eLife Assessment

This fundamental work by Mäkelä et al. presents compelling experimental evidence supported by a theoretical model that the amount of chromosomal DNA can become limiting for the total rate of mRNA transcription and consequently protein production in the model bacterium Escherichia coli. The work is based on a mutant that allows inhibition of DNA replication while following growth at the single-cell level due to cell filamentation. The work significantly advances our understanding of growth and of the central dogma, and will be of considerable interest within both systems biology and microbial physiology.

eLife Assessment

This fundamental study generated a single cell atlas of mouse periosteal cells under both steady-state and fracture healing conditions to address the knowledge gap regarding cellular composition of the periosteum and their responses to injury. Based on convincing transcriptome analyses and experimental validation, the authors identified the injury induced fibrogenic cell (IIFC) as a characteristic cell type appearing in the bone regeneration process and proposed that the IIFC is a progenitor undergoing osteochondrogenic differentiation. This study will provide a significant publicly accessible dataset to reexamine the expression of the reported periosteal stem and progenitor cell markers.

eLife Assessment

This manuscript describes an important study of a new lipid-mediated regulation mechanism of adenylyl cyclases. The biochemical evidence provided is convincing and will trigger more research in this mechanism. This manuscript will be of interest to all scientists working on lipid regulation and adenylyl cyclases.

eLife Assessment

The neurotrophic factor Neuritin can moderate T-cell tolerance and immunity through both regulatory T (Treg) and effector T cells, promoting Treg cell expansion and suppression while dampening effector T cells to mediate the inflammatory response. Neuritin expression influences the membrane potential, ion channels, and nutrient transporter expression patterns of CD4+ T cells, contributing to differential metabolic states in Treg and effector T cells. These findings are solid and important for understanding immune regulation involving Treg cells and effector T cells.

eLife Assessment

This important work presents data showing that all non-proneural phenotypes of the Inhibitor of DNA binding (Id) protein Emc are mediated through inappropriate nonapoptotic caspase activity. Using the developing Drosophila retina as a model the authors show that Emc acts by transcriptionally regulating the Death-Associated Inhibitor of Apoptosis 1 (diap1) gene, which impacts on Notch signaling by caspase-dependent increase of Delta protein. These are compelling findings, interesting for the caspase/apoptosis field as they add more non-apoptotic functions of caspases to the list, as well as for the Id field, which examines how Id proteins inhibit cell differentiation.

eLife Assessment

This important study, which will be of interest to those studying the evolution and maintenance of antibiotic resistance, addresses the hypothesis that antibiotic resistance arising de novo during treatment will carry a higher fitness cost and will revert to susceptibility more readily than resistance that has been transmitted between hosts. There are, however, concerns that the 'putatively transmitted isolates' in this study do not necessarily represent resistant isolates that have been transmitted between hosts. The support for the central claim of different patterns of reversion between isolates with de novo resistance and putatively transmitted resistant isolates is currently incomplete.

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 and further links to how the results align with the underlying biology could have further strengthened the study. 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

So et al. present an optimized protocol for single-nuclei RNA sequencing of adipose tissue in mice, ensuring better RNA quality and nuclei integrity. The authors use this protocol to explore the cellular landscape in both lean and diet-induced obese mice, identifying a dysfunctional hypertrophic adipocyte subpopulation linked to obesity. The data analyses are solid, and the findings are supported by the evidence presented. This study provides valuable information for the field of adipose tissue biology and will be particularly helpful for researchers using single-nuclei transcriptomics in various tissues.

eLife Assessment

The specific questions taken up for study by the authors-in mice of HDAC and Polycomb function in the context of vascular endothelial cell (EC) gene expression relevant to the blood-brain barrier, (BBB)-are potentially useful in the context of vascular diversification in understanding and remedying situations where BBB function is compromised. The strength of the evidence presented is incomplete, and to elaborate, it is known that the culturing of endothelial cells can have a strong effect on gene expression.

