eLife assessment

The paper will be of broad interest to fungal biologists and fungal immunologists seeking to understand the biosynthesis of the fungal cell wall, in particular of ß-1,6-glucan synthesis and the importance of this so far understudied constituent of the cell wall for cell wall integrity and immune response. The study is of fundamental significance and adds structural clarity to the presence, genetic, and biochemical basis of this difficult-to-analyze carbohydrate. It opens the potential for understanding its role in immune recognition and potentially as a drug target. Overall, the data is compelling, properly controlled and analyzed, but a few aspects need to be reconsidered.

eLife assessment

This study presents an important finding of dynamic reprogramming of global H3K4me2 during mouse oocyte-to-embryo transition. While the H3K4me2 epigenome data is convincing, the interpretation and the potential mechanistic claims of the authors are incomplete in the current shape with the primary concerns regarding the contribution of Kdm1b or Kdm1a, as well as the specificity of the inhibitor and the antibody. The work will be of interest to researchers interested in epigenetic reprogramming.

eLife assessment

The authors have conducted a convincing study utilizing machine learning algorithms to construct a validated radiotherapy sensitivity score (NPC-RSS) for predicting radiosensitivity in nasopharyngeal carcinoma patients that will be useful in a translational/clinical setting for predicting the best radiotherapy route for patients. They have also explored the biological mechanisms underlying the relationship between NPC-RSS and radiotherapy response, thus implicating certain pathways that could be targeted to enhance radiotherapy response or prevent radio-resistance.

eLife assessment

This study presents a valuable description of the cellular and transcriptional landscape of the tumor microenvironment in 27 gastric cancer (GC) patients based on their H. pylori status (HpGC, ex-HpGC, non-HpGC). The single-cell RNA sequencing dataset and computational analysis are convincing and provide a starting point that is of value for understanding H pylori-associated GC cell type composition, cell transitions, and mechanisms of response to therapy. The section correlating immunotherapy outcomes with GC cell type compositions from bulk RNAseq would have been strengthened by further comparing H. pylori GC versus non H. pylori GC.

eLife assessment

This study provides a useful inventory of genes that are up- or down-regulated during the early metamorphic development of male and female larvae and proposes that the microRNA cluster miR-277/34 is involved in the development of sexual differences during early metamorphosis of Drosophila melanogaster, although its precise role remains unclear. The strength of evidence, based on a combination of diverse methods including mRNA and small RNA sequencing, in silico analyses, in vitro assays, and loss-of-function experiments, is incomplete as it lacks a general model and an examination of the potential effects of the miR-277/34 mutations on phenotypes such as morphology or developmental time. This work will be of interest to developmental biologists interested in sexual dimorphism and in the interplay between hormones and microRNAs during development.

eLife assessment

This potentially valuable study reports new and unexpected roles of STAG3 in regulating exit from pluripotency in mouse embryonic stem cells (mESCs). However, the evidence for the proposed role of STAG3 in the post-transcriptional regulation of gene expression is viewed as yet incomplete. The work will be of interest to colleagues studying stem cells, early steps in differentiation, and gene regulation.

eLife assessment

In this important study, the authors employed three types of theoretical/computational models (coarse-grained molecular dynamics, analytical theory and field-theoretical simulations) to analyze the impact of salt on protein liquid-liquid phase separation. These different models reinforce each other and together provide convincing evidence to explain distinct salt effects on ATP mediated phase separation of different variants of caprin1. The insights and general approach are broadly applicable to the analysis of protein phase separation.

eLife assessment

This study provides a useful analysis of the changes in chromatin organization and gene expression that occur during the differentiation of two cell types (anterior endoderm and prechordal plate) from a common progenitor in zebrafish. Although the findings are consistent with previous work, the evidence presented in the study appears to be incomplete and would benefit from more rigorous interpretation of single-cell data, more in-depth lineage tracing, overexpression experiments with physiological levels of Ripply, and a clearer justification for using an explant system. With these modifications, this paper will be of interest to zebrafish developmental biologists investigating mechanisms underlying differentiation.

eLife assessment

This fundamental work advances our understanding of the regulation of corneal stem cell fate and differentiation, identifying Sox9 as a player in this process. The evidence supporting the conclusions is compelling, with rigorous genomic experiments and genetic mouse models that are state-of-the-art in the field. The work will be of broad interest to developmental, stem cell, and transcriptional biologists.

eLife assessment

This manuscript addresses a mechanism by which dopamine (DA) regulates synaptic plasticity. The authors build upon their previous finding that DA applied after a timing pattern that ordinarily induces long-term depression (LTD) now induces long-term potentiation (LTP). The new findings that this "DA-dependent LTP" involves de novo protein synthesis, a cyclicAMP signalling pathway, and calcium-permeable AMPA receptors (CP-AMPARs) are of valuable significance. The conclusions are convincing and largely supported by the evidence provided.

eLife assessment

This valuable study investigates how hearing impairment affects neural encoding of speech, in particular the encoding of hierarchical linguistic information. The current analysis provides incomplete evidence that hearing impairment affects speech processing at multiple levels, since the novel analysis based on HM-LSTM needs further justification. The advantage of this method should also be further explained. The study can also benefit from building a stronger link between neural and behavioral data.

eLife assessment

The study has identified a cell type in muscle that is characterized as an adipogenic progenitor cell that is capable of promoting regeneration through the action of BDNF, a prominent growth factor regulated by GDNF in Schwann cells. These results represent an important cellular explanation for nerve regeneration. The revised analysis is solid but the work remains incomplete due to a lack of evidence that BDNF is produced during the process through the action of GDNF.

