eLife Assessment

This valuable study unravels the mechanisms underlying mammalian sperm-oocyte recognition and penetration, shedding light on cross-species interactions. It provides solid evidence that exposure of sperm to oviductal fluid or OVGP1 proteins from bovine, murine, or human sources imparts species-specific zona pellucida (ZP) recognition, ensuring that only sperm from the corresponding species can penetrate the ZP, regardless of its origin. These findings hold significant potential for reproductive biology, offering insights to enhance porcine in vitro fertilization (IVF), which frequently suffers from polyspermy, as well as advancing human IVF through improved intrinsic sperm selection.

eLife Assessment

This study presents an important finding on the molecular mechanism for transduction of environmentally induced polyphenism. The evidence supporting the claims of the author is solid. This paper would be of interest to those studying aphids wing dimorphism.

eLife Assessment

This manuscript focuses on the identification of RNA crosslinks within the HIV RNA genome under different conditions i.e. in infected cells and in virions using a new method called HiCapR. These cross-links reveal long-range interactions that can be used to determine the structural arrangement of the viral RNA, providing valuable data that show differences in the genomic organization in different conditions. The data analysis, however, is incomplete and based on extensive computational analysis from a limited number of datasets.

eLife Assessment

This work presents valuable data demonstrating that a camelid single-domain antibody can selectively inhibit a key glycolytic enzyme in trypanosomes via an allosteric mechanism. The claim that this information can be exploited for the design of novel chemotherapeutics is solid but limited by the modest effects on parasite growth, as well as the lack of evidence for cellular target engagement in vivo.

eLife Assessment

This important study investigates the propensity of the intravacuolar pathogen, Leishmania, to scavenge lipids which it utilizes for its accelerated growth within macrophages. Although some of the data compellingly links increased lipid acquisition to parasite growth, data to support the underlying mechanism to describe the proposed model is incomplete. The study adds to other work that has implicated pathogen-derived processes in the selective recruitment of vesicles to the pathogen-containing vacuole, based on the content of the cargo.

eLife Assessment

The authors present a useful agent-based model to study the tensile force generated by myosin mini-filaments in actin systems (bundles and networks); by numerically solving a mechanical model of myosin-II filaments, the authors provide insights into how the geometry of the molecular components and their elastic responses determine the force production. This work is of interest to biophysicists (in particular theoreticians) investigating force generation of motor molecules from a biomechanical engineering and physics perspective. The authors convincingly show that cooperative effects between multiple myosin filaments can enhance the total force generated, but not the efficiency of force generation (force per myosin) if passive cross-linkers are present. This work would benefit from a more extensive discussion of the relevance of the results in view of the existing experimental literature.

eLife Assessment

This useful study uses the MMTV-Neu-YD5 mouse model for HER2-dependent breast cancer to generate transcriptomic and proteomic datasets from extracted primary tumour samples. The data sets generated appear to be solid and will be of interest to the community. However, mechanistic studies to support the conclusion that mitochondrial function is increased in the tumours remain incomplete and would benefit from experiments that would directly interrogate aspects such as cellular heterogeneity, and signalling.

eLife Assessment

This important study combines compelling experiments with optogenetic actuation and convincing theory to understand how signalling proteins control the switch between cell protrusion and retraction, two essential processes in single cell migration. The authors examine the importance of the basal concentration and recruitment dynamics of a guanine exchange factor (GEF) on the activity of the downstream effectors RhoA and Cdc42, which control retraction and protrusion. The experimental and theoretical evidence provides a model of RhoA's involvement in both protrusion and retraction and shows that these complex processes are highly dependent on the concentration and activity dynamics of the components.

eLife Assessment

Using experiments in the white fly, this manuscript provides evidence that the bacterial symbiont Wolbachia can be transmitted from parasitoid wasps to their insect hosts. Characterizing the transfer of Wolbachia between insect species is a valuable attempt to explain the widespread of this intracellular bacterium. This paper is incomplete as it does not furnish sufficient data to support several of its claims for which additional methods and data are necessary.

eLife Assessment

This study provides a convincing explanation for why HIV-1 Vif causes a qualitatively different cell cycle arrest to its accessory gene counterpart Vpr. The authors use elegant time-dependent microscopy reporter assays in immortalized tumor cell models to show that HIV-1 Vif causes a pseudo-metaphase arrest rather than a G2 arrest. The metaphase arrest correlates with dysregulation of the kinetochore that could be explained by the loss of phosphatase functions that determine chromosome-microtubule interactions. These valuable findings lay the groundwork for additional studies examining the mechanisms and consequences of this Vif-dependent phenotype in the viral life cycle and in primary cells more relevant to HIV-1 pathogenesis.

eLife Assessment

This study reports important findings about pre-saccadic foveal prediction and the extent to which it is influenced by the visibility of the saccade target relative to its background. The results and research methodology are solid, although the neural substrates of oscillatory pre-saccadic enhancement for high-opacity targets remain unclear. This work should be of broad interest to visual neuroscientists, as well as those aiming to understand perception in the context of eye movements and modeling of visually guided actions.

eLife Assessment

This is an interesting and important paper that grew from a careful clinical assessment of an unusual patient with hypoparathyroidism whose parathyroid glands synthesize and secrete a mutant form of PTH made. This mutant PTH (R25C-PTH), when studied in mice and in vivo, has interesting properties. It can homodimerize and can raise blood calcium and lower blood phosphate levels: the opposite to the human phenotype in the index patient. These investigators perform a careful and convincing comparison of native PTH (1-34), an anabolic drug for osteoporosis treatment, and this R25C-mutant of PTH for their effects on bone mass, strength, microarchitecture, and metabolic activity. This dimeric mutant of PTH has anabolic properties raising the possibility that such forms of PTH could be developed as potent therapies for low bone mass states.