eLife Assessment

This study investigates the role of the Cadherin Flamingo (Fmi) in cell competition in developing tissues in Drosophila melanogaster. The findings are valuable in that they show that Fmi is required in winning cells in several competitive contexts. The evidence supporting the conclusions is solid, as the authors identify Fmi as a potential new regulator of cell competition, however, they don't delve into a mechanistic understanding of how this occurs.

eLife Assessment

The authors have reported an important study in which they use a double-blind design to explore pharmacological manipulations in the context of a behavioral task. While the sample size is small, the use of varied methodology, including electrophysiology, behavior, and pharmacology, makes this manuscript particularly notable. Overall, the findings are solid and motivate future explanations into the relationships between acetylcholine and motivation.

eLife Assessment

The paper reports the important discovery that the mouse dorsal inferior colliculus, an auditory midbrain area, encodes sound location. The evidence supporting the claims is solid, being supported by both optical and electrophysiological recordings. The observations described should be of interest to auditory researchers studying the neural mechanisms of sound localization and the role of noise correlations in population coding.

eLife Assessment

This useful work reveals differential activity to food and shock outcomes in central amygdala GABAergic neurons. Solid evidence supports claims of unconditioned stimulus activity that changes with learning. However, the evidence regarding claims related to valence or salience signaling in these neurons is inadequate. This work will be of interest to neuroscientists studying sensory processing and learning in the amygdala.

eLife Assessment

This important study reveals that Excitatory Amino Acid Transporters play a role in chromatic information processing in the retina. The combination of (double) mutants, behavioral assays, immunohistochemistry, and electroretinograms provides solid evidence supporting the appropriately conservative conclusions. The work will be of interest to neurobiologists working on color vision or retinal processing.

eLife Assessment

This important study explores the neural basis for a well known auditory illusion, often utilized in movie soundtracks, in which a sequence of two complex tones can be perceived as either rising or falling in pitch depending on the context in which they are presented. Convincing single-neuron data and analyses are presented to show that correlates of these pitch-direction changes are found in the ferret primary auditory cortex. While these findings provide an interesting link between cortical activity and perception, the manuscript could be clearer on the wider implications of the failure of traditional decoding models to account for these results.

eLife Assessment

This revised version of the study is important, showing that age-related gut microbiota modulate uric acid metabolism through the NLRP3 inflammasome pathway and thereby regulate susceptibility to age-related gout. Several experimental approaches (mechanistic insights) and methods (data quality) are still incomplete. If strengthened, this paper would be of broad interest to researchers working on gout and the microbiota.

eLife Assessment

This article describes a novel mechanism allows Drosophila to combat enteric pathogens while also preserving the beneficial indigenous microbiota. The authors provide compelling evidence that oral infection of Drosophila larvae by pathogenic bacteria activate a valve that traps the intruders in the anterior midgut, allowing them to be killed by antimicrobial peptides. This is an important finding revealing a new mechanism of host defense in the gut of insects.

eLife Assessment

This useful study presents a novel microscopy technique called "Expansion Tiling Light Sheet Microscopy" and an accompanying computational pipeline for the faster collection and analysis of 3D volumetric images in animals like planarians. This approach produces beautiful 3D microscropy images and is solid on a technical level. However, due to the use of antibody reagents that visualize many – but not all – neurons and muscle subtypes, the evidence for the biological conclusions in this study remains incomplete. With the claims appropriately contextualized, this paper will be of interest to cell biologists working on imaging and analyzing whole animals.

eLife Assessment

This study provides a valuable perspective on visual cortex architecture by identifying two cortical gradients that change across the lifespan and have distinct functional and structural features. The first gradient captures well-mapped variations in cortical thickness and myelination markers from early sensory to higher-order cortex, while the second gradient shows divergence in these measures with a more localized structure, notably predicting a previously unknown cluster of visual field maps in the anterior temporal lobe. The large-scale lifespan data are compelling, but the evidence overall is incomplete with key questions around methodical checks and implementation, the standard of evidence for the new visual maps, and how the gradient model relates to sharp tissue boundaries parcellating the cortex.