eLife assessment

The study provides potentially fundamental insight into the function and evolution of daily rhythms. The authors investigate the function of the putative core circadian clock gene Clock in the cnidarian Nematostella vectensis. While it parts still incomplete, the evidence suggests that, in contrast to mice and fruit flies, Clock in this species is necessary for daily rhythms under constant conditions, but not under a rhythmic light/dark cycle, suggesting that the major role of the circadian oscillator in this species could be a stabilizing function under non-rhythmic environmental conditions.

eLife assessment

This fundamental study for the first time defines genetically the role of the Clock gene in basal metazoa, using the cnidarian Nematostella vectensis. With convincing evidence, the study provides insight into the early evolution of circadian clocks. Clock in this species is necessary for daily rhythms under constant conditions, but not under a rhythmic light/dark cycle, suggesting that the major role of the circadian oscillator in this species could be a stabilizing function under non-rhythmic environmental conditions.

eLife assessment

This study provides valuable insights into the regulation of metabolic flux between glycolysis and respiration in yeast, particularly focusing on the role of inorganic phosphate. The authors propose a novel mechanism involving Ubp3/Ubp10 that potentially mitigates the Crabtree effect, offering substantial, solid evidence through a variety of well-designed assays. This study could reshape our understanding of metabolic regulation with broad biological contexts.

eLife assessment

Picard et al. propose a Facial Expression Pain Signature (FEPS) derived from functional magnetic resonance imaging (fMRI) data to predict facial expressions associated with painful heat stimulation. This important work advances our understanding of the brain mechanisms associated with facial expressions of pain. It provides solid evidence that facial expressions of pain contain information that is complementary to other pain-related brain processes. The work will be of broad interest to researchers from varied fields ranging from neurosciences to psychology and affective sciences.

eLife assessment

This paper provides important insights into the role of rice OsNF-YB7, an ortholog of Arabidopsis LEC1, in chlorophyll biosynthesis, uncovering the genetic and molecular basis for negative regulation of chlorophyll production in the rice embryo. Mutational analysis, gene expression profiles and protein interaction combine for convincing evidence that OsNF-YB7 represses chlorophyll biosynthesis.

eLife assessment

This important study contributes to our understanding on how prior exposure to a non-pathogenic Leptospira strain could prime the host to prevent severe leptospirosis following infection with a pathogenic strain. The work described is solid and broadly supports the claims, with minor weaknesses that could be addressed in future studies. The work will be of interest to scientists interested in host-pathogen interactions and leptospirosis.

eLife assessment

This study presents a light-entrainable synthetic oscillator in bacteria, the optorepressilator. The authors develop a toolbox using optogenetics that makes the cellular oscillator easily controllable. This toolbox is valuable, contributing both to bioengineering and to the understanding of biological dynamical systems. The comparison with a mathematical model, population, and single-cell measurements demonstrate convincingly that the planned system was achieved and is suitable to control and study biological oscillators.

eLife assessment

This important study reports the cryo-electron microscopy structure of a multi-protein complex that recognizes the 5'-end cap of mRNAs and plays a critical role in mRNA export. The structural and biochemical analyses in this study provide convincing evidence to support the major claims of the authors, with the inclusion of more functional characterizations in cell-based systems having corroborated the claims further and and thus strengthening the study. This paper would be of interest to structural biologists and RNA biologists working on mRNA metabolism.

eLife assessment

The author demonstrates that deficiency or pharmacological inhibition of O-glcNac transferase (OGT) enhances tumor immunity in colorectal cancer models. This useful study unveils that OGT deficiency triggers a DNA damage response that can affect immune status in colorectal cancers. It provides convincing evidence showing that OGT-mediated processing of HSF1 is crucial in maintaining genomic integrity.

eLife assessment

In this important study, the authors manually assessed randomly selected images published in eLife between 2012 and 2022 to determine whether they were accessible for readers with deuteranopia, the most common form of color vision deficiency. They then developed an automated tool designed to classify figures and images as either "friendly" or "unfriendly" for people with deuteranopia. Such a tool could be used by journals or researchers to monitor the accessibility of figures and images, and the evidence for its utility was solid: it performed well for eLife articles, but performance was weaker for a broader dataset of PubMed articles, which were not included in the training data. The authors also provide code that readers can download and run to test their own images, and this may be of most use for testing the tool, as there are already several free, user-friendly recoloring programs that allow users to see how images would look to a person with different forms of color vision deficiency. Automated classifications are of most use for assessing many images, when the user does not have the time or resources to assess each image individually.

eLife assessment

This study presents a valuable strategy to co-deliver peptides and adjuvants to antigen-presenting cells by engineering the Virus-like particle (VLP). The evidence supporting the claims of the authors is convincing, but the antitumour efficacy is unimpressive and would benefit from more antitumor experiments. The work will be of broad interest to bioengineers and medical biologists focusing on cancer vaccines.

eLife assessment

This manuscript describes a valuable study aimed at identifying the substrate specificity of two cell wall hydrolases LSS and LytM in S. aureus. The authors show that LytM has a novel function of cleaving D-Ala-Gly instead of only Gly-Gly by using synthetic substrates and compelling NMR-based real-time kinetics measurements.