eLife Assessment

In this manuscript the authors established a novel three-dimensional culture system for stratified epithelia that allows epithelial cells to undergo epithelial-to-mesenchymal transition (EMT) and subsequent mesenchymal-to-epithelial transition (MET) while migrating through a membrane with 3.0-µm micropores, and, thus, provides a valuable tool to study EMT and possibly wound regeneration or metastasis. Furthermore, a set of experiments provides solid data suggesting that TGF beta signaling and actin polymerization promote movement of epithelial cells into the pores, while Piezo1 and Keratin 6 prevent keratinocyte migration and EMT.

eLife Assessment

This work represents an important contribution to our understanding of how membrane energetics influence protein conformation and function in mechano-sensitive channels. Through extensive molecular dynamics simulations and energetic analysis, the study demonstrates how the channel structure is shaped by a balance of protein and membrane-induced forces, effectively reconciling experimental data from different membrane environments. However, while much of the computational data is convincing, some aspects of the energetic analysis and models employed remain incomplete.

eLife Assessment

This important work substantially advances our understanding of the interaction among gut microbiota, lipid metabolism, and the host in type 2 diabetes. However, some evidence is incomplete, particularly in the mouse experiments with FMT. Additional experiments will be required to strengthen the authors' interesting findings.

eLife Assessment

The study presents important findings on inositol-requiring enzyme (IRE1α) inhibition on diet-induced obesity (overnutrition) and insulin resistance where IRE1α inhibition enhances thermogenesis and reduces the metabolically active and M1-like macrophages in adipose tissue. The evidence supporting the conclusions is convincing and the work will be of interest to cell biologists and biochemists working in metabolism, insulin resistance, and inflammation.

eLife Assessment

This study describes the impact of mycobacterial genetic diversity on host-infection phenotypes by assessing the effect of different M. tuberculosis lineages on granulomatous inflammation using a 3D in vitro granuloma model. Despite being descriptive and showing mostly correlative relationships, the useful findings and data provide some solid support regarding the functional impact of M. tuberculosis natural diversity on host-pathogen interactions. The study will interest researchers working on mycobacteria and how genetic diversity influences virulence and immunity outcomes.

eLife Assessment

This manuscript describes the impact of modulating signaling by a key regulatory enzyme, Dual Leucine Zipper Kinase (DLK), on hippocampal neurons. The results are interesting and will be important for scientists interested in synapse formation, axon specification, and cell death. The authors have carefully addressed the comments made by the reviewers and the findings are convincing in large part due to the use of extensive mouse genetics, detailed gene expression of enriched genes, and recognition of neuron vulnerability.

eLife Assessment

This study presents important findings on the function of enteric glia expressing proteolipid protein 1 (PLP1+ glia). The evidence supporting the claims of the authors is solid, although the inclusion of additional data showing the mechanisms by which PLP1+ enteric glia acts on Paneth cells would have strengthened the study. The work will be of interest to colleagues studying intestinal biology.

eLife Assessment

This study on mouse Ly49 receptors expressed on natural killer (NK) cells shows that Ly49A, in the presence of the corresponding MHC Class I allele, can lead to NK cell licensing, thereby providing valuable insights into the mechanisms of NK cell modulation by Ly49 receptors. The work may have significant implications for studies of human Killer-cell immunoglobulin-like receptors (KIR) expressing and other NK cells. Overall, the study was well-developed with convincing evidence.

eLife Assessment

Zanetti et al use convincing biophysical and cellular assays to investigate the interaction of the birnavirus VP3 protein with the early endosome lipid PI3P. The study provides valuable insights and will be of interest to virologists. In future studies, it would be interesting to demonstrate that VP3-PIP3P is a specific interaction and not a general interaction with other PIPs.

eLife assessment

These important findings stand out from other similar studies via some convincing demonstration of behavioural and neural relationships between two helping tasks – one focusing more on social perception, one more on its influence on social behaviour – that were performed more than 300 days apart. The claims however would be stronger with a larger sample size.

eLife Assessment

This study presents a useful finding that targeting amino acid metabolism can overcome Trastuzumab resistance in HER2+ breast cancer. The evidence supporting the claims of the authors is solid and the authors may want to validate their results in additional cell lines to strengthen their conclusions. Moreover, the authors should clarify the source of patient samples and why the manuscript focused on epigenetic regulations instead of major transcription factors. The work will be of interest to scientists working in the field of breast cancer.

eLife Assessment

This is an important study reporting that activation of the presynaptic GPR55 receptor suppresses synaptic transmission by modulating GABA release through the reduction of the readily releasable pool without affecting the presynaptic AP waveform and calcium influx. The evidence supporting this claim is compelling and based on an impressive array of techniques including patch-clamp recordings from the axon terminals of cerebellar Purkinje cells and fluorescent imaging of vesicular exocytosis. However, a few technical issues leave some questions open, these include uncertainty regarding the specificity of pharmacological agents and the nature of the endogenous process that would activate this pathway in vivo. In the current form, the evidence indicating that synaptic vesicles become insensitive to VGCC activation in the presence of GPR55 is weak and would need to be supported with additional experimental data.

eLife Assessment

Overall, this is an important work: the new methodology of hamFISH is a key additional tool for the assessment of the expression of multiple genes simultaneously. The authors provide convincing evidence of the utility of this approach on Medial Amygdala (MeA) tissue leveraging previous a transcriptomic dataset for gene selection. The authors also present a deeper dive into putative relationships between the on-tissue expression of subsets of genes and connectivity and behavioral regulation. The putative biological insights are intriguing, although preliminary, but notably they set up questions for future studies.

eLife Assessment

In this valuable contribution, the authors present an approach based on a complex systems theoretical framework to characterize diet-host-microbe interactions and to develop targeted bacteriotherapies using a three-phase workflow. Overall, the solid results provide a reference for microbial community research and insights to guide future studies. However, the theoretical systems approach would benefit from further description, and some claims regarding oxalate bacterial metabolism in complex microbial communities could be strengthened. This study will interest researchers working on gut microbiomes specifically those seeking to modulate host-microbial interactions.

eLife Assessment

This important study investigates the function of a critical regulator of human early cardiac development. The convincing examination of GATA6 function is thorough and well-executed. The study will be of interest to scientists working on how the human heart acquires its identity.

eLife Assessment

The study by Pudlowski et al. shows that a previously-identified protein complex, composed of delta- and epsilon-tubulin together with TEDC1 and TEDC2, functions in generating centriolar triplet microtubules, and that this is crucial for the proper formation of centriolar subdomains and the stability of centrioles throughout the cell cycle. This is an important study that advances our understanding of centriole biogenesis and structure and is supported by convincing evidence based on knockout cell lines, immunoprecipitation, and ultrastructure expansion microscopy. The work is of interest to cell biologists, in particular researchers with interest in centrosome biology.

eLife Assessment

This manuscript describes an important finding of the transcriptional control of a chimeric gene transfer agents (GTA) cluster in Bartonella by a processive anti-termination factor (BrrG). The evidence provided is solid. This manuscript will interest researchers working on transcriptional regulation, horizontal gene transfer, and phages.

