI3K subunit p110α in macrophage function in vitro and inflammatory responses in vivo. Solid data overall supports a role for RAS-p110α signalling in regulating macrophage activity and so inflammation, however for many of the readouts presented the magnitude of the phenotype is not particularly pronounced. Further analysis would be required to substantiate the claims that RAS-p110α signalling plays a key role in macrophage function. Of note, the molecular mechanisms of how exactly p110α regulating the functions in macrophage have not yet been established.

eLife assessment

The study is useful by attempting to present a new approach of combining two measurements (pHLA binding and pHLA-TCR binding) in order to refine predictions of which patient mutations are likely presented to and recognized by the immune system, but the evidence is incomplete. Whereas the novel methodology proposed is compelling, this article lacks a detailed explanation of the chosen model. The experimental validation confirming the computational predictions with actual immune responses is limited due to sample constraints.

eLife assessment

The manuscript by Jingsong Zhou and colleagues uncovers why the extraocular muscles (EOMs) are preserved while other muscles undergo degenerative changes in amyotrophic lateral sclerosis (ALS). In this work, the authors have used a mouse model of familial ALS that carries a G93A mutation in the Sod1 gene to demonstrate that NaBu treatment partially restores the integrity of NMJ in the limb and diaphragm muscles of G93A mice. The findings of the study offer important information that EOMs are spared in ALS because they produce protective factors for the NMJ and, more specifically, factors secreted by EOM-derived satellite cells. While most of the experimental approaches are convincing, the use of sodium butyrate (NaBu) in this study needs further investigation, as NaBu might have a variety of biological effects. Overall, this work may help develop future therapeutic interventions for patients with ALS.

eLife assessment

This manuscript reports important data on the stability of nucleosomes with dsDNA substrates containing defined mismatches at three defined nucleosomal positions. Compelling evidence obtained by single-molecule FRET experiments shows that certain mismatches lead to more stable nucleosomes likely because mismatches kink to enhance DNA flexibility leading to higher nucleosome stability. The biological significance and implications of the findings remain unclear.

eLife assessment

This study presents important insights on the impact of SARS-CoV-2 variants on the binding and neutralization of a small library of nanobodies. The authors should be applauded for their comprehensive in vitro and in silico analyses of nanobody targeting of SARS-CoV-2 variants. The evidence supporting the claims of the authors is now convincing. This work will be of great interest to researchers in the fields of antibody/nanobody engineering and SARS-CoV-2 therapeutics.

eLife assessment

The fundamental study by Galicia C. et al. captured the GTP-bound active structure of CtRoco, a homolog of human LRRK2, using conformation-specific nanobodies. This convincing body of work reports the first structure of a GTP-bound ROCO protein, illustrating how GTP facilitates the dimer-to-monomer transition of CtRoco and functional activation.

eLife assessment

This is an important study that investigates how neural networks can learn to stochastically replay presented sequences of activity according to learned transition probabilities. The authors use error-based excitatory plasticity to minimize the difference between internally predicted activity and stimulus-driven activity, and inhibitory plasticity to maintain E-I balance. The approach is solid but the choice of learning rules and parameters is not always always justified, lacking a formal derivation and concrete experimental predictions.

eLife assessment

This valuable study delineates the cellular contributions of BMP signaling in liver development and function. The findings are convincing, and the study employs state-of-the-art molecular, genetic, and cellular approaches to demonstrate that hepatic stellate cells play a central role in liver health by mediating cell-to-cell crosstalk via the production of specific BMP proteins. This study will be of interest to scientists interested in developmental biology and organ physiology.

eLife assessment

This study assessed antibody levels, which are indicative of protection, resulting from both COVID-19 vaccination and natural infection in a representative sample of the Canadian population. The work provides solid evidence that Individuals who received a booster vaccination and had a prior infection had the highest antibody levels, particularly when either the vaccination or natural infection had occurred within the past six months. These findings are of fundamental importance in supporting the value of booster vaccination in populations vulnerable to severe COVID-19.

eLife assessment

This study presents an important finding that Obox4 and Dux act redundantly in regulating zygotic genome activation in mice. The evidence supporting the claims of the authors is solid. The work will be of interest to researchers interested in early embryo development and epigenetic reprogramming.

eLife assessment

This important study presents a detailed characterization of two distinct cellular morphologies of haematopoietic stem cells undergoing endothelial to haematopoietic transition in zebrafish. It brings new information on how regulation of apico-basal polarity influences cellular behaviour, shape, and interaction with neighbouring cells. The evidence supporting the existence of these two distinct morphologies is convincing, using state-of-the-art confocal microscopy and image analysis of 2D-cartography.