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, as the authors acknowledge, further control of the acoustic signals and infants' language environment is necessary for the results to be used in clinical applications. The work contributes to the field of neurodevelopment.

eLife assessment

This work revealed numerous distinct lineages that evolved within a local human population in Alberta, Canada, leading to persistent cases of E. coli O157:H7 infections for over a decade and highlighting the ongoing involvement of local cattle in disease transmission, as well as the possibility of intermediate hosts and environmental reservoirs. This is a useful study that also showed a shift towards more virulent stx2a-only strains becoming predominant in the local lineages. The paper's evidence supporting the role played by cattle in the transmission system of E. coli O157:H7 in Alberta is currently incomplete, based on potential sampling issues associated with the selection of isolates as raised by the reviewers.

eLife assessment

This important study shows that Type 3 secretion translocons in E. 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, and comparing other translocons and additional cellular assays will provide further strength. This paper is broadly relevant to those investigating host-pathogen interactions in diverse organisms.

eLife assessment

This valuable study presents interesting results aimed at explaining the effects of a human mutation on the mitochondrial import protein TIMM50 on mitochondrial function and neuronal excitability. While the evidence supporting the conclusions is solid, the interpretation of some of the results requires revision and moderation. This paper will be of interest to scientists in the mitochondria field.

eLife assessment

Periods in which experience regulates early plasticity in sensory circuits are well established, but the mechanisms that control these critical periods are poorly understood. In this important study, the authors examine early-life critical periods that regulate the Drosophila antennal lobe and show that constant odor exposure markedly reduces the volume, synapse number, and function of a specific glomerulus. The authors offer mostly compelling evidence, that these changes are mediated by the invasion of ensheathing glia into the glomerulus where they phagocytose connections via a mechanism involving the engulfment receptor Draper.

eLife assessment

This study offers a useful discussion of the well-accepted abundance-occupancy relationship in macroecology. While using the ebird large dataset to revisit the theme is interesting, multiple unresolved confounding factors exist, leaving the results inadequate to overturn the repeatedly confirmed abundancy-occupancy relationship.

eLife assessment

This study presents valuable experimental and numerical results on the motility of a magnetotactic bacterium living in sedimentary environments, particularly in environments of varying magnetic field strengths. The evidence supporting the claims of the authors is solid, although the statistical significance comparing experiments with the numerical work is weak. The study will be of interest to biophysicists interested in bacterial motility.

eLife assessment

This important study integrates microfluidic experiments and mathematical modeling to investigate how flow dynamics and biofilm growth and detachment influence each other. Using Pseudomonas aeruginosa as a model organism, the study identifies several key effects and stages in biofilm development, albeit with some weaknesses in clearly defining the setup and some of their interpretations. The comparison between experimental results and theoretical models is convincing, providing a robust analysis of the biofilm's behavior under varying flow conditions. The findings will be helpful for researchers working on biofilms and their applications.

eLife assessment

This important study explores how cells maintain subcellular structures in the face of constant protein turnover, focusing on neurons, whose synapses must be kept stable over long periods of time for memory storage. Using proteins from knock-in mice expressing tagged variants of the synaptic scaffold protein PSD95, nanobodies, and multiple imaging methods, there is compelling evidence that PSD95 proteins form complexes at synapses in which single protein copies are sequentially replaced over time. This happens at different rates in different synapse types and is slowest in areas where PSD95 lifetime is the longest and long-term memories are stored. While of general relevance to cell biology, these findings are of particular interest to neuroscientists because they support the hypothesis put forward by Francis Crick that stable synapses, and hence stable long-term memories, can be maintained in the face of short protein lifetimes by sequential replacement of individual subunits in synaptic protein complexes.

eLife assessment

This important study reports that a transcription factor stimulating mRNA synthesis can stabilize its target transcripts. The convincing results demonstrate, with multiple independent approaches, co-transcriptional binding, stabilization of a family of mRNAs, and cytoplasmic activities of the transcription factor Sfp1. The results lead to the conclusion that the co-transcriptional association of Sfp1 with specific transcripts is a critical step in the stabilization of such transcripts in the cytoplasm.

eLife assessment

The manuscript presents a potentially important strategy to stimulate mammalian Müller glia to proliferate in vivo by manipulating cell cycle components. The findings are likely to appeal to retinal specialists and neuroscientists in general. However, the evidence that these cells become neurogenic is lacking/incomplete, suggesting that additional barriers exist to stimulate the regeneration of retinal neurons.

eLife assessment

The authors provide solid evidence that any contribution of oligodendrocyte precursors to the developing cortex from the lateral ganglionic eminence is minimal in scope. The methods used support the conclusions, with some technical concerns that the authors can address with further experimentation. These are considered valuable additions to our understanding of the origins of oligodendrocytes in the forebrain during development.

eLife assessment

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

eLife assessment

Goswami and colleagues used rod-specific Gls1 (the gene encoding glutaminase 1) knockout mice to investigate the role of GLS1 in photoreceptor health when GLS1 was deleted from developing or adult photoreceptor cells. This study is important as it shows the critical role of glutamine catabolism in photoreceptor cell health using in vivo model systems. The evidence supporting the authors' claims is convincing. The current manuscript would further benefit from validating the evidence with additional supporting data from IND-cKO with tamoxifen induction at adult age, testing GLS1 activity to provide glutamate for synaptic transmission, and examining metabolic crosstalk between RPE and neural retinas.

eLife assessment

This study is a potentially important contribution to the field of protein biosynthesis pathways and their link to aging, especially regarding the thorough analysis of variation in measures expected to correlate with elongation rate in old and new daughter cells derived from old and new mother cells. However, the imaging results, analysis, and methodologies are incomplete, as in its current form several key questions remain unanswered.

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 study provides valuable new insights into insect cognition and problem-solving in bumblebees. The authors present convincing evidence that bumblebees lack causal understanding in a string-pulling task, and find support for bumblebees instead using image-matching for this task.

eLife assessment

This study reports important results and new insights into humoral immune responses to Plasmodium falciparum sexual stage proteins. The experiments are based on the use of target-agnostic memory B cell sorting and screening approaches as well as several state-of-the-art technologies. The authors present compelling evidence that one antibody, B1E11K, is cross-reactive with multiple proteins containing glutamate-rich repeats through homotypic interactions, a process similar to what has been observed for Plasmodium circumsporozoite protein repeat-directed antibodies.

eLife assessment

The ThermoMaze represents a valuable tool to control the rest/exploration states of an animal. The data, collected and analyzed using solid and validated methodology, demonstrate its use in addressing previously elusive questions. This will facilitate future work with more in-depth analysis of place cell activity to further support for some of the claims.