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 manuscript offers valuable theoretical predictions on how horizontal gene transfer (HGT) can lead to alternative stable states in microbial communities. Using a modeling framework, solid theoretical evidence is provided to support the claimed role of HGT. However, given that the model has many degrees of freedom, a more comprehensive analysis of the role of different parameters could strengthen the study. Additionally, potential interactions between plasmids that carry out HGT are not discussed in the model. This paper would be of interest to researchers in microbiology, ecology, and evolutionary biology.

eLife Assessment

This important study combines virology experiments and mathematical modeling to determine the nuclear export rate of each of the eight RNA segments of the influenza A virus, leading to the proposal that a specific retention of mRNA within the nucleus delays the expression of antigenic viral proteins. The proposed model for explaining the differential rate of export is compelling, going beyond the state of the art, but the experimental setup is only in partial support and further studies will be needed to confirm the proposed mechanism.

eLife Assessment

This study reports a model of 8 somatosensory areas of the rat cortex consisting of 4.2 million morphologically and electrically detailed neurons. The authors carry out simulation experiments aimed at understanding how multiscale organization of the cortical network shapes neural activity. While the reviewers found the results to be solid, they note that they could have likely been obtained using a much smaller portion of the model. Nonetheless, the release of the modeling platform represents a significant contribution to the field by providing a valuable resource for the scientific community.

eLife Assessment

This important study investigates the implications of human endogenous retrovirus (HERV) activity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM). These findings indicate significant associations that coincide with previous literature, which has suggested roles for differential HERV activity in degenerative, inflammatory, and aging-related pathologies of the central nervous system (CNS), as well as neurotropic infections. These seminal studies can be strengthened with minor improvements to the methodologies of characterizing differential HERV activity, further characterizing downstream mechanisms by which HERV activity impacts disease and by an expansion of the datasets utilized to include additional cohorts. These compelling findings are of immediate importance to clinicians, policymakers, and researchers interested in the underlying etiology of human health and disease.

eLife Assessment

This study investigated the influence of genomic information and timing of vaccine strain selection on the accuracy of influenza A/H3N2 forecasting. The authors utilised appropriate statistical methods and have provided solid evidence that is an important contribution to the evidence base. While the study addresses a key aspect of public health, the impact is rather limited by its exclusive reliance on predictive methods using genomic information, without incorporating phenotypic data.

Editors Assessment:

DNA has huge potential as a data storage medium because of its incredibly high storage density and stability. This work addresses the potential of modified bases, specifically 5-methylcytosine (5mC), in enhancing DNA data storage systems. This paper introduces a transcoding scheme named R+, which incorporates this modified 5mC base to increase information density beyond the standard limits. By encoding various file types into DNA sequences of between 1.3 to 1.6 kb in size, this method achieves an average recovery rate of 98.97% (with reference), validating the effectiveness of the method. On top of a wet-lab protocol (hosted in protocols.io) for the experimental validation of the transcoding scheme, it also includes open source code for in-silico simulation tests. Peer review scruitinising the protocols and validation are reusable and provide convincing results. As nanopore sequencing has enabled reading of these modified bases, it is timely making them applicable as extra letters in the molecular alphabet for DNA data storage

This evaluation refers to version 1 of the preprint

eLife Assessment

The authors report how a previously published method, ReplicaDock, can be used to improve predictions from AlphaFold-multimer (AFm) for protein docking studies. The level of improvement is modest for cases where AFm is successful; for cases where AFm is not as successful, the improvement is more significant, although the accuracy of prediction is also notably lower. The evidence for the ReplicaDock approach being more predictive than AFm is particularly convincing for the antibody-antigen test case. Overall, the study makes a valuable contribution by combining data- and physics-driven approaches.

eLife Assessment

This manuscript reports important findings that the methyltransferase METTL3 is involved in the repair of abasic sites and uracil in DNA, mediating resistance to floxuridine-driven cytotoxicity. Convincing evidence shows the involvement of m6A in DNA based on single cell imaging and mass spec data. The authors present evidence that the m6A signal does not result from bacterial contamination or RNA, but the text does not make this overly clear.

eLife Assessment

This valuable study marks a significant advancement in brain aging research by centering on Asian populations (Chinese, Malay, and Indian Singaporeans), a group frequently underrepresented in such studies. It unveils solid evidence for anatomical differences in brain aging predictors between the young and old age groups. Overall, this study broadens our understanding of brain aging across diverse ethnicities.

eLife Assessment

This valuable study examines the variability in spacing and direction of entorhinal grid cells, providing convincing evidence that such variability helps disambiguate locations within an environment. This study will be of interest to neuroscientists working on spatial navigation and, more broadly, on neural coding.

eLife Assessment

This important study reports a detailed quantification of the population dynamics of Salmonella enterica serovar Typhimurium in mice. Bacterial burden and founding population sizes across various organs were quantified, revealing pathways of dissemination and reseeding of the gastrointestinal tract from systemic organs. Using various techniques, including genetic distance measurements, the authors present compelling evidence to support their conclusions, thus presenting new knowledge that will be of broad interest to scientists focusing on infectious diseases.

eLife Assessment

The current human tissue-based study provides compelling evidence correlating hippocampal expressions of RNA guanine-rich G-quadruplexes with aging and with Alzheimer's Disease presence and severity. The results are fundamental and will rejuvenate our understanding of aging and AD's pathogenesis.