eLife assessment

This carefully executed study provides a comparison of the chemical composition of mouse urine across strain and sex with the responses of vomeronasal sensory neurons, which are responsible for detecting chemical social cues. While the authors did not examine all molecular classes found in mouse urine or directly test whether the urinary volatile chemicals that vary with sex and strain are effective vomeronasal neuron ligands, solid data are provided that will be of significant interest to those studying chemical communication in rodents. This work should provide a valuable foundation for future research that will determine which molecules drive sex- and strain-specific vomeronasal responses.

eLife assessment

This study is focused on the question of how Nrp1 contributes to the regulation of vascular permeability and whether or why there are differences between different vascular beds. The scientific concept of this paper suggests a possible role of Nrp1 on perivascular cells as a participant in the regulation of vascular permeability. This concept is interesting and potentially useful. However, the methodology and quantitative analysis are currently inadequate to fully support the claims.

eLife assessment

This important study uses cellular automata and evolution algorithms to offer an alternative to long-range signalling models of developmental patterning. The computational evidence that local rules suffice to produce a robust and global pattern is convincing. With some additional insights that connect the theoretical findings back to real biological examples, this work could be of interest to the broad community of developmental and systems biologists.

eLife assessment

This study presents valuable data on the antigenic properties of neuraminidase proteins of human A/H3N2 influenza viruses sampled between 2009 and 2017. The antigenic properties are found to be generally concordant with genetic groups. Compared to a previous version, additional analyses have strengthened the work, with solid evidence supporting the claims of the authors.

eLife assessment

This study presents an important finding that implicates a rhodopsin gene duplication in the progression of autosomal dominant retinitis pigmentosa in patients. The authors utilize a retinal organoid model to demonstrate a similar disease phenotype and suggest defects can be ameliorated by using photoregulin. The data supporting the conclusions are solid, but there are some concerns regarding the strength of the phenotype in retinal organoids. This work will be of broad interest to vision researchers.

eLife assessment

This important work examines the potential utility of socio-emotional and socio-cognitive mental training on hippocampal subfield structure and function, and cortisol levels. The authors provide convincing evidence that CA1-3 volume is sensitive to socio-emotional training, with changes related to function plasticity and cortisol levels. Further, the authors provide evidence of change across all subfields and training modules related to stress.

eLife assessment

This manuscript describes a potentially important theoretical framework to link predictive coding, error-based learning, and neuronal dynamics. The provided evidence is solid, but some details would benefit from additional clarification. The exposition of the manuscript is targeted for a specialist audience.

eLife assessment

This study presents a new and important theoretical account of spatial representational drift in the hippocampus. The evidence supporting the claims is convincing, with a clear and accessible explanation of the phenomenon. Overall, this study will likely attract researchers exploring learning and representation in both biological and artificial neural networks.

eLife assessment

This important study utilizes a viral-mediated short hairpin RNA (shRNA) approach to investigate in a novel way the role of the wild-type PHOX2B transcription factor expressed in critical chemosensory neurons in the brainstem retrotrapezoid nucleus (RTN) region for maintaining normal CO2 chemoreflex control of breathing in adult rats. The convincing results show blunted ventilation during elevated inhaled CO2 (hypercapnia) with knockdown of PHOX2B, accompanied by a reduced expression of Gpr4 and Task2 mRNA for the proposed RTN neuron proton sensor proteins GPR4 and TASK2. These results indicate that maintained expression of wild-type PHOX2B affects respiratory control in adult animals, complementing previous studies showing that PHOX2B-expressing RTN neurons may be critical for chemosensory control throughout the lifespan, and with implications for neurological disorders involving the RTN, which will be of interest to neuroscientists studying respiratory neurobiology as well as the neurodevelopmental control of motor behavior.

eLife assessment

This is a binocular rivalry study that uses ECG to present visual stimuli pulsing in line with cardiac events, to examine whether systole-entrained stimuli (i.e. presented during the period where the heart has contracted) are suppressed within visual awareness. Arguably out of line with this idea, the dominance durations were increased for systole-entrained stimuli. The manuscript addresses an important, precisely defined, and theoretically well-motivated question using sophisticated experimental and statistical methods. The interpretation of these results is not straightforward, however, such that they currently only provide incomplete support for the claims.

eLife assessment

Using in vitro and in vivo experiments, the authors show that astrocytes swell after inhibition of aquaporin 4 (AQP4) with TGN-020, which is indicative of tonic water efflux from these cells under physiological conditions. Though potentially valuable, the study is currently incomplete due to possible off-target effects of TGN-020, limited mechanistic information underlying the detected effects, and potential limitations of some of the adopted experimental techniques. These findings can be especially relevant for cortical spreading depression in ischemic stroke or seizure and to get a comprehensive understanding of neuron-astrocyte interactions.