eLife assessment

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

eLife assessment

This study uses a deep neural network approach to challenge the role of spatially selective neurons like place, head or border cells for position decoding. The findings are important as they suggest that such functional cell types may emerge naturally from object recognition in complex visual environments, but are neither necessary, nor particularly critical for position decoding. However, direct evidence supporting this conclusion remains incomplete.

eLife assessment

This important study examined the complexity of emergent dynamics of large-scale neural network models after perturbation (perturbational complexity index, PCI) and used it as a measurement of consciousness to account for previous recordings of humans at various anesthetized levels. The evidence supporting the conclusion is solid and constitutes a unified framework for different observations related to consciousness. There are many fields that would be interested in this study, including cognitive neuroscience, psychology, complex systems, neural networks, and neural dynamics.

eLife assessment

This is a conceptually appealing study in which the authors identify genes whose function is important for the development of inhibitory (GABA) neurons, and then demonstrate that a diet rich in ketone body β-hydroxybutyrate partially suppresses specific mutant phenotypes. The authors provide compelling evidence that features methods, data and analyses more rigorous than the current state-of-the-art. Conceptually, this is evidence of a rescue of a developmental defect with dietary metabolic intervention, linking, in an elegant way, the underpinning genetic mechanisms with novel metabolic pathways that could be used to circumvent the defects.

eLife assessment

The authors are interested in the developmental origin of the neurons of the cerebellar nuclei. In this valuable study, they 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 neurons is an exciting finding, and it enriches our understanding of cerebellar development. The claims are reasonably well supported by the solid evidence because the authors use a wide range of technical approaches, including transgenic mice that allow them to disentangle the influence of distinct developmental organisers.

eLife assessment

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

eLife assessment

The ExA-SPIM methodology developed will be important to the field of light sheet microscopy as the new technology provides an impressive field of view making it possible to image the entire expanded mouse brain at cellular and subcellular resolution. The authors provide solid evidence that mostly supports the conclusions.

eLife assessment

The paper investigates a potential cause of a type of severe epilepsy that develops in early life because of a defect in a gene called KCNQ2. The significance is fundamental because it substantially advances our understanding of a major research question. The strength of the evidence is convincing because appropriate methods are used that are in line with the state-of-the art.

eLife assessment

This study attempts to solve long-standing puzzles about inversion polymorphisms in Drosophila melanogaster by invoking sexually antagonism and negative frequency dependent selection. While the idea developed here is a valuable contribution to the field, the description of the empirical work and the simulations remain incomplete, as they do not provide a full picture of what exactly has been done.

eLife assessment

This important study reveals that the malaria parasite protein PfHO, though lacking typical heme oxygenase activity, is vital for the survival of Plasmodium falciparum. Structural and localization analyses showed that PfHO is essential for apicoplast maintenance, particularly in gene expression and biogenesis, indicating a novel adaptive role for this protein in parasite biology. While the results supporting the claims of the authors are convincing, the lack of data defining a molecular understanding or mechanism of action of the protein in question limits the impact of the study.

eLife assessment

This study investigates the conditions under which abstract knowledge transfers to new learning. It presents evidence across a number of behavioral experiments that when explicit awareness of learned statistical structure is present, knowledge can transfer immediately, but that otherwise similar transfer requires sleep-dependent consolidation. The valuable results provide new constraints on theories of transfer learning and consolidation, though limitations in the statistical approach and interpretation make the current evidence incomplete.

eLife assessment

This study presents valuable findings on the role of a well-studied signal transduction pathway, the Slit/Robo system, in the context of the assembly of the hematopoietic niche in the Drosophila embryo. The evidence supporting the claims of the authors is solid. However, one aspect that needs attention is whether the cells are migrating and not being pushed to a more dorsal position through dorsal closure and/or other similar large-scale embryo movement. This does not detract from the very interesting analysis of PSC morphogenesis and will interest developmental biologists working on molecular mechanisms of tissue morphogenesis.

eLife assessment

To elucidate the precise function of variants in the UTRs, the authors established and conducted a massively parallel poly(ribo)some profiling method to compare ribosome associations and effects of genetic variants. The approach and results are valuable, as this is a new approach to studying UTRs. However, the experimental and analytic validation seems to be incomplete, as the results are less robust than expected.

eLife assessment

This important study further validates DNAH12 as a causative gene for asthenoteratozoospermia and male infertility in humans and mice. The data supporting the notion that DNAH12 is required for proper axonemal development are generally convincing, although more experiments would solidify the conclusions. This work will interest reproductive biologists working on spermatogenesis and sperm biology, as well as andrologists working on male fertility.

eLife assessment

The authors developed a method to allow a hypothermic agent, neurotensin, to cross the blood-brain barrier so it could potentially protect the brain from seizures and the adverse effects of seizures. The work is important because it is known that cooling the brain can protect it but developing a therapeutic approach based on that knowledge has not been done. The paper is well presented and the data are convincing. Revisions to clarify some of the methods and results, and to address effects on chronic seizures and tolerability would improve the paper.

eLife assessment

The authors develop a self-returning self-avoiding polymer model of chromosome organization and show that their framework can recapitulate at the same time local density and large-scale contact structural properties observed experimentally by various technologies. The presented theoretical framework and the results are valuable for the community of modelers working on 3D genomics. The work provides solid evidence that such a framework can be used, is reliable in describing chromatin organization at multiple scales, and could represent an interesting alternative to standard molecular dynamics simulations of chromatin polymer models.

eLife assessment

This valuable study presents a computational model that simulates walking motions in Drosophila and suggests that, if sensorimotor delays in the neural circuitry were any longer, the system would be easily destabilized by external perturbations. The hierarchical control model is sensible and the evidence supporting the conclusions is solid. However, because the modular model has many interacting components with varying degrees of biological realism, it is difficult to judge the degree to which the observed differences between simulation and empirical data are meaningful, and the precise source of the discrepancies.