[Editors' note: this paper was reviewed by Review Commons.]

eLife Assessment

This important study provides information on the TMEM16 family of membrane proteins, which play roles in lipid scrambling and ion transport. By simulating 27 structures representing five distinct family members, the authors captured hundreds of lipid scrambling events, offering insights into the mechanisms of lipid translocation and the specific protein regions involved in these processes. However, while the data on groove dilation is compelling, the evidence for outside-the-groove scramblase activity without experimental validation is inadequate and is based on a limited set of observed events.

eLife Assessment

This study presents valuable data on the increase in individual differences in functional connectivity with the auditory cortex in individuals with congenital/early-onset hearing loss compared to individuals with normal hearing. The evidence supporting the study's claims is convincing, although additional work using resting-state functional connectivity in the future could further strengthen the results. The work will be of interest to neuroscientists working on brain plasticity and may have implications for the design of interventions and compensatory strategies.

eLife Assessment

This fundamental study provides a critical challenge to a great many studies of the neural correlates of consciousness that were based on post hoc sorting of reported awareness experience. The evidence supporting this criticism is compelling, based on simulations and decoding analysis of EEG data. The results will be of interest not only to psychologists and neuroscientists but also to philosophers who work on addressing mind-body relationships.

eLife Assessment

The authors investigated the mechanisms underlying the pause in striatal cholinergic interneurons (SCINs) induced by thalamic input, identifying that Kv1 channels play a key role in this burst-dependent pause. The valuable study provides mechanistic insights into how burst activity in SCINs leads to a subsequent pause, highlighting the involvement of D1/D5 receptors. The experimental evidence is solid; however, the reviewers suggest further clarifying the mechanism by which clozapine reduces D5R ligand-independent activity in the L-DOPA-off state.

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 regulates the functions in macrophages have not yet been established.

eLife Assessment

This manuscript reports important findings that the methyltransferase METTL3 is involved in the repair of abasic sites and uracil in DNA, mediating resistance to floxuridine-driven cytotoxicity. The presented evidence is conclusive for the involvement of m6A in DNA involving single cell imaging and mass spectrometry data. The authors present convincing evidence that the m6A signal does not result from bacterial contamination or RNA.

eLife Assessment

This study makes a valuable contribution to understanding Bayesian inference in dynamic environments by demonstrating how humans integrate prior beliefs with sensory evidence, revealing an overestimation of environmental volatility while accurately tracking noise. The evidence is solid, supported by robust model fitting and principled factorial model set analyses, though limitations in sample size and inconclusive findings on memory capacity tradeoffs reduce the overall impact. Future work should expand validation across datasets, enhance model comparisons, and explore the generalizability of reduced Bayesian frameworks to strengthen the conclusions and broader relevance of the study.

eLife Assessment

This manuscript presents a useful mean-field model for a network of Hodgkin-Huxley neurons retaining the equations for ion exchange between the intracellular and extracellular space. The mean-field model derived in this work relies on approximations and heuristic arguments that, on the one hand, allow a closed-form derivation of the mean-field equations, but also raise questions about their justifications and the degree to which the results agree with experiments as well as direct numerical simulations. Therefore, the evidence for the utility of this approach is at present incomplete.

eLife Assessment

This important study uses diffusion magnetic resonance imaging to non-invasively map the white matter fibres connecting the zona incerta and cortex in humans. The authors present convincing evidence to indicate that these connections are organized along a rostro-caudal axis. The findings will be of interest to researchers interested in neuroanatomy and cortico-subcortical connectivity.

eLife Assessment

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

eLife Assessment

This report used a new double knockout mouse model to investigate the role of two neuropeptides, substance P and CGRPa, in pain signaling. There is convincing evidence that double knockout of these two molecules, both of which have historically been associated with pain, does not affect nociception or acute pain behaviors in males and females. This finding is fundamental, as it challenges the hypothesis that these peptides are essential for pain transmission, even when targeted together. This paper will be of interest to those interested in the neurobiology of pain and/or neuropeptide function.

eLife Assessment

This important study provides convincing data from in vitro models and patient-derived samples to demonstrate how modulation of GSK3 activity can reprogram macrophages, revealing potential therapeutic applications in inflammatory diseases such as severe COVID-19. The study stands out for its clear and systematic presentation, strong experimental approach, and the relevance of its findings to the field of immunology.

eLife Assessment

This study provides valuable insights into the behavioral, computational, and neural mechanisms of regime shift detection, by identifying distinct roles for the frontoparietal network and ventromedial prefrontal cortex in sensitivity to signal diagnosticity and transition probabilities, respectively. The findings are supported by solid evidence, including an innovative task design, robust behavioral modeling, and well-executed model-based fMRI analyses, though claims of neural selectivity would benefit from more rigorous statistical comparisons. Overall, this work advances our understanding of how humans adapt belief updating in dynamic environments and offers a framework for exploring biases in decision-making under uncertainty.

eLife Assessment

This valuable study implicates a specific Wolbachia gene in driving the male-killing phenotype in a moth: This is a contribution to a growing body of literature from the authors in which they authors have nicely teased apart the loci responsible for male killing across diverse insects. The conclusions are supported by solid evidence.

eLife Assessment

This study provides compelling data regarding the molecular characterization of a rare tumor type with few treatment options. This fundamental work significantly advances our mechanistic understanding of solitary fibrous tumours, a critical first step towards targeted precision medicine approaches. The results of this study will be of broad interest to cancer biologists and experimental oncologists.

eLife Assessment

This valuable contribution combines high-resolution histology with magnetic resonance imaging in a novel way to study the organisation of the human amygdala. The main findings convincingly show the axes of microstructural organisation within the amygdala and how they map onto the functional organisation. Overall, the approach taken in this paper showcases the utility of combining multiple modalities at different spatial scales to help understand brain organisation.