eLife assessment

This fundamental work unravels how female Drosophila can assess their social context via chemosensory cues and modulate the sperm storage process after copulation accordingly. A convincing set of rigorous experiments uncovers specific pheromones that influence the excitability of the female brain receptivity circuit and their propensity to discard inseminate from a mating. This insight into neuronal mechanisms of sexual behavior plasticity is of general interest to scientists working in the fields of animal behavior, neuroscience, evolution, and sexual selection, as well as insect chemosensation and reproduction.

eLife assessment

This study presents valuable findings relevant to research on olfactory neurogenesis and long-term adaptation. The evidence, at this stage, is incomplete. First, the effects described could, in part, also be attributed to "downregulation" of OR subtype-specific neurogenesis upon sensory deprivation, instead of selectively increased neurogenesis. Second, additional control experiments would be needed to support the main claims and rule out alternative explanations.

eLife assessment

This study presents a valuable dataset regarding chromatin remodeling by the BAF complex in the context of meiotic sex chromosome inactivation. Solid data generally support the conclusions, although there is room for improvement. This work will be of interest to researchers working on chromatin and reproductive biology.

eLife assessment

This important study links the activity of polymerase III to the regulation of virulence gene expression in the deadliest malaria parasite, Plasmodium falciparum. It identifies Maf1 as a Pol III inhibitor that enables the parasite to respond to external stimuli such as magnesium chloride plasma levels by downregulating Pol III-transcribed ruf6 genes and subsequently regulated var genes. While the evidence presented is generally convincing, some of the results are incomplete, and the mechanistic link between external signals and Maf1 activation remains unknown.

eLife assessment

This study presents fundamental findings that advance our understanding of the role of phenotypic aging in cancer risk. This article presents compelling results that show Phenotypic Age Acceleration (PhenoAgeAccel) can predict cancer incidence of different types and could be used with genetic risk to facilitate the identification of cancer-susceptible individuals. These results will be of broad interest to the research community and clinicians.

eLife assessment

This valuable study presents findings on DNA methylation as an efficient epigenetic transcriptional regulating strategy in bacteria. The authors utilized single-molecule real-time sequencing to profile the DNA methylation landscape across three model pathovars of Pseudomonas syringae, identifying significant epigenetic mechanisms through the Type-I restriction-modification system, which includes a conserved sequence motif associated with N6-methyladenine. The evidence presented is solid and the study provides novel insights into the epigenetic mechanisms of P. syringae, expanding the understanding of bacterial pathogenicity and adaptation.

eLife assessment

This study presents a valuable computational model for elaborating on the interpretation of chromosomal mosaicism in preimplantation embryos. The evidence supporting the claims of the authors is incomplete due to the assumption that is possible to quantify the cells in the embryo, oversimplification of mitotic errors, and the inclusion of the self-correction premise. The work will be of interest to embryologists, and geneticists working on reproductive medicine.

eLife assessment

This useful work by Park attempts to use machine learning algorithms to identify correlates of different observed shedding patterns in two COVID-19 cohorts. The evidence supporting the study conclusions is incomplete due to the lack of uniformity in assays between the 2 cohorts, relevant metadata (previous infection/vaccination status, viral variant), early viral load data in the cohorts, and incomplete statistical analyses. With a strengthened analysis, the work may be of interest to virologists, clinicians, and public health scientists.

eLife assessment

This study address a fundamental question: Do lipid rafts play a role in trafficking in the secretory pathway? By performing carefully controlled experiments with synthetic membrane proteins derived from the transmembrane region of LAT, the authors describe, model and quantify the importance of transmembrane domains in the kinetics of trafficking of a protein through the cell, from the ER to the cell surface via the Golgi. While their findings are solid, further experiments that relate to the existence and nature of domains at the TGN are necessary to provide a direct connection between the phase partitioning capability of the transmembrane regions of membrane proteins and the sorting potential of rafts.

eLife assessment

This paper addresses a fundamental issue in the field of autophagy: how is a protein responsible for autophagosome-lysosome fusion recruited to mature autophagosomes but not immature ones? The work succeeds in its ambition to provide a new conceptual advance. The evidence supporting the conclusions is convincing, with fluorescence microscopy, biochemical assays, and molecular dynamics simulations. This work will be of broad interest to cell biologists and biochemists studying autophagy, and also those focusing on lipid/membrane biology.

eLife assessment

This study explores the role of calcyphosine-like (CAPSL) in Familial Exudative Vitreoretinopathy (FEVR) via the MYC pathway, offering valuable insights into disease mechanisms that are supported by a solid, multi-pronged approach. The overall significance of the study might, however, be limited due to weak support from human genetic studies.