eLife Assessment

The authors present three valuable transgenic models carrying three representative exon deletions of the dystrophin gene. The findings are supported by rigorous biochemical assays and state-of-the-art microscopy methods, although the evidence, while overall solid, is only partially developed, and some points could be improved.

eLife Assessment

This study analyzes a cohort of small intestine neuroendocrine tumors, and the description of tumor-intrinsic programs that govern such rare cancers is felt to be valuable. The methods are for the most part felt to be solid, however, some broad concerns were raised that the possible separation of samples by a program may be impacted by fresh versus frozen sequencing. Similarly, the heterogeneity of the SiNET tumor microenvironment is unclear given a mixing of subtypes and the proliferation of NE and immune cells in SiNET could be influenced by technical factors. Recommendations were made to extend these data with other published datasets of SiNET tumors, expanding technical clarity and details, and validating findings using cell lines/PDX if available.

eLife Assessment

The study by Chen and Phillips provides evidence for a dynamic switch in the small RNA repertoire of the Argonaute protein NRDE-3 during embryogenesis in C. elegans. The work is supported by solid experimental data, although some conclusions regarding the functional role of specific RNA granules remain uncertain. Nevertheless, this study offers valuable insights into RNA regulation and developmental biology, with broader implications for understanding small RNA pathways in other systems.

eLife Assessment

This study presents valuable findings on changes in neuronal alpha activity elicited by prolonged pain in healthy human participants. The evidence supporting the claims of the authors, however, is incomplete and would benefit from clarifications of analytical strategies, additional statistical analyses, and shaping of the interpretations. With the methodological and interpretative parts strengthened, the work will be of interest to neuroscientists investigating the brain mechanisms of pain to identify new approaches to pain treatment

eLife Assessment

The study is a valuable addition to the field, showing how particulate matter may be acting via nociceptor neurons towards neutrophilic asthma exacerbations. The solid evidence for the role of a nociceptive pathway in model systems is relevant to human asthma in its current form but would be further strengthened by mechanistic insights. This would be particularly relevant to further translational research towards blocking the exacerbating effect of air pollution on asthma.

eLife Assessment

This important study presents the first identification of the odorant receptor for the trail pheromone in termites. The evidence supporting the conclusions is compelling, with state-of-the-art neurophysiological and genetic methods. The work will be of broad interest in multiple disciplines, such as entomology, chemical ecology, and sensory physiology.

eLife Assessment

This valuable study builds on previous work by the authors by presenting a potentially key method for correcting optical aberrations in GRIN lens-based micro endoscopes used for imaging deep brain regions. By combining simulations and experiments, the authors show that the obtained field of view is significantly increased with corrected, versus uncorrected microendoscopes. The evidence supporting the claims of the authors is solid, although some aspects of the manuscript should be clarified and missing information provided. Because the approach described in this paper does not require any microscope or software modifications, it can be readily adopted by neuroscientists who wish to image neuronal activity deep in the brain.

eLife Assessment

The study provides valuable insight into the biological significance of SARS-CoV-2 by using a series of computational analyses of viral proteins. While evidence is solid, it is obscured by a lack of clarity about the objectives of the analyses and in the overall writing of the article. The study will be impactful to the researchers in the field but will benefit from improved presentation.

eLife Assessment

This important paper employs multiple experimental approaches and presents evidence that changes in membrane voltage directly affect ERK signaling to regulate cell division. This result is relevant because it supports an ion channel-independent pathway by which changes in membrane voltage can affect cell growth. The reviewers point out that some experimental results and interpretations are compelling, but the strength of evidence is incomplete and additional experiments are needed to rule out other possible interpretations of the data.

Editors Assessment:

This paper reports the establishment of the International Cannabis Genomics Research Consortium (ICGRC) web portal leveraging the open source Tripal platform to enhance data accessibility and integration for Cannabis sativa (Cannabis) multi-omics research. With the aim of bringing together the wealth of publicly available genomic, transcriptomic, proteomic, and metabolomic data sets to improve cannabis for food, fiber and medicinal traits. Tripal is a content management system for genomics data, presenting a ready-to-use specialized ‘omics modules for loading, visualization, and analysis, and is GMOD (Generic Model Organism Database) standards-compliant. The paper explaining how this was put together, what data and features are available, and providing a case study for other communities wanting to create their own Tripal platform. Covering their setup and customizations of the Tripal platform, and how they re-engineered modules for multi-omics data integration, and addition of many other custom features that can be reused. Peer review fixed a few minor bugs and added clarifications on how the platform will be updated.