eLife Assessment

This important study provides insights into the role of the cerebellum in fear conditioning, addressing a key gap in the literature. The evidence presented is solid overall, although the theoretical framing and clarity of the results can be improved and some concerns remain about the reliability of results based on small numbers of trials. This work will be of interest to both the extinction learning and cerebellar research communities.

eLife Assessment

This research addresses an important and timely topic in cancer treatment, as the authors present a novel computational tool, 'retriever,' which has the potential to revolutionize personalized cancer treatment strategies by predicting effective drug combinations for triple-negative breast cancer. The strength of the evidence presented is solid, as evidenced by the systematic testing of 152 drug response profiles and 11,476 drug combinations.

eLife Assessment

This important study provides new evidence on the role of norepinephrine (NE) release in the hippocampus in response to environmental transitions (event boundaries), providing a potential link between NE signaling and the segmentation of episodic memories. The work is solid, employing innovative techniques such as fiber photometry with the GRAB-NE sensor for NE measurement, the analysis of public electrophysiology hippocampal datasets, and well-controlled experiments. While further analysis could strengthen some claims, this work offers insights into memory, neuromodulation, and hippocampal function.

eLife Assessment

This study examined the important question of how neurons code temporal information across the hippocampus, dorsal striatum, and orbitofrontal cortex. Using a behavioral task in the rat that requires discrimination between short and long time intervals, the authors conclude that time intervals are represented in all three regions and that synchronized activity of time-coding cells across the brain regions is coordinated by theta rhythms. However, several weaknesses are noted, and in its current form, the study provides incomplete evidence for understanding how temporal information is processed and coordinated throughout these brain networks.

eLife Assessment

This is an important study providing convincing evidence that increased blood pressure variability impairs myogenic tone and diminishes baroreceptor reflex. The study also provides evidence that blood pressure variability blunts functional hyperemia and contributes to cognitive decline. The authors use appropriate and validated methodology in line with the current state-of-the-art.

eLife Assessment

The authors show that: 1) following brief peripheral optogenetic stimulation of forepaw proprioceptors in mice, sensory-evoked responses in primary motor cortex (M1) are delayed relative to primary somatosensory cortex (S1); 2) the responses in both cortical areas follow a triphasic pattern of activation-suppression-activation; 3) directly activating cortical parvalbumin-positive (PV) inhibitory interneurons mimicked both the suppression and rebound components of the sensory-evoked response; and 4) partially suppressing activity in S1 reduces the sensory-evoked response in M1. The conclusions are convincing and build on prior work on cortical circuits related to the mouse forelimb from this group (Yamawaki et al., 2021, eLife, doi:10.7554/eLife.66836). More rigorously determining whether the peripheral stimulation approach used evokes movements would strengthen the conclusions. It is also possible that these effects would differ for peripheral mechanoreceptor stimulation. Overall, this in vivo work assessing sensory responses in forepaw-related cortical circuits represents a valuable comparison to previously published work.

eLife Assessment

This important study examines heterochromatin domain dynamics using a model system that allows reversible transition from an embryonic stem cell to a 2-cell-like state. The authors present a solid resource to the research community that will further the understanding of changes in the chromatin-bound proteome during the 2C-to-ESC transition. However, conclusions related to the functional roles of the interaction between the SWI/SNF complex component SMARCAD1 and the DNA Topoisomerase II Binding protein (TOPBP1) remain incomplete.

eLife Assessment

This important study shows that Type 3 secretion translocons in Edwardsiella tarda and other bacteria activate the NAIP-NLRC4 inflammasome. The data from cellular and biochemical experiments showing that EseB is required for activation of the NLRC4 inflammasome are convincing. This paper is broadly relevant to those investigating host-pathogen interactions in diverse organisms.

eLife Assessment

This paper reports important findings on giant organelle complexes containing endosomes and lysosomes (termed endosomal-lysosomal organelles form assembly structures [ELYSAs]) present in mouse oocytes and 1- to 2-cell embryos. The data showing the localization and dynamics of ELYSAs during oocyte/embryo maturation are convincing. This work will be of interest to general cell biologists and developmental biologists.

eLife Assessment

This study convincingly shows that aquaporin-mediated cell migration plays a key role in blood vessel formation during zebrafish development. In particular, the paper implicates hydrostatic pressure and water flow as mechanisms controlling endothelial cell migration during angiogenic sprouting. This fundamental study is highly novel and significantly advances our understanding of cell migration during morphogenesis. As such, this work will be of great interest to developmental and cell biologists working on organogenesis, angiogenesis, and cell migration.

eLife Assessment

This important study presents compelling observational data supporting a role for transcription and polysome accumulation in the separation of newly replicated bacterial chromosomes. The study is generally thorough and rigorous in nature, although there are several instances where revisions would help clarify for the reader that the evidence is primarily circumstantial in nature and that a direct causal relationship between polysome accumulation has yet to be tested. With regard to the latter, the model's predictions could possibly be tested by examining the impact of translation inhibitors on nucleoid organisation. The authors could also compare the radial dimensions of the nucleoid with cell width to confirm that the nucleoid is radially confined across all conditions, a critical assumption of the model.

eLife Assessment

This study provides valuable scRNA-seq and scATAC-seq data for testicular tissues from patients with spermatogenesis disorders. By examining the transcriptomic and epigenetic changes in Sertoli cells, the authors uncovered key regulatory mechanisms underlying male infertility and identified potential therapeutic targets. While some of the cellular profiling results are convincing, the analyses for differential profiling of NOA cases and epigenomics data remain incomplete.

eLife Assessment

This manuscript describes a fundamental investigation of the functioning of Cas9 and in particular on how variant xCas9 expands DNA targeting ability by an increase-flexibility mechanism. The authors provide compelling evidence to support their mechanistic models and the relevance of flexibility and entropy in recognition. This work can be of interest to a broad community of structural biophysicists, computational biologists, chemists, and biochemists.