eLife assessment

This valuable and ambitious review examines seasonal dormancy in various species, including hibernating mammals (excluding bats and bears) and ectotherms. It provides a solid test of hypotheses on dormancy timing, considering energetic constraints and life history as alternative drivers. The review will be of interest to evolutionary biologists.

eLife assessment

This study presents an important methodology to increase the efficiency and precision of gene editing in human hematopoietic stem and progenitor cells. The evidence supporting the claims is convincing in that primitive LTC-ICs were minimally affected as a result of the editing procedure and the lack of edits at predicted off-target sites. The work will be of interest to biologists studying hematopoietic stem and progenitor cells and genome editing for potential clinical applications.

eLife assessment

The OpuA Type I ABC importer uses two substrate binding domains to capture extracellular glycine betaine and present the substrate to the transmembrane domain for subsequent transport and correction of internal dehydration. This study presents valuable findings addressing the question of whether the two substrate binding domains of OpuA dock and physically interact in a salt-dependent manner. The single-molecule fluorescence resonance energy transfer and cryogenic electron microscopy data that are presented provide convincing support for the existence of a transient interaction between the substrate binding domains that depends on ionic strength, laying a foundation for future studies exploring how this interaction is involved in the overall transport mechanism.

eLife assessment

This important paper reveals that one of the major roles of the WDR5 WIN site is to promote ribosome synthesis, and that by attacking the WIN site with inhibitors ribosome attrition occurs creating new vulnerabilities that can be therapeutically exploited. This deficiency of ribosomal proteins also provokes the p53 response. The data from a variety of approaches is generally very convincing, and together buttresses the authors' conclusions and interpretations quite nicely; overall, this paper will provide a justification for pre-clinical and translational studies of WDR5 interaction site inhibitors.

eLife assessment

This study identifies the molecular determinants of LRMP co-regulation of HCN 4 activity. The evidence supporting the conclusions, which is compelling, is backed by rigorous electrophysiological and spectroscopic analysis. The work is important because it greatly enhances our understanding of the mechanisms of HCN channel regulation in a tissue-specific manner and highlights a functional role for more disordered regions that have yet to be structurally resolved.

eLife assessment

This fundamental study advances our understanding of the role of senescent osteoclasts (SnOCs) in the pathogenesis of spine instability. The authors provide compelling evidence for the SnOCs to induce sensory nerve innervation. Accordingly, reduction of SnOCs by the senolytic drug Navitoclax markedly reduces spinal pain sensitivity. This work will be of broad interest to regenerative biologists working on spinal pain.

eLife assessment

This important study sheds light on the mechanisms underlying a rare brain disease, offering insight into the role of microglia in this complex pathophysiology. The evidence presented is solid, utilizing state-of-the-art laboratory models to explore cellular interactions and disease development. While further research is needed, this study will be of interest to neuroscientists and clinicians aiming to understand and combat similar neurodegenerative disorders.

eLife assessment

This study offers valuable insights into the structural architecture of the mammalian egg-sperm fusion synapse, shedding light on the role of specific proteins in fertilization. The significance of the findings lies in the potential identification of a pentameric complex involved in gamete fusion by AlphaFold Multimer. The strength of evidence for the approach/methodology is solid, while the experimental validation is incomplete in supporting these interactions. This work will be of interest to biomedical researchers working on fertility and reproductive health.

eLife assessment

In this study, the authors provide valuable evidence that the LGE is not a significant source of oligodendrocytes for the cortex. The reviewers did find some technical considerations that call for some modulation of the strength of the authors' conclusions and also pointed out some aspects of the data that were incomplete as presented.

eLife assessment

This useful work describes a novel microscopy-based method to correlate the degree of pigmentation with the gene expression profile of human-induced pluripotent stem cell-derived Retinal Pigmented Epithelial (iPSC-RPE) cells at the single cell level. The presented evidence is solid in showing that there is heterogeneous gene expression in iPSC-derived RPE cells, and there is no significant correlation with the pigmentation. By analyzing the expression of some genes related to function, lysosomal- and complement-related pathways were partially enriched in darker cells. This methodology can be used by other researchers interested in analyzing gene expression related to microscopic images.

eLife assessment

This useful study reports that a week or more of hypoxia exposure in mice increases erythropoiesis and decreases the number of iron-recycling macrophages in the spleen, compromising their capacity for red blood cell phagocytosis – reflected by increased mature erythrocyte retention in the spleen. Compared to an earlier version, the study has been strengthened with mouse experiments under hypobaric hypoxia and complemented by extensive ex vivo analyses. Unfortunately, while some of the evidence is solid, the work as it currently stands only incompletely supports the authors' hypotheses. While the study would benefit from additional experiments that more directly buttress the central claims, it should be of interest to the fields of hemopoiesis and bone marrow biology and possibly also blood cancer.