*This evaluation refers to version 1 of the preprint *

eLife Assessment

This study presents a valuable finding on the identification of a complex consisting of NHE1, hERG1, β1/integrin and NaV1.5 on the membrane of breast cancer cells. The evidence supporting the claims of the authors is somewhat incomplete. The inclusion of clarification of some experimental design and the amendment of cropping Western blot data would have strengthened the study. The work will be of interest to scientists working on breast cancer.

eLife Assessment

SGLT2 inhibitors (SGLT2i) have assumed important roles in reducing cardiovascular risk, particularly in those with diabetes. It has become appreciated that its protective effects are likely beyond their ability to lower blood sugar levels. This research presents a novel approach to studying the SGLT2i mechanism of action which is yet to be fully elucidated.

eLife Assessment

This study provides a valuable new perspective on how motor learning occurring in one state generalizes to new states (for example, a different limb posture). The proposed model improves upon previous theories in its ability to predict patterns of generalization, but evidence supporting this specific proposed model over possible alternatives is incomplete. The newly proposed theory appears promising but would be more convincing if its conceptual and theoretical basis were clearer and more rigorously derived.

eLife Assessment

This important work advances our understanding of factors influencing early childhood development. The large sample size and methodology applied make the findings of this study convincing; however, support for some of the claims made by the authors is incomplete. The work will be of interest to researchers in developmental science and early childhood pediatrics.

eLife Assessment

This important work addresses the role of Marcks/Markcksl during spinal cord development and regeneration. The study is exceptional in combining molecular approaches to understand the mechanisms of tissue regeneration with behavioural assays, which is not commonly employed in the field. The data presented is convincing and comprehensive, using many complementary methodologies.

Editors Assessment:

PhysiCell is an open source multicellular systems simulator for studying many interacting cells in dynamic tissue microenvironments. As part of the PhysiCell ecosystem of tools and modules this paper presents a PhysiCell addon, PhysiMeSS (MicroEnvironment Structures Simulation) which allows the user to accurately represent the extracellular matrix (ECM) as a network of fibres. This can specify rod-shaped microenvironment elements such as the matrix fibres (e.g. collagen) of the ECM, allowing the PhysiCell user the ability to investigate physical interactions with cells and other fibres. Reviewers asked for additional clarification on a number of features. And the paper now clear future releases will provide full 3D compatibility and include working on fibrogenesis, i.e. the creation of new ECM fibres by cells.

This evaluation refers to version 1 of the preprint

eLife Assessment

This important paper demonstrates that different PKA subtypes exhibit distinct subcellular localization at rest in CA1 neurons. The authors provide compelling evidence that when all tested PKA subtypes are activated by norepinephrine, catalytic subunits translocate to dendritic spines but regulatory subunits remain unmoved. Furthermore, PKA-dependent regulation of synaptic plasticity and transmission can be supported only by wildtype, dissociable PKA, but not by inseparable PKA.

eLife Assessment

In this potentially important study, the authors conducted atomistic simulations to probe the salt-dependent phase separation of the low-complexity domain of hnRN-PA1 (A1-LCD). The authors have identified both direct and indirect mechanisms of salt modulation, provided explanations for four distinct classes of salt dependence, and proposed a model for predicting protein properties from amino acid composition. There is a range of opinions regarding the strength of evidence, with some considering the evidence as incomplete due to the limitations in the length and statistical errors of the computationally intense atomistic MD simulations.

eLife Assessment

This manuscript presents a valuable new quantitative crosslinking mass spectrometry approach using novel isobaric crosslinkers. The data are solid and the method has potential for a broad application in structural biology if more isobaric crosslinking channels are available and the quantitative information of the approach is exploited in more depth.