eLife assessment

This study presents a useful finding for the prevention of diarrhea with loperamide in patients with early HER2-positive breast cancer treated with nab-paclitaxel in combination with pyrotinib. The evidence supporting the claims of the authors is somewhat incomplete. The enrollment of patients as a control group who have not received prophylactic treatment for diarrhea would have strengthened the study, and the addition of double-blinding for the assessment of treatment may be necessary. The work will be of interest to scientists working in the field of clinical breast cancer treatment.

eLife assessment

This valuable study uses in vitro and in vivo methods to identify HpARI proteins from H. polygyrus as modulators of the host immune system. Based on comprehensive approaches for investigating differential roles of HpARI proteins, the data are solid, but there are some concerns whether the claims are fully validate. This paper is relevant to those who investigate host-pathogen interactions at the systems and molecular levels.

eLife assessment

This important work describes the activation of astrocytes via the nuclear translocation of PKM2 in an animal model of multiple sclerosis. This study provides convincing evidence of the interaction between TRIM21 and PKM2 as the crucial molecular event leading to the translocation of PKM2 and a metabolic shift towards glycolysis dominance, fostering proliferation in stimulated astrocytes. This finding is significant as it underscores the potential of targeting glycolytic metabolism to mitigate neurological diseases mediated by astrocytes, offering a strong rationale for potential therapeutic interventions.

eLife assessment

Unlocking the potential of molecular genetic tools (optogenetics, chemogenetics, sensors, etc.) for the study of systems neuroscience in nonhuman primates requires the development of effective regulatory elements for cell-type specific expression to facilitate circuit dissection. This study provides a valuable building block, by carefully characterizing the laminar expression profile of two optogenetic enhancers, one designed for general GABA+ergic neurons (h56D) and the second (S5E2) for parvalbumin+ cell-type selective expression in the marmoset primary visual cortex. This study contributes solid evidence to our understanding of these tools but is limited by the understandably small number of animals used.

eLife assessment

This important study describes the discovery and further engineering of a red light-activated, chloride-conducting Channelrhodopsin (ACR) that could be used to inhibit neuronal activity. The evidence for the spectral confirmation and biophysical characterization of MsACR and raACR, and ion selectivity are solid; however, the evidence supporting the use of the tools in vivo is incomplete and missing proper controls. In addition, benchmarking against other inhibitory tools is somewhat missing. With the in vivo part strengthened, this paper would interest neuroscientists seeking more efficient ways to inhibit neuronal activity.

eLife assessment

This important study offers convincing evidence that fmo-4 plays essential roles in established lifespan interventions and downstream of its paralog fmo-2, a beneficial advancement in our understanding of this enzyme family that underscores their importance in longevity and stress resistance. The study also suggests a connection between fmo-4 and dysregulation of calcium signalling. The authors' conclusions and interpretations were generally based on solid genetic methodology and evidence.

eLife assessment

The study by Kleinman and Foster identifies a role for VTA dopamine signaling in modulating hippocampal replay and sharp-wave ripples, specifically highlighting how VTA inactivation leads to aberrant replay activities in scenarios without reward changes and during exposure to novel environments. This valuable work contributes to our understanding of the neurobiological mechanisms underlying spatial memory and learning, suggesting that dopamine plays a pivotal role in linking reward context and novelty to memory consolidation processes. However, the evidence as currently presented is incomplete. More rigorous statistical reporting and histological verification of the experimental approach, and a more consistent approach to experimental dosing and timing, which are crucial for confirming the reproducibility and reliability of the observed effects, are needed.

eLife assessment

This useful study reports a reanalysis of one experiment of a previously published report to characterize the dynamics of neural population codes during visual working memory in the presence of distracting information. The evidence supporting the claims of dynamic codes is incomplete, as only a subset of the original data is analyzed, there is only modest evidence for dynamic coding in the results, and the result might be affected by the signal-to-noise ratio. This research will be of interest to cognitive neuroscientists working on the neural bases of visual perception and memory.

eLife assessment

This study provides an in-depth exploration of the impact of X-linked ZDHHC9 gene mutations on cognitive deficits and epilepsy, with a particular focus on the expression and function of ZDHHC9 in myelin-forming oligodendrocytes (OLs). These valuable findings offer insights into ZDHHC9-related X-linked intellectual disability (XLID) and shed light on the regulatory mechanisms of palmitoylation in myelination. The experimental design and analysis of results are solid, providing a reference for further research in this field.

eLife assessment

This valuable study investigates the development of high-level visual responses in infants, finding that neural responses specific to faces are present by 4-6 months, and those to other object categories later. The study is methodologically solid, using state-of-the-art experimental design and analysis approaches. The findings should be of interest to researchers in the fields of cognitive psychology and neuroscience.

eLife assessment

This study presents important findings indicating that tinnitus patients have abnormal auditory prediction signals. The results are based on well-controlled experiments for a large cohort of patients. The reported observations constitute a new set of convincing evidence for the strong link between tinnitus and central auditory processing disorders and will be of interest to clinicians, auditory scientists, and neuroscientists studying prediction mechanisms.

eLife assessment

This study presents fundamental new findings introducing a new approach for the reprogramming of brain glial cells to corticospinal neurons. The data is highly compelling, with multiple lines of evidence demonstrating the success of this new assay. These exciting findings set the stage for future studies of the potential of these reprogrammed cells to form functional connections in vivo and their utility in clinical conditions where corticospinal neurons are compromised.

eLife assessment

This important study using engineered mouse models provides a first and compelling demonstration of a pathogenic phenotype associated with lack of expression of p53AS, an isoform of the p53 protein with a different C-terminus than canonical p53. The role of this isoform has been elusive so far and this first demonstration represents a substantial advance in our understanding of the complex role(s) of p53 isoforms. The revised manuscript adequately addresses previous concerns.