eLife assessment

This study presents valuable framework and findings to our understanding of the brain as a fractal object by observing the stability of its shape property within 11 primate species and by highlighting an application to the effects of aging on the human brain. The evidence provided is solid but the link between brain shape and the underlying anatomy remains unclear. This study will be of interest to neuroscientists interested in brain morphology, and to physicists and mathematicians interested in modeling the shapes of complex objects.

eLife assessment

In this valuable study, the authors examine the role of the cytoskeletal regulatory protein Abba in governing the process of cell genesis in the developing cortex. This study provides insights into the mechanisms of microcephaly, a developmental malformation. The evidence supporting the study was felt to be solid, but the reviewers did note some technical weaknesses that limit the strength of some of the interpretations.

eLife assessment

This is an important study on changes in newborns' neural abilities to distinguish auditory signals at 37 weeks of gestation. The evidence of change in neural discrimination as a function of gestational age is convincing, but further analysis of the acoustic signals and description of the infants' language environment would strengthen the interpretation of the results. The work contributes to the field of neurodevelopment and suggests potential clinical applications in neurodevelopmental disorders.

eLife assessment

This important study investigates the structural organization of a series of diblock elastin-like polypeptide condensates. The methodology is highly compelling, as it combines multiscale simulations and fluorescence lifetime imaging microscopy experiments. The results increase our understanding of model biomolecular condensates.

eLife assessment

This study shows compelling evidence that the less common D-serine stereoisomer is transported in the kidney by the neutral amino acid transporter ASCT2 and that it is a non-canonical substrate for sodium-coupled monocarboxylate transporter SMCTs. With a multi-hierarchical approach, this important study further shows that Ischemia-Reperfusion Injury in the kidney causes a specific increment in renal reabsorption carried out, in part, by ASCT2.

eLife assessment

This valuable study further discloses the function of LRRK2 in BDNF-dependent synaptic processes in identifying postsynaptic actin cytoskeleton as a convergent site of LRRK2 pathophysiological activity. Multiple approaches in different cellular models provide mostly solid (but at times preliminary) evidence to support (many) of the conclusions, overall consistent with bioinformatics analyses covering previously published work. While an exciting start that should be pursued, examples are suggested by reviewers to add in additional experimentation to better support the expansive interpretation. The identification of mechanisms of LRRK2 action at the synapse is considered highly significant, as better knowledge in this regard may provide insight into why dopaminergic cells die with over-active LRRK2.

eLife assessment

This is a valuable study of the spatial organization of innate granulomas following Chromobacterium violaceum infection and the expression of CC and CXC chemokines in the granuloma at several time points following infection. There is a wealth of information to be gained from this study. However, the analysis of these granulomas is incomplete, with room for orthogonal validation of some of the key findings with additional animals (using ISH or IHC), in addition to a more quantitative analysis of some of the currently more qualitative conclusions.

eLife assessment

This study presents a valuable finding on the association between DUX4 expression with features of immune evasion in human tissue and clinical outcomes in patients with advanced urothelial cancer. The evidence supporting the claims of the authors is convincing, using a range of corroborative statistical techniques. Compared to an earlier version, the quality of the manuscript has been enhanced, for example Figure 5 now illustrates the key features of survival probability estimates over time for patients assigned to with the test or training set.

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 useful manuscript explores conditions for epigenetic inheritance by studying the stability of simple network models to permanent and transient perturbations. A novel aspect of the study is that it unifies non-genetic inheritance phenomena across cell divisions of unicellular organisms and in the germline of multicellular organisms. However, the models studied are more a collection of vignettes of numerical studies than a systematic study, therefore the evidence presented remains incomplete. As a first step towards building a more systematic theoretical framework, this work will be of interest to colleagues in the field of epigenetic inheritance.

eLife assessment

This fundamental study reports compelling findings that intermediate states exist in epithelial-mesenchymal transition (EMT) during natural development and differentiation of mammalian neural crest cells, similar to recent reports in cancer. The authors determined that there were at least two paths to delamination and migration - one that occurs during S-phase of cell cycle and another during G2/M phase, and that the process of delamination is not restricted to cell fate. Finally, the authors showed that expression of Dlc1 may be used to identify cells in an intermediate state of EMT as well as their spatial location in the mouse embryo. The work will be of interest to developmental biologists, neurobiologists and cancer researchers.