eLife Assessment

This study provides important computational insights into the dynamics of PROTAC-induced degradation complexes, offering a convincing demonstration that differences in degradation efficacy can be linked to linker properties. The analyses address reproducibility considerations comprehensively, reinforcing the study's conclusions. Overall, these findings are significant for advancing cancer treatments and will be of broad interest to both biochemists and biophysicists.

eLife Assessment

This study provides a valuable approach to image and analyze in vivo metabolic flux through glucose turnover kinetics in glioblastoma tumor microenvironments. The evidence for the method's validity is convincing, which establishes the dynamic Deuterium Metabolic Imaging technique as an effective tool enabling non-invasive exploration of various tumors.

eLife Assessment

Seminal plasma is a crucial component of semen that can affect sperm capacitation. However, the role of seminal plasma components, including fatty acids, in sperm function and fertility is poorly understood. In this important study, the authors provide a solid evidence of the testosterone-induced metabolic shift in the epithelial cells of seminal vesicle to support an fatty acid synthesis and also describe the potential effect of oleic acid on sperm motility.

eLife Assessment

This important study addresses the idea that defective lysosomal clearance might be causal to renal dysfunction in cystinosis. With mostly solid data, the authors observe that restoring expression of vATPase subunits and treatment with Astaxanthin ameliorate mitochondrial function in a model of renal epithelial cells, opening opportunities for translational application to humans.

eLife Assessment

This is an important and convincing study of the morphological properties of Purkinje cell dendrites and dendritic spines in adult humans and mice, and the anatomical determinants of multi-innervation by climbing fibers. The data will provide a helpful resource for the field of cerebellar computation.

eLife Assessment

Combining experiments in microfluidic devices and computer simulation, this study provides a valuable analysis of the relevant parameters that determine the motility of (multicellular) magnetotactic bacteria in sediment-like environments. Despite the limitations imposed by the specific experimental design of the pores, the study presents convincing evidence that there is an optimum in the biological parameters for motile life under such conditions.

eLife Assessment

This valuable study assesses epigenetic clocks across ancestries, including in the context of accelerated aging in Alzheimer's Disease patients. It provides convincing evidence for population differences in age estimation accuracy across a variety of epigenetic clocks, but the degree to which these differences reflect continuous variation in ancestry, and/or are confounded by environmental or power differences is not entirely clear; consequently, the evidence that reduced portability is rooted in genetics is incomplete. Given the accelerating use of epigenetic clocks across fields, this study is nevertheless likely to be of interest to researchers working on human genetic and epigenetic variation or who apply epigenetic clocks to diverse human populations.

eLife Assessment

Using several hundreds of samples and cutting-edge genomic methods, including BioNano, PacBio HiFi, and advanced bioinformatic pipelines, the authors identify six large chromosomal inversions segregating in over 100 species of Lake Malawi cichlids. This important study provides compelling evidence for the presence of these six inversions, their differential distribution among populations, and the association of chromosome 10 inversion with a sex-determination locus. This work also provides a starting point for further investigating the role of these inversions with respect to local adaptation, speciation, sex determination, hybridization, and incomplete lineage sorting in cichlids, which represent ~5% of the extant vertebrate species and are one of the most prominent examples of adaptive radiations.

eLife Assessment

This important work advances our understanding of intraflagellar transport, ciliogenesis, and ciliary-based signaling, by identifying the interactions of IFT172 with IFT-A components, ubiquitin-binding, and ubiquitination, mediated by IFT172 C-terminus and its role in ciliogenesis and ciliary signaling. The results of the structural analysis of the IFT172 C-terminus and the evidence for the interaction between IFT172 and IFT-A components are convincing. However, the analysis of ubiquitin-binding and ubiquitination mediated by IFT172 is incomplete.

eLife Assessment

This study presents an important finding that has identified 27 differentially methylated regions as a signature for non-invasive early cancer detection and predicting prognosis for colorectal cancer. The findings demonstrate promising clinical potential, particularly for improving cancer screening and patient monitoring. However, the evidence supporting the claims of the authors is incomplete due to a small sample size and some methodological concerns. The work will be of interest to researchers interested in cancer diagnosis or colorectal cancer monitoring.

eLife Assessment

This study presents a valuable and simplified classification system for predicting clinical outcomes in RPLS patients. The evidence supporting the claims of the authors is solid, although the elaboration of the marker selection process would have strengthened the study. The work will be of interest to scientists working in the field of retroperitoneal liposarcoma.

eLife Assessment

This work presents a valuable extension of qFit-ligand, a computational method for modeling conformational heterogeneity of ligands in X-ray crystallography and cryo-EM density maps. The evidence presented for improved capabilities through careful validation against the previous version, notably in expanding ligand sampling within the conformational space, is solid yet still incomplete. The enhanced methodology demonstrates practical utility for challenging applications, including macrocyclic compound modeling and crystallographic drug fragment screening.

eLife Assessment

This important study uses recently developed EEG analysis methods to investigate spatial distractor suppression in a combined visual search/working memory task. The reported results are compelling, although they are open to multiple interpretations. The study will be of interest to cognitive neuroscientists and psychologists working on visual attention and memory.

eLife Assessment

This study offers a valuable treatment of how the population of excitatory and inhibitory neurons integrates principles of energy efficiency in their coding strategies. The convincing analysis provides a comprehensive characterisation of the model, highlighting the structured connectivity between excitatory and inhibitory neurons. The role of the many free parameters are discussed and studied in depth.

eLife Assessment

This short manuscript uses mutation counts in phylogenies of millions of SARS-CoV-2 genomes to show that mutation rates systematically differ between regions that are paired or unpaired in the predicted RNA secondary structure of the viral genome. Such an effect of pairing state is not unexpected, but its systematic demonstration using millions of viral genomes is valuable and convincing.