eLife Assessment

This useful study by Nandy and colleagues examined relationships between behavioral state, neural activity in cortical area V4, and trial-by-trial variability in the ability to detect weak visual stimuli. They present solid evidence indicating that certain changes in arousal and eye-position stability, along with patterns of synchrony in the activity of neurons in different layers of V4, can show modest correspondences to changes in the ability to correctly detect a stimulus. These findings are likely to be of interest to those who seek a deeper understanding of circuit mechanisms that underlie perception.

eLife Assessment

This useful manuscript addresses some key molecular mechanisms on the neuroprotective roles of soluble TREM2 in neurodegenerative diseases. Thw study will advance our understanding of TREM2 mutations, particularly on the damaging effect of known TREM2 mutations, and also explain why soluble TREM2 can antagonize Aβ aggregation. However, the primary experimental method, MD simulations, suffers from limited sampling, rendering the results incomplete for definite conclusions.

eLife Assessment

The study provides a valuable showcase of a workflow to perform large-scale characterization of drug mechanisms of action using proteomics in which on-target and off-targets of 166 compounds using proteome solubility analysis in living cells and cell lysates were determined. The evidence supporting the claims of the authors is solid, however, the inclusion of more replicate experiments and more statistical rigor would have strengthened the study. This will be of broad interest to medicinal chemists, toxicologists, computational biologists and biochemists.

eLife Assessment

This landmark study elucidates the intricate structural mechanisms by which both covalent and non-covalent synthetic ligands can co-occupy the binding pocket of the nuclear receptor transcription factor PPARγ. Through a compelling integration of structural, biochemical, and biophysical evidence, the authors challenge the reliability of two commonly used covalent inhibitors. These findings have far-reaching implications for the broader field of nuclear receptor research. This work will be of high interest to structural biologists and biochemists exploring ligand interactions within the nuclear receptor superfamily.

eLife Assessment

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

eLife Assessment

This study demonstrates mRNA-specific regulation of translation by subunits of the eukaryotic initiation factor complex 3 (eIF3) using convincing methods, data, and analyses. The investigations have generated important information that will be of interest to biologists studying translation regulation. However, the physiological significance of the gene expression changes that were observed is not clear.

eLife Assessment

The study is considered important with solid evidence that demonstrates the impact of plasma membrane nano-domains and protein interactions in the plant defence response to viruses. It includes a molecular understanding of the role of a calcium dependent kinase (CPK3) and a remorin protein in the cell-to-cell spread of viruses and cytoskeletal dynamics demonstrating, conclusively, the role of CPK3 with multiple lines of evidence. The work opens avenues to investigate different viruses and other plasma membrane proteins to gain a fuller picture of the involvement of plasmodesmata and other nanodomains in virus spreading.

eLife Assessment

This valuable work describes results from a set of simulation and empirical studies of a set-up assessing exploratory behavior in a potentially rewarding environment that contains danger. The core idea is that an instrumental agent can be helped to be both effective and safe, thus avoiding excessive danger, during exploratory behavior, if its influence is flexibly gated by an independent Pavlovian fear learning system. The conclusion that safe, but effective exploration can be achieved based on a flexibly weighted combination of a Pavlovian and an instrumental agent is solid.

eLife Assessment

The authors identify a novel relationship between exosome secretion and filopodia formation that has implications for cancer cell metastasis and neuronal synapse formation. Further, they identify the exosomal cargo, THSD7A, as a regulator of this process. The data presented is convincing, and represents an important advancement in our understanding of how these two biological processes are linked and play roles in regulating cell migration and cell-cell communication.

eLife Assessment

This valuable study investigates how the size of an LLM may influence its ability to model the human neural response to language recorded by ECoG. Overall, solid evidence is provided that larger language models can better predict the human ECoG response. Further discussion would be beneficial as to how the results can inform us about the brain or LLMs, especially about the new message that can be learned from this ECoG study beyond previous fMRI studies on the same topic. This study will be of interest to both neuroscientists and psychologists who work on language comprehension and computer scientists working on LLMs.