eLife assessment

This valuable study by Bartas and colleagues examined how patterns of monosynaptic input to specific cell types in the ventral tegmental area are altered by drugs of abuse. The authors applied a dimensionality reduction approach (principal component analysis) and showed that various drugs of abuse, and somewhat surprisingly the anesthesia alone (ketamine/xylasin), caused changes in the distribution of inputs labeled by the transsynaptic rabies virus. While there are some issues to be addressed, the evidence supporting the conclusions is overall solid, and provides information that is of value to the field, as well as a cautionary note on the interpretation of rabies virus-based tracing experiments.

eLife assessment

This study makes a valuable contribution to spatial transcriptomics by rigorously benchmarking cell-type deconvolution methods, assessing their performance across diverse datasets with a focus on biologically relevant, previously unconsidered aspects. The authors demonstrate the strengths of RCTD, cell2location, and SpatialDWLS for their performance, while also revealing the limitations of many methods when compared to simpler baselines. By implementing a full Nextflow pipeline, Docker containers, and a rigorous assessment of the simulator, this work offers robust insights that elevate the standards for future evaluations and provides a resource for those seeking to improve or develop new deconvolution methods. The thorough comparison and analysis of methods, coupled with a strong emphasis on reproducibility, provide solid support for the findings.

eLife assessment

This study represents a valuable finding on the neuron-glia communication and glial responses to traumatic brain injury (TBI). The data supporting the authors' conclusions on TBI analysis, RNA-seq on FACS sorted astrocytes, genetic analyses on Pvr-JNK/MMP1 are solid. However, cellular aspects of the response to TBI, statistical analysis, and molecular links between Pvr-AP1 are incomplete, which could be further strengthened in the future by more rigorous analyses.

eLife assessment

Dasgupta and colleagues make a valuable contribution to the understanding how the guidance factor Sema7a promotes connections between mechanosensory hair cells and afferent neurons of the zebrafish lateral line system. The authors provide solid evidence that loss of Sema7a function results in fewer contacts between hair cells and afferents through comprehensive quantitative analysis. Additional work is needed to distinguish the effects of different isoforms of Sema7a to determine whether there are specific roles of secreted and membrane bound forms.

eLife assessment

This important study discovered DBT as a novel gene implicated in the resistance to MG132-mediated cytotoxicity and potentially also in the pathogenesis of ALS and FTD, two fatal neurodegenerative diseases. The authors provided convincing evidence to support a mechanism by which loss of DBT suppresses MG132-mediated toxicity via promoting autophagy. This work will be of interest to cell biologists and biochemists, especially in the FTD/ALS field.

eLife assessment

This valuable study investigates the role of mechanosensory feedback during swallowing in adult Drosophila. The authors provide convincing evidence that three mechanotransduction channel genes are required for ingestion rhythms and localize the role of these genes to a specific subpopulation of pharyngeal mechanosensory neurons. However, there is incomplete evidence to support the conclusions that these sensory neurons are necessary for swallowing, respond to stretch during swallowing, and connect to the motor neurons that control swallowing. This work may be of interest to neuroscientists interested in motor control of feeding behavior.

eLife assessment

This work identifies cnidarian neuropeptides and pairs them to their GPCR, then shows that neuropeptide signaling systems have evolved and diversified independently in cnidarians and bilaterians. Neuropeptide-receptor partners were experimentally identified using established and widely used methodologies including single cell mapping, providing compelling evidence for the conclusions of the paper. This impressive accomplishment provides fundamental new insights into the evolution of neuropeptide signaling systems and will be of broad interest to neurobiologists and evolution of development researchers.

eLife assessment

Chen and colleagues utilize an in situ explant model of the neural retina and retinal pigment epithelium (RPE), along with small molecule inhibition of key metabolic enzymes and targeted metabolomic analysis, to decipher key differences in metabolic pathways used by rods, cones, Muller glia, and the RPE. They conclude that rods are heavily reliant on oxidative metabolism, cones are heavily reliant on glycolysis, and multiple mechanisms exist to decouple glycolysis from oxidative metabolism in the retina. This study provides valuable metabolomic data and insights into the metabolic flexibility of different retinal cells. However, current evidence is still incomplete as several of the conclusions from the paper stand in contradiction to other published findings and the authors naturally suggests experiments that will be needed in the future to validate the hypothesized pathways and refute existing published data. Such future validation includes animal models with tissue specific knockout of the key enzymes probed in the study; inhibiting the targets of this study with more than 1 small molecule that is structurally different, and at different doses and timings; using retinal explants from matured animals; performing labeled metabolite tracing experiments; and direct assessment of mitochondrial function (via OCR) under various manipulations.