eLife assessment

This study presents a dataset obtained through a single cell RNA-Sequencing of sea cucumber regenerating intestine 9 days post evisceration. The data were collected and analyzed using standard single cells analysis from n=2 adult sea cucumbers captured from the wild, which represents a useful resource for future studies. Although cell type validation is attempted, it is performed on samples from the same 2 animals (and not independent samples), rendering the validation incomplete. Further, the RNA localization images provided in the paper could benefit from improved spatial context, and many strong statements in the discussion should be better justified and supported by the presented data. With the validation part strengthened, this paper would be of interest to development and regeneration fields.

eLife assessment

Transient receptor potential mucolipin 1 (TRPML1) functions as a lysosomal ion channel whose variants are associated with lysosomal storage disorder mucolipidosis type IV. This important report describes local and global structural changes driven by the binding of regulatory phospholipids and by mutations allosteric that allosterically cause gain or loss of channel function. Most of the claims related to the allosteric regulation of TRPML1 have solid support by two new cryo-EM structures, that of the gain of function Y404W mutant and that of the wild-type channel bound to the inhibitor PI(4,5)P2. The new cryo-EM findings are evaluated within the context of previously reported TRPML1 structures, and a proposed allosteric gating mechanism is partially supported by functional electrophysiology results.

eLife assessment

The study addresses a central question in systems neuroscience (validation of active inference models of exploration) using a combination of behavior, neuroimaging, and modelling. The data provided are useful but incomplete due to issues with multiple comparisons and lack of model validation.

eLife assessment

The study presents a valuable finding that the Endothelin B receptor (ETBR) expressed by the satellite glial cells (SGCs) in the dorsal root ganglions (DRG) inhibited sensory axon regeneration in both adult and aged mice. The evidence supporting most of the conclusions was solid, and the work will be of interest to neuroscientists working on axon regeneration and the involvement of non-neuronal cell types in regulating axon regeneration. Although the proposed mechanism is intriguing and the methodology is robust, the molecular mechanisms by which ETBR regulates axon regeneration are not fully elucidated.

eLife assessment

This is a very interesting study that links inflammatory reactivity and T-cell immunity in pathologies associated with pneumonia in the context of the aging process (telomerase functionality). The authors have relied on results from experiments using a mouse model (Terc-deletion), that is used in studies on aging. The questions are relevant, the methodology is appropriate, and the results represent a set of useful findings. However, on the whole, the evidence is not very strong owing to the low power of the study, some flaws in experimental design, lack of rigorous controls, and inadequate approaches to analyzing immune function, thus making the study incomplete in support of its claims.

eLife assessment

This valuable report describes the control of the activity of the RNA-activated protein kinase, PKR, by the Vaccinia virus K3 protein. A strength of the manuscript is the powerful combination of a yeast-based assay with high-throughput sequencing and its convincing experimental use to characterize large numbers of PKR variants. A minor weakness is that the scope of the screen conducted could still be extended, for example in terms of the segments of PKR included.

eLife Assessment:

This fundamental study substantially advances our understanding of the role of different-sized soil invertebrates in shaping the rates of leaf litter decomposition, using an experiment across seasons along an aridity gradient. The authors provide compelling evidence that the summed effects of all invertebrates (with large-sized invertebrates being more active in summer and small-sized invertebrates in winter) on decomposition rates result in similar levels of leaf litter decomposition across seasons. The work will be of broad relevance to ecosystem ecologists interested in soil food webs, and researchers interested in modeling carbon cycles to understand global warming.

eLife assessment

This valuable study identifies biallelic variants of DNAH3 in unrelated infertile men and reports infertility in DNAH3 knockout mice. The authors demonstrate that compromised DNAH3 activity decreases the expression of IDA-associated proteins in the spermatozoa of human patients and knockout mice, providing convincing evidence that DNAH3 is a novel pathogenic gene for asthenoteratozoospermia and male infertility. The study will be of substantial interest to clinicians, reproductive counselors, embryologists, and basic researchers working on infertility and assisted reproductive technology.

eLife assessment

This important study provides convincing evidence that both psychiatric dimensions (e.g. anhedonia, apathy, or depression) and chronotype (i.e., being a morning or evening person) influence effort-based decision-making. This is of importance to researchers and clinicians alike, who may make inferences about behaviour and cognition without taking into account whether the individual may be tested or observed out-of-sync with their phenotype. The current study can serve as a starting point for more targeted investigation of the relationship between chronotype, altered decision making and psychiatric illness.

eLife assessment

This study describes fundamental 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 compelling 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 study presents valuable 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. The experiments are well-designed with appropriate controls, and the study provides solid evidence for the new form of cerebellar synaptic plasticity.

eLife assessment

This study presents important findings on the differential activity of noradrenergic and dopaminergic input to dorsal hippocampus CA1 in head-fixed mice traversing a runway in a virtual environment that is familiar or novel. The data are rigorously analysed, and the observed divergence in the dynamics of activity in the dopaminergic and noradrenergic axons is solid. Future studies, using specific manipulations of the two distinct midbrain inputs combined with behavioral testing, are required to strengthen the claim that distinct signals to the hippocampus cause distinct behavioral effects.

eLife assessment

The authors present 16 new well-preserved specimens from the early Cambrian Chengjiang biota. These specimens potentially represent a new taxon which could be useful in sorting out the problematic topology of artiopodan arthropods - a topic of interest to specialists in Cambrian arthropods. The authors provide solid anatomical and phylogenetic evidence in support of a new interpretation of the homology of dorsal sutures in trilobites and their relatives.