eLife Assessment

This valuable study significantly enhances our understanding of how various ligands and receptors interact within the Notch signaling pathway. By developing novel cell-based assay systems, the authors systematically analyzed the effects of different ligand-receptor combinations on pathway activation. The convincing data reveal intriguing and unexpected differences and provide a foundation for interpreting Notch signalling in both normal and disease-related contexts.

eLife Assessment

This important study uses in vitro and in vivo methods to identify HpARI proteins from H. polygyrus as modulators of the host immune system. The data from comprehensive approaches for investigating differential roles of HpARI proteins are convincing. This paper is relevant to those who investigate host-pathogen interactions at the systems and molecular levels.

eLife Assessment

This is an important study on the damage-induced checkpoint maintenance and termination in budding yeast that provides novel and convincing evidence for a role of the spindle assembly checkpoint and mitotic exit network in halting the cell cycle after prolonged arrest in response to irreparable DNA double strand breaks (DSBs). The study identifies particular components from these checkpoints that are specifically required for the establishment and/or the maintenance of a cell cycle block triggered by such DSBs. The authors propose an interesting model for how these different checkpoints intersect and crosstalk for timely resumption of cell cycling even without repairing DNA damage that has been revised by addressing the bulk of the reviewers' comments to the first version of the manuscript.

eLife Assessment

This important study examines the role of Microrchidia (MORC) proteins in the human malaria parasite Plasmodium falciparum. Solid experimental results, including genome editing and chromatin profiling methods (ChIP-seq and Hi-C), provide a comprehensive picture of the critical role MORC plays in shaping parasite chromatin. Depletion of MORC results in a lethal collapse of heterochromatin and parasite death, nominating the factor as a new target of antimalarial therapies.

eLife Assessment

This valuable study focuses on the regulation of Notch signaling during the immune response in Drosophila. The authors provide solid evidence in support of roles for Su(H) and Pkc53E-induced phosphorylation in Drosophila immunity. The work will be of interest to colleagues in immunity and receptor signaling.

eLife Assessment

This important study provides a new perspective on how human immunity shapes the antigenic evolution of pathogens. By combining theory and simulation the authors make a compelling case for the importance of eco-evolutionary interactions in population-level virus-host dynamics, which arise due to coupling between the dynamics of immune memories and viral variants. Although the work does not propose improved data-driven viral forecasting methods, it makes a conceptual contribution that advances the field's understanding of this problem's intrinsic difficulty.

eLife Assessment

This study presents a valuable methodological advancement in quantifying thoughts over time. A novel multi-dimensional experience-sampling approach is presented, identifying data-driven patterns that the authors use to interrogate fMRI data collected during naturalistic movie-watching. The experimentation is inventive and the analyses carried out are convincing.

eLife Assessment

This study presents an important finding on the involvement of a Caspase 3-dependent pathway in the elimination of synapses for retinogeniculate circuit refinement and eye-specific territory segregation. This work fits well with the concept of "synaptosis" which has been proposed in the past but lacked in vivo support. Despite its elegant design and many strengths, the evidence supporting the claims of the authors is incomplete, particularly regarding whether Caspase-3 expression can really be isolated to synapses vs locally dying cells, whether microglia direct or instruct synapse elimination, and whether astrocytes are also involved. The work will be of interest to investigators studying cell death pathways, neurodevelopment, and neurodegenerative disease.

eLife Assessment

This valuable paper provides an unbiased landscape for the cerebellar cortical outputs to the brainstem nuclei. By conducting anatomical and physiological analyses of the axonal terminals of Purkinje cells, the data provide convincing evidence that Purkinje cells innervate brainstem nuclei directly. The results show that in addition to previously known inputs to vestibular and parabrachial nuclei, Purkinje cells synapse onto the pontine central grey nucleus but have little effect on the locus coeruleus and mesencephalic trigeminal neurons.