eLife assessment

The valuable findings in this study show that subpopulations of peripheral sensory neurons display different capacities for regeneration after a similar injury. Nociceptor neurons have greater regeneration over mechanoreceptor, proprioceptors and motor neurons. This differential responsiveness of neuronal subtypes was traced to activation of different transcriptional programs, which were carefully analyzed and quantitated, resulting in solid evidence for the conclusions.

eLife assessment

The authors identify a population of neurons with a specific complement of markers that originate in a distinct location from where cerebellar nuclear precursor cells have been thought to originate, that show distinct developmental properties. The discovery of a new germinal zone giving rise to a new population of CN neurons is an important finding, and it enriches our understanding of cerebellar development. The claims are supported by solid evidence and the authors use a wide range of technical approaches, including transgenic mice, that allow them to disentangle the influence of distinct developmental organizers.

eLife assessment

This study convincingly demonstrates the ability of reverting a neurodevelopmental defect with a dietary intervention. While the exact mechanisms remain to be elucidated, the authors establish a simple but important system to study the PI3K/Akt/FOXO pathway but also the action of ketone bodies and their potential therapeutic use. This study will be of particular interest to the large community of scientists studying E/I disequilibrium in the nervous system.

eLife assessment

This valuable study presents new observations on white matter organisation at the micron scale, using a combination of synchrotron imaging and diffusion MRI across two species. Notably, the authors provide solid evidence for the fasciculation of axons within major fibre bundles into laminar structures, though these structures are not consistently observed across modalities or species. The study will be of general interest to neuroanatomists and those interested in white matter imaging.

eLife assessment

This study describes important findings related to early disruptions in disinhibitory modulation exerted by VIP+ interneurons, in CA1 in a transgenic model of Alzheimer's disease pathology. The authors provide a convincing analysis at the cellular, synaptic, network, and behavioral levels on how these changes correlate and might be related to behavioral impairments during these early stages of AD pathology.

eLife assessment

This paper expands the genetic toolset that was previously developed by the Rao lab to introduce the conditional downregulation of neurotransmission components in Drosophila. As a proof of principle, the authors tested their new collection and provide evidence of the contribution of CNMamide (a neuropeptide) to the temporal control of locomotor activity patterns. These are overall important findings supported by compelling evidence.

eLife assessment

This fundamental study provides an unprecedented understanding of the roles of different combinations of NaV channel isoforms in nociceptors' excitability, with relevance for the design of better strategies targeting NaV channels to treat pain. Although the experimental combination of electrophysiological, modeling, imaging, molecular biology, and behavioral data is convincing and supports the major claims of the work, some results remain inconclusive and need to be strengthened by further evidence. The work may be of broad interest to scientists working on pain, drug development, neuronal excitability, and ion channels.

eLife assessment

The large-conductance Ca2+ activated K+ channel BKCa has been reported to promote breast cancer progression. The present study presents convincing evidence that an intracellular subpopulation of this channel reprograms breast cancer cells towards the Warburg phenotype, one of the metabolic hallmarks of cancer. This important finding advances the field of cancer cell metabolism and has potential therapeutic implications.

eLife assessment

This is a useful study that identifies circadian changes in the gene expression profile of cultured mouse astrocytes. Mechanistic details linking circadian rhythmicity in HERP, a regulator of calcium signals in the endoplasmic reticulum, to altered phosphorylation of Connexin 43 remain currently incomplete. With improved manuscript clarity and statistical analysis, this work could be of interest to the field of astrocyte and circadian biology.

eLife assessment

This fundamental work substantially advances our understanding of cell migration, especially in that of cranial neural crest. The additional evidence provided to support the conclusion is exceptional, with rigorous biochemical assays for materials used and with intensive genetic interventions. The work will be of broad interest to developmental biologists and cell biologists.

eLife assessment

This important study reports a novel approach to studying cerebellar function based on the idea of selective recruitment using fMRI. It provides convincing evidence for task-dependent gating of neocortical input to the cerebellum during a motor task and a working memory task. The study will be of interest to a broad cognitive neuroscience audience.

eLife assessment

This important study reports the fungal composition and its interaction with bacteria in the Caesarean section scar diverticulum. The data are solid and supportive of the conclusion. This work will be of interest to researchers and clinicians who work on women's health.

eLife assessment

This study presents fundamental insights into the heterogeneity of chronic myeloid leukemia (CML) stem cells and their response to tyrosine kinase inhibitor therapy, shedding light on potential mechanisms underlying treatment failure. The study's robust methodology, supported by validation with bulk RNA-seq data and surface marker analysis, provides compelling evidence for the identified associations between cellular composition and treatment outcome. These findings contribute to our understanding of CML pathogenesis and may inform the development of more targeted therapeutic strategies.