eLife assessment

This study provides valuable new insights into how multisensory information is processed in the lateral cortex of the inferior colliculus, a poorly understood part of the auditory midbrain. By developing new imaging techniques that provide the first optical access to the lateral cortex in a living animal, the authors provide convincing in vivo evidence that this region contains separate subregions that can be distinguished by their sensory inputs and neurochemical profiles, as suggested by previous anatomical and in vitro studies. This work provides a foundation for future research exploring how this part of the auditory midbrain contributes to multisensory-based behavior.

eLife assessment

The work by Han and collaborators describes valuable findings on the role of Akkermansia muciniphila during ETEC infection. If confirmed, these findings will add to a growing list of beneficial properties of this organism. Although the strength of the evidence used to justify the conclusions in the manuscript is solid, the issues raised about the sequencing method used should be addressed.

eLife assessment

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

eLife assessment

This study presents valuable findings on the relationship between prediction errors and brain activation in response to unexpected omissions of painful electric shocks. The strengths are the research question posed, as it has remained unresolved if prediction errors in the context of biologically aversive outcomes resemble reward-based prediction errors. The evidence is solid but there are weaknesses in the experimental design, where verbal instructions do not align with experienced outcome probabilities. It is further unclear how to interpret neural prediction error signaling in the assumed absence of learning. The work will be of interest to cognitive neuroscientists and psychologists studying appetitive and aversive learning.

eLife assessment

This useful study describes the second earliest known winged ovule without a capule in the Famennian of Late Devonian. Using solid mathematical analysis, the authors demonstrate that three-winged seeds are more adapted to wind dispersal than one-, two- and four-winged seeds. The manuscript will help the scientific community to understand the origin and early evolutionary history of wind dispersal strategy of early land plants.

eLife assessment

This valuable study provides in vivo evidence for the synchronization of projection neurons in the olfactory bulb at gamma frequency in an activity-dependent manner. This study uses optogenetics in combination with single-cell recordings to selectively activate sensory input channels within the olfactory bulb. The data are thoughtfully analyzed and presented; the evidence is solid, although some of the conclusions are only partially supported.

eLife assessment

To test if somatic mutations in cancer genomes are enriched with mutations in polyadenylation signal regions, the authors observed an increased enrichment of somatic mutations that may affect the function of polyA signals and confirmed that these mutations may influence gene expression through a minigene expression experiment. This important study advances our understanding of noncoding somatic mutations by identifying a novel class of mutations that affect 3'UTR polyadenylation signals enriched in tumor suppressor genes in cancer. The evidence supporting the conclusions is convincing, with rigorous statistical analyses and experimental validation.

eLife assessment

The manuscript reports fundamental findings that extra-embryonic visceral yolk sac endoderm is critical for NAD de novo synthesis during early organogenesis, and perturbations of this pathway may cause Congenital NAD Deficiency Disorder. The supporting evidence is solid. This work will be of interest to developmental biologists.

eLife assessment

The authors have developed a biosensor for programmed cell-death. They use this biosensor to provide valuable measurements of cell death in a specific early time window of development. However, the title and the discussion suggest a broader window of applicability of the results. The evidence supporting the claims is therefore incomplete. The authors should modify the introduction and discussion to examine their work in the context of extant literature and modify their title to reflect the conclusion that "Zebrafish live imaging reveals around 2%of motor neurons die through apoptosis during a 24-120 hour window in early development".

eLife assessment

This study evaluated the role of transcutaneous auricular vagal nerve stimulation (taVNS) in patients with subarachnoid hemorrhage (SAH) randomized to taVNS vs sham, finding that those with active taVNS exhibited increased parasympathetic activity. The findings are important and cross-disciplinary, while the level of evidence is solid.

eLife assessment

This valuable study investigates the role of Drp1 in early embryo development, providing solid evidence on how this protein influences mitochondrial localization and partitioning during the first embryonic divisions. The research employs the Trim-Away technique to eliminate Drp1 in zygotes, revealing critical insights into mitochondrial clustering, spindle formation, and embryonic development.

eLife assessment

This important paper implicates S-acylation of Cys-130 in recruitment of the inflammasome receptor NLRP3 to the Golgi, and it provides convincing evidence that S-acylation plays a key role in response to the stress induced by nigericin treatment. While Cys-130 does seem to play a previously unappreciated role in membrane association of NLRP3, further work will be needed to clarify the details of the mechanism.

eLife assessment

This manuscript presents important observations on the early changes that occur in calcium signaling, TMEM16a channel activation, and mitochondrial dysfunction in salivary gland cells in a murine model of autoimmune Sjögren's disease. The study reports that in response to DMXAA treatment which induces a murine model of Sjögren's disease, salivary gland cells show significant changes in saliva release, calcium signaling, TMEM16a activation, mitochondrial function, and sub-cellular morphology of the endoplasmic reticulum. The work is compelling and will be of strong interest to physiologists working on secretion, calcium signaling, and mitochondria.

eLife assessment

This manuscript provides an important advance in our understanding of the molecular events that promote osteoclast fusion. Compelling data support the conclusion that an oxidized form of the ubiquitous protein La promotes osteoclast fusion following enrichment at the cell surface of osteoclast progenitors. These data improve our understanding of the processes that regulate bone resorption and will be of broad interest to researchers in the fields of cell biology and musculoskeletal physiology.

eLife assessment

This study presents important findings linking circHMGCS1 and miR-4521 in diabetes-induced vascular endothelial dysfunction. Overall, the evidence supporting the claims of the authors is convincing. The work will be of interest to biomedical scientists working with cardiovascular and/or RNA biology, particularly those studying diabetes.

eLife assessment

This study investigates the mechanistic connection between glycosylation at the N162 site of the Fc gamma receptor FcγRIIIa and the regulation of NK cell-mediated antibody-dependent cytotoxicity. The compelling findings, derived from novel isotope labeling approaches and state-of-the-art NMR spectroscopy techniques, underscore the impact of glycan composition on receptor stability and immune function. This research offers fundamental insights that could aid in the development of more effective therapeutic antibodies. The manuscript will be of interest to researchers in the fields of immunology and therapeutic antibody development.