eLife Assessment

This important study reports that the neurohormone, bursicon, and its receptor, play a role in the seasonal polyphenism of the bug Cacopsylla chinensis. Low temperature activates the bursicon signaling pathway during the transition from the summer to the winter form, affecting cuticle pigment and thickness as well as chitin content. The solid experiments reveal how bursicon signaling, which is modulated by the microRNA miR-6012, regulates features of polyphenism related to the exoskeleton, although it is less clear what the upstream regulatory events are.

eLife Assessment

This study presents valuable findings on what networks of genes were impacted by introgression from Denisovans, to identify the biological functions involved in high-altitude adaptation in Tibet. This study applies solid and previously validated methodology to identify genes with signatures of both introgression and positive selection. This paper would be of interest to population geneticists, anthropologists, and scientists studying the genetic basis underlying high-altitude adaptation.

1. Humans have a very general ability to solve problems and achieve goals across diverse domains.
2. AI systems could become much more intelligent than humans.
3. If we create highly intelligent AI systems, their decisions will shape the future.
4. Highly intelligent AI systems won’t be beneficial by default.

eLife Assessment

ProtSSN is a valuable approach that generates protein embeddings by integrating sequence and structural information, demonstrating improved prediction of mutation effects on thermostability compared to competing models. The evidence supporting the authors' claims is solid, with well-executed comparisons. This work will be of particular interest to researchers in bioinformatics and structural biology, especially those focused on protein function and stability.

eLife assessment

This fundamental work provides creative and thoughtful analysis of rodent foraging behavior and its dependence on body reference frame-based vs world reference frame-based cues. Compelling evidence demonstrates that a robust map, capable of supporting taking novel shortcuts, is learned primarily if not exclusively based on self-motion cues, which has rarely if ever been reported outside of the human literature. The work, which will be of interest to a broad audience of neuroscientists, provides a rich discussion about the role of the hippocampus in supporting the behavior that should guide future neurophysiological investigations.

eLife Assessment

This fundamental work provides creative and thoughtful analysis of rodent foraging behavior and its dependence on body reference frame-based vs world reference frame-based cues. Compelling evidence demonstrates that a robust map, capable of supporting taking novel shortcuts, can be learned primarily if not exclusively based on self-motion cues, which has rarely if ever been reported outside of the human literature. The work, which will be of interest to a broad audience of neuroscientists, provides a rich discussion about the role of the hippocampus in supporting the behavior that should guide future neurophysiological investigations.

eLife Assessment

This valuable study addresses potential roles of the master regulator of X chromosome inactivation, the Xist long non-coding RNA, in autosomal gene regulation. Using data from mouse cells, the authors propose that Xist can coat specific autosomal promoters, which in turn leads to the attenuation of their transcriptional activity, complementing recently published results from humans. While the evidence from individual genes is suggestive, shortcomings in the data and statistical analyses leave the evidence currently incomplete. The work would be of interest to anyone studying gene regulation and noncoding RNAA

eLife Assessment

This study provides important insights into the mechanistic basis of neurological manifestations of RNA polymerase III-related disease by creating a mutant mouse to dissect transcriptional changes. The data provide compelling evidence for disease progression initiated by a global reduction in tRNA levels leading to integrated stress and innate immune responses and neuronal loss. The work will be of interest to those engaged in the study of chromosome biology, developmental biology and neurodegeneration.

eLife Assessment

This study aims to analyse the effect of polymorphism on meiotic recombination in subspecies of Saccharomyces. The detection of reciprocal and non-reciprocal events is based on sequencing the haploid products of meiosis, and frequencies are compared between strains having introgressed genomic segments and strains lacking such segments. Unfortunately, the method used are inadequate for quantifying the non-reciprocal events.

eLife Assessment

This study presents a valuable finding in understanding the role of plectin in the development and progression of hepatocellular carcinoma (HCC). The evidence supporting the conclusions is convincing because multiple orthogonal ways were used to demonstrate the requirement of this target in liver cancer models. However, the study is incomplete as the downstream molecular activities of plectin that mediate the cancer phenotypes were not fully evaluated.