eLife Assessment

This phenomenological study reported that cold exposure induced mRNA expression of genes related to lipid metabolism in the paraventricular nucleus of the hypothalamus (PVH). While the paper does not address cell-type specificity or the functional role of lipids in PVH, the findings might still serve as a useful basis for others to explore their relevance to brain responses to cold. In the revised manuscript, the authors made adequate editions, such as new immunostaining and immunoblotting of AGTL and HSL in the PVH, and pharmacological inhibition of lipid peroxidation and lipolysis. The authors also increased the sample size of some experiments and revised the text to limit their data interpretation. Thus, the reviewers considered that these studies are solid in conclusively describing how the PVH is reprogrammed at the level of gene expression by cold exposure.

eLife Assessment

This important study describes a first-in-human trial of autologous p63+ stem cells in patients with idiopathic pulmonary fibrosis, a lethal condition for which effective treatments are lacking. The authors provide convincing evidence that P63+ progenitor cell therapy can be safely delivered in patients with ILD, warranting movement to a Phase 2. However, given that this is a Phase 1 study with a small sample size, conclusions regarding efficacy should not yet be made.

eLife Assessment

The authors implement a valuable multi-tissue approach to dissect the physiologic consequences of JNK inhibition in parallel with dietary perturbation via sucrose. The conclusions of disrupted liver, muscle and adipose metabolism being central to these effects are solid, as they are supported by a combination of experimental dissection and network modeling approaches.

eLife Assessment

In their important manuscript, Costa et al. establish an in vitro model for dorsal root ganglion (DRG) axonal asymmetry, revealing that central and peripheral axon branches have distinct patterns of microtubule populations that are linked to their differential regenerative capacities. The authors employ creative tissue culture methods to demonstrate how these branches develop uniquely in vitro, offering a potential explanation for long-observed regeneration disparities. The convincing evidence provides a contribution to our understanding of the neuronal cytoskeleton and axonal regeneration.

eLife Assessment

This important study investigates the role of ATG6 in regulating NPR1, a key protein in the plant immune response. The authors present compelling evidence that ATG6 not only interacts with NPR1 in both the cytoplasm and nucleus but also enhances its stability and nuclear accumulation, leading to increased resistance to Pst DC3000/avrRps4 infection in Arabidopsis thaliana. The work incorporates a variety of approaches from molecular biology, confocal imaging, and biochemistry, which together strengthen the conclusions.

eLife Assessment

This important study investigates the signaling pathways regulating retinal regeneration. Convincing evidence shows that the sphingosine-1-phosphate (S1P) signaling pathway is inhibited following retinal injury. Small-molecule activators and inhibitors support a model in which S1P signaling must be inhibited to generate Müller glial progenitor cells-a key step in retinal regeneration. The presented results support the major conclusions. However, whether the drug treatments directly or indirectly affect the Müller cells remains unclear.

eLife Assessment

This study presents a valuable finding that synthetically lethal kinase genes FYN and KDM4 may play a role in drug resistance to kinase inhibitors in TNBC. The evidence supporting the claims of the authors is solid, although the exploration of the upstream mechanisms regulating KDM4A or the downstream pathways through which FYN upregulation confers drug resistance would have strengthened the study. The work will be of interest to medical biologists working in the field of breast cancer.

eLife Assessment

In this useful study, the authors tested a novel approach to eradicating HIV reservoirs by constructing a herpes simplex virus (HSV)-based therapeutic vaccine and evaluating efficacy in experimental infections of chronically SIV-infected, antiretroviral therapy (ART)-treated macaques. While mean viremia at rebound was lower in the HSV vaccine-treated group, the evidence presented appears to be incomplete, as the group size was small and the viral load at rebound was highly variable. This is a revised paper, but the support for the conclusions, particularly the effect of the HSV-vectored therapeutic vaccine on the SIV reservoir in the SIV-infected macaques, remains limited.

eLife Assessment

The results highlight an important physiological function of PGAM in the differentiation and suppressive activity of Treg cells by regulating serine synthesis. This role is proposed to intersect with glycolysis and one-carbon metabolism. Although the study's conclusion is supported by solid evidence from in-vitro cellular and in-vivo mouse models, there are some weaknesses and the reviewers suggested ways to improve the manuscript.

eLife Assessment

This valuable study uses single-molecule imaging for characterization of factors controlling the localization, mobility, and function of RNase E in E. coli, a key bacterial ribonuclease central for mRNA catabolism. While the supporting evidence for the differential roles of RNAse E's membrane targeting sequence and the C-terminal domain (CTD) is solid, the work could be further strengthened by clarifying some experimental discrepancies, restructuring the narration order, and exploring the generality of some observations and their physical basis, such as the membrane-RNase E interactions and the unstructured nature of the RNase E C-terminal domain. This interdisciplinary study will be of interest to cell biologists, microbiologists, biochemists, and biophysicists.

eLife Assessment

This important study reports single-nucleus multiomics-based profiling of transcriptome and chromatin accessibility of mouse XX and XY primordial germ cells (PGCs). The main conclusions of this study, which will be of interest to developmental and reproductive biologists, as well as andrologists, are supported by convincing data.

eLife Assessment

In this useful study, the authors tested a novel approach to eradicate the HIV reservoir by constructing a herpes simplex virus (HSV)-based therapeutic vaccine designed to reactivate HIV from latently infected cells and induce an immune response to kill such infected cells. Testing this approach with SIV in a primate model, the authors report that the SIV reservoir was reduced. However, the evidence presented appears to be incomplete because the animal group size was small and the SIV reservoir size highly variable.

eLife Assessment

This valuable paper describes the stiffness of meiotic chromosomes in both oocytes and spermatocytes. The authors identify differences in stiffness between meiosis I and II chromosomes, as well as an age-dependent increase in stiffness in meiosis I (and meiosis II) chromosomes, results that are highly significant for the field of chromosome biology. The report is, however, mostly descriptive and the mechanisms underlying age-dependent changes in chromosome stiffness remain unclear. The evidence suggesting that changes in stiffness are independent of cohesin, which is known to deteriorate with age, is still incomplete.