eLife assessment

This important manuscript reports interactions between genetic variation, DNA accessibility, and chromatin structure in gene expression at a genome wide scale. The authors found that most of these interactions occur within topologically associating domains (TADs) and 3D genome structure data can be efficiently used to guide the discovery of significant genetic and epigenetic influences on gene expression. Overall, this convincing study highlights the importance of 3D chromatin structure in controlling how gene expression is regulated by genetic and epigenetic processes.

eLife assessment

This study presents valuable findings that could be utilized for identifying women at risk for preeclampsia before the onset of the disease. The novel aspect of this study lies in the utilization of exosomes of two different sizes. The data are solid: the methods, data, and analysis broadly support the claims. This work will be of interest to medical researchers and clinicians who work on preeclampsia and women's health.

eLife assessment

This fundamental study significantly advances our understanding of how parasites evade the host complement immune system. The new cryo-EM structure of the trypanosome receptor ISG65 bound to complement component C3b is highly compelling and well-supported by biochemical experiments. This work will be of broad interest to parasitologists, immunologists, and structural biologists.

eLife assessment

This study advances our understanding of the allosteric regulation of anaerobic ribonucleotide reductases (RNRs) by nucleotides, providing valuable new structural insight into class III RNRs containing ATP cones. The cryo-EM structural characterization of the system is solid, but some open questions remain about the interpretation of activity/binding assays and the newly incorporated HDX-MS results. The work will be of interest to biochemists and structural biologists working on ribonucleotide reductases and other allosterically regulated enzymes.

eLife assessment

This useful study tests the hypothesis that Mycobacterium tuberculosis infection increases glycolysis in monocytes, which alters their capacity to migrate to lymph nodes as monocyte-derived dendritic cells. The authors conclude that infected monocytes are metabolically pre-conditioned to differentiate, with reduced expression of Hif1a and a glycolytically exhaustive phenotype, resulting in low migratory and immunologic potential. However, the evidence is incomplete as the use of live and dead mycobacteria still limits the ability to draw firm conclusions. The study will be of interest to microbiologists and infectious disease scientists.

eLife assessment

This important study shows, based on analyses of single-cell RNA-seq data sets of thymus cells, that transposable elements (TEs) are broadly expressed in thymic stromal cells, especially in medullary thymic epithelial cells and plasamacytoid dendritic cells. The authors also show that at least some TE-derived peptides are presented by MHC-I molecules in the thymus. The study provides solid findings supporting a role of TEs in thymic T-cell selection and immune self-tolerance.

eLife assessment

This important study provides an example of integrating computational and experimental approaches that lead to new insights into the energy landscape of a model kinase. Compelling use of molecular dynamics simulations and NMR spectroscopy provide a conformational description of active and excited states of the kinase; one of which has not been captured in previously solved crystal structures. Overall, this comprehensive study expands our understanding of the architecture and allosteric features of the conserved bilobal kinase domain structure.

eLife assessment

The authors describe an important tool, GromovMatcher, that can be used to compare proteomic data from various experimental approaches. The underlying method is innovative, the algorithm is clearly described, and the validation that is presented is convincing.

eLife assessment

This study explores the physical principles underlying fluid flow and luminal transport within the endoplasmic reticulum; its important contribution is to highlight the strong physical constraints imposed by viscous dissipation in nanoscopic tubular networks. In particular, the work presents convincing evidence that commonly discussed mechanisms such as tubular contraction are unlikely to be at the origin of the observed transport velocities. As this study is solely theoretical and concerned with order of magnitude estimates, its main conclusions await experimental validation. The work will be of relevance to cell biologists and physicists interested in organelle dynamics.

eLife assessment

This useful manuscript describes a proteomic analysis of plasma from subjects before and after an exercise regime consisting of endurance and resistance exercise. The work identifies a putative new exerkine, CD300LG, and finds associations of this protein with aspects of insulin sensitivity and angiogenesis, but the evidence to support the main claims remains incomplete.

eLife assessment

This valuable manuscript presents ImmCellTyper, a new toolkit for CyTOF data analysis. The semi-supervised clustering tool, BinaryClust, integrates prior biological knowledge and demonstrates competitive performance in various benchmarks, but there is room for strengthening the evidence base by addressing concerns about incomplete benchmarking results and the limited consideration of CyTOF markers with binary distribution. Overall, the manuscript offers solid potential for enhancing CyTOF data analysis methodologies.

eLife assessment

This valuable study provides new insight into how non-synaptic interactions affect the activity of adjacent gustatory neurons housed within the same sensillum. The electrophysiological, behavioral, and genetic data supporting the study's conclusions are solid, although the inclusion of additional control experiments would strengthen the study. This work will be of interest to neuroscientists studying chemosensory processing or regulation of neuronal excitability.