eLife assessment

This study provides useful evidence substantiating a role for long noncoding RNAs in liver metabolism and organismal physiology. Using murine knockout and knock-in models, the authors invoke a previously unidentified role for the lncRNA Snhg3 in fatty liver. The revised manuscript has improved and most studies are backed by solid evidence and will be of interest to the field of metabolism.

eLife assessment

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

eLife assessment

This paper makes fundamental contributions to understanding the mechanisms by which the conserved guidance cue UNC-6/Netrin controls the long-range growth and targeting of axons. Using state-of-the-art genetics and in vivo imaging, the authors provide solid support for the finding that UNC-6/Netrin can act via both chemotaxis and haptotaxis, though additional studies would be necessary to make these findings stronger. The paper's insights will be of interest to a variety of cell and developmental biologists and neuroscientists.

eLife assessment

This is a valuable study in the Jurkat T cell line that calls attention to phosphorylation of formin-like 1 β role and its role in polarization of CD63 positive extracellular vesicles (referred to as exosomes). The evidence presented in the Jurkat model is solid, but concerns have been raised about the statistical analysis and more details would be required to fully assess the significance of the results. For example, ANOVA is the method described, but it requires large amounts of normally distributed data in multiple groups and cannot be used to make pairwise comparisons within groups, which would require a post-hoc method (which is not discussed). In addition, the data showing forming-like 1 β in primary human T cells without and with a CAR are provided without quantification and don't investigate any of the novel claims, so doesn't address the relevance of Formin-like 1 β beyond the Jurkat model. Nonetheless, the consistent trends in the body of the study do provide reliable support for the claims.

eLife assessment

The intrinsic chirality of actin filaments (F-actin) is implicated in the chiral arrangement and movement of cellular structures, but it was unknown how opposite chiralities can arise when the chirality of F-actin is invariant. Kwong et al. present evidence that two actin filament-based cytoskeletal structures, transverse actin arcs and radial stress fibers, drive clockwise and anti-clockwise rotation, respectively. This fundamental work, which has broad implications for cell biology, is supported by compelling data.

eLife assessment

This important study presents work on the molecular mechanism driving asymmetric cell division and fate decisions during embryonic development of echinoids. The evidence supporting the claims of the authors is solid overall but with some concerns about quantification and a lack of explanation for some of the findings. The work will be of interest to developmental biologists and cell biologists working in the field of self-renewal.

eLife assessment

This manuscript describes the characterization of the conformational dynamics of two chemokine receptors at the single-molecule level using FRET. The authors make a convincing case for attributing the distinct interaction and pharmacology of the two receptors to differences in their conformational energy landscape. These important findings will be of interest to scientists working on activation mechanisms of GPCRs and signal transduction.

eLife assessment

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

eLife assessment

This manuscript reports a detailed model of juvenile rat somatosensory cortex, consisting of 4.2 million morphologically and biophysically detailed neuron models, arranged in space and connected according to diverse experimental data - a valuable tool for the field. The construction of the model is based on a solid methodology, but the supporting evidence is incomplete, as it is currently not emulating known local connection probabilities and variations in cortical thickness. It should be noted that, by necessity, such a large-scale model development involves many assumptions, interpolations, and decisions that could have compounding downstream effects on further analyses that may be difficult to disambiguate.

eLife assessment

This important study substantially advances our understanding of energy landscapes and their link to animal ontogeny. The evidence supporting the conclusions is compelling, with high-throughput telemetry data and advanced track segmentation methods used to develop and map energy landscapes. The work will be of broad interest to animal ecologists.

eLife assessment

This manuscript describes a novel computational method to investigate cell evolutionary trajectory for scRNA-seq samples. This is an important tool for estimating pseudotime in the evolutionary path through modelling the bifurcations in a Gaussian process. While the evaluation of the method is extensive and compelling, the reviewers suggested further analyses to ensure that the method is indeed robust. When these issues are addressed, this will be of substantive value to biologists interested in scRNA-seq bioinformatic methods.

eLife assessment

This important study reports numerous attempts to replicate reports on transgenerational inheritance of a learned behavior, pathogen avoidance, in C. elegans. While the authors observe parental effects that are limited to a single generation (also called intergenerational inheritance), the authors failed to find any evidence for transmission over multiple generations, or transgenerational inheritance. The experiments presented are meticulously described, making for compelling evidence that in the authors' hands transgenerational inheritance cannot be observed, although there remains the possibility that subtle differences in culture conditions or lab environment explain the failure to reproduce previous observations. Given the prominence of the original reports of transgenerational inheritance, the present study is of broad interest to anyone studying genetics, epigenetics, or learned behavior.

eLife assessment

The authors proposed a novel deep learning framework to estimate posterior distributions of tissue microstructure parameters. This provides a valuable methodology with practical implications for automatically estimating parameter distributions from different biophysical models. The experiments show solid evidence for generalizing the method to use data from different protocol acquisitions and work with models of varying complexity.

eLife assessment

This study shows that Znhit1, a regulator of chromatin and of the histone variant H2A.Z, is required for progression through meiotic prophase. It is an important observation that describes the role of epigenetics and gene expression during meiosis. The analysis is based on complementary approaches at the cytological, single-cell, and genomic levels that provide solid evidence for the role of Znhit1 in the control of gene expression and in the loading of H2A.Z in mouse spermatocytes.

eLife assessment

This work describes a convincingly validated non-invasive tool for in vivo metabolic phenotyping of aggressive brain tumors in mice brains. The analysis provides a valuable technique that tackles the unmet need for patient stratification and hence for early assessment of therapeutic efficacy. However, wider clinical applicability of the findings can be attained by expanding the work to include more diverse tumor models.