eLife Assessment

By combining Synthetic Genetic Array (SGA) analysis with state-of-the-art imaging techniques, this study provides strong evidence that sphingolipid metabolism controls the maturation of Parkinson's disease-associated Synphilin-1 inclusion bodies (SY1 IBs) on the mitochondrial surface in a yeast model. The authors present compelling proof that perturbing the sphingolipid metabolic pathway leads to delayed SY1 IB maturation and enhanced SY1-triggered toxicity. Altogether, the authors show the important role of sphingolipid metabolism in the detoxification process of misfolded proteins by facilitating large IB formation on the mitochondrial outer membrane.

eLife Assessment

This important study presents an original and promising approach to combine convolutional neural networks of visual processing with evidence accumulation models of decision-making. While the methodological approach is technically sophisticated and the evidence is solid, there is still a gap between the model and the behavioral data. The study will be of interest to researchers working in the fields of machine learning and cognitive modeling.

eLife Assessment

The study presents a potentially valuable approach to genetically modify cells to produce extracellular matrices with altered compositions, termed cell-laid, engineered extracellular matrices (eECM). The evidence supporting the authors' conclusions regarding the utility of eECM for endogenous repair is solid, although there are some disagreements on the chondrogenicity of lyophilized constructs which was viewed as lacking robust evidence for endochondral ossification.

eLife Assessment

This important study provides solid evidence to support the anti-tumor potential of citalopram, originally an anti-depression drug, in hepatocellular carcinoma (HCC). In addition to their previous report on directly targeting tumor cells via glucose transporter 1 (GLUT1), they tried to uncover additional working mechanisms of citalopram in HCC treatment in the current study. The data here suggested that citalopram may regulate the phagocytotic function of TAM via C5aR1 or CD8+T cell function to suppress HCC growth in vivo.

eLife Assessment

Using a unique cerebellar disruption approach in non-human primates, this study provides valuable new insight into how cerebellar inputs to the motor cortex contribute to reaching. Evidence for many claims is solid, but several analyses - especially with respect to control at the end of the reaches - could be expanded or clarified. Additional details about the behavioral task and a clearer description about the limits of the disruption approach with respect to selectivity are also warranted.

eLife Assessment

This valuable short paper is an ingenious use of clinical patient data to address an issue in imaging neuroscience. The authors clarify the role of face-selectivity in human fusiform gyrus by measuring both BOLD fMRI and depth electrode recordings in the same individuals; furthermore, by comparing responses in different brain regions in the two patients, they suggested that the suppression of blood oxygenation is associated with a decrease in local neural activity. While the methods are compelling and provide a rare dataset of potentially general importance, the presentation of the data in its current form is incomplete.

eLife Assessment

This study shows that strip cropping -- planting different crops in strips on the same field -- enhances the taxonomic diversity of ground beetles relative to corresponding monocultures in multiple experiments with different crops in the Netherlands. While these findings are important for demonstrating the potential beneficial effects of this form of intercropping, the information presented is incomplete with regard to sampling design and data obtained.

eLife Assessment

This is a useful and potentially significant set of experiments. The authors found that cmk-1 and tax-6 act in separate habituation processes, primarily in AFD, and both serve to habituate the thermosensory reversal response. They found that cmk-1 primarily acts in AFD and tax-6 primarily acts in RIM (and FLP for naïve responses). While the study is significant, it is currently somewhat incomplete as key control experiments are needed in order to support the conclusions.

eLife Assessment

In this valuable manuscript, authors ablate cerebellar oligodendrocytes during postnatal development and show that synchrony of calcium transients in Purkinje neurons and behaviours are affected even at later stages. While the work is solid, it is incomplete in that the causal relationship between the two has not been sufficiently explored.

eLife Assessment

In this valuable study, ectopic expression and knockdown strategies were used to assess the effects of increasing and decreasing Cyclic di-AMP on the developmental cycle in Chlamydia. The authors convincingly demonstrate that overexpression of the dacA-ybbR operon results in increased production of c-di-AMP and early expression of the transitionary gene hctA and late gene omcB. Whilst these results are intriguing, the model currently proposed is over-simplified and likely incomplete.

eLife Assessment

The manuscript represents a fundamental advance in designing peptide inhibitors targeting Cdc20, a key activator and substrate-recognition subunit of the APC/C ubiquitin ligase. Supported by compelling biophysical and cellular evidence, the study lays a strong foundation for future developments in degron-based therapeutics. The unexpected findings regarding degradation efficiency highlight intriguing questions that merit further investigation. This work will interest researchers focused on peptide drug design targeting complex protein interactions.

eLife Assessment

This study presents a valuable finding on the alterations in the autophagic-lysosomal pathway in a Huntington's disease model. The evidence supporting the claims of the authors is solid. However, the observed changes in autophagy are moderate, the images were not fully represented by the quantification results, and some of the short forms used in the text are not clearly stated; these issues hinder further evaluation of the claims. The work will be of interest to neuroscientists working on HD.

eLife Assessment

This valuable study on Pseudomonas subverting host immunity identifies a new immune evasion strategy. There is solid evidence for the cleavage of VgrG2B by Caspase 11 and the generation of fragments that inhibit activity of the NLRP3 inflammasome. This work should be of interest to immunologists and microbiologists.

eLife Assessment

This study provides valuable insights into the lesser-known effects of the sodium-potassium pump on how nerve cells process signals, particularly in highly active cells like those of weakly electric fish. The authors use a detailed mathematical model to show how the pump can shift a cell's normal firing patterns and disrupt the coordination of signals when inputs change quickly. The computational methods used to establish the claims in this work are solid and can be used as a starting point for further studies, yet the conclusions would be strengthened with experimental evidence or testable predictions regarding some of the proposed mechanisms across different cell types.

eLife Assessment

This well-designed study provides important findings concerning the way the brain encodes prediction about self-generated sensory inputs. The authors report that neurons in auditory cortex respond to mismatches in locomotion-driven auditory feedback and that those responses can be enhanced by concurrent mismatches in visual inputs. While there remain alternative explanations for some of the data, these findings provide convincing support for the role of predictive processing in cortical function by indicating that sensorimotor prediction errors in one modality influence the computation of prediction errors in another modality.

eLife Assessment

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