eLife Assessment

This study presents a valuable examination of the prevalence of interactions between amino acids from different periods of Earth's history and coenzymes. While the premise of this work is well founded and the analysis is solid, with more data, the interpretation could change. This manuscript would be of interest to evolutionary biologists and biophysicists.

eLife Assessment

This revised study provides valuable information on the single nucleus RNA sequencing transcriptome, pathways, and cell types in pig skeletal muscle in response to conjugated linoleic acid (CLA) supplementation. Based on the comprehensive data analyses, the data are considered compelling and provide new insight into the mechanisms underlying intramuscular fat deposition and muscle fiber remodeling. The revised study clarifies major aspects of its methodology and analysis, addresses previous reviewer concerns, and contributes significantly to the understanding of nutritional strategies for fat infiltration in pig muscle.

eLife Assessment

This important study addresses two questions: (i) how danger signaling is altered for people with childhood adversities, and (ii) how this differs across different operationalizations of adversity. The latter is of particularly broad interest to multiple fields, given that childhood adversity is operationalized very differently across the literature. The study provides compelling evidence using a large sample size and rigorous statistical methods. These data will be of interest to scientists and clinicians interested in early life adversity, statistical approaches for quantifying stress exposure, or aversive learning.

eLife Assessment

This study explores the mechanistic link between glycosylation at the N162 site of the Fc gamma receptor FcγRIIIa and the modulation of NK cell-mediated antibody-dependent cytotoxicity. Using innovative isotope labeling strategies and advanced NMR spectroscopy techniques, the authors provide compelling evidence of how glycan composition influences receptor stability and immune function. These findings offer fundamental insights that may contribute to the development of more effective therapeutic antibodies. The manuscript will be of significant interest to immunologists and researchers focused on therapeutic antibody design.

eLife Assessment

This valuable study focuses on gene regulatory mechanisms essential for hindbrain development. Through molecular genetics and biochemistry, the authors propose a new mechanism for the control of Hox genes, which encode highly conserved transcription factors essential for hindbrain development. The strength of evidence is solid, as most claims are supported by the data. This work will be of interest to developmental biologists.

eLife Assessment

This work reports an important new method for activity-dependent neuronal labeling in Drosophila using in situ hybridization, with the potential to establish a new standard in the field. The authors demonstrate the method's applicability by generating compelling evidence of the function of male-specific neurons in both aggression and courtship behaviors. These results and the new method will be of great interest to the neuroscience community.

eLife Assessment

The manuscript by Kolbeck and co-workers is an important contribution to understanding the physical mechanism that controls a key step in the retroviral infectious cycle. The authors employ a wide range of experimental techniques, complemented with Montecarlo simulations, that result in convincing evidence of compaction of HIV DNA by the viral integrase. This manuscript would benefit from in-depth discussion and analysis of the biophysical implications of the results.

eLife Assessment

This valuable paper reports image analysis pipelines for the automated segmentation of micronuclei and the detection and sorting of micronuclei-containing cells, which could be powerful tools for researchers studying micronuclei. While the development of the pipelines is solid, a proof-of-principle experiment is not entirely conclusive and leaves open the possibility that additional refinements are required, which would be facilitated by a more detailed explanation of the methods used.

eLife Assessment

This manuscript provides valuable mechanistic insight into NSCLC progression, both in terms of tumour metastasis and the development of chemoresistance. The authors draw upon a range of techniques and assays and although the evidence shown is solid, suggestions by the two reviewers will strengthen the message. The work presented will be of interest to cancer biologists and more broadly to those interested in NSCLC translational studies.

eLife Assessment

This manuscript reports on the crystal structures of two glycosaminoglycan (GAG) lyases from the PL35 family, along with in vitro enzyme activity assays and comprehensive structure-guided mutagenesis. While the study provides structural insights into the broad substrate specificity of these enzymes, the incomplete structural models, lack of key data such as Mn²⁺ binding confirmation, and reliance on basic docking methods diminish the overall impact. Although the work is useful for specialists in carbohydrate-active enzymes, additional data, and more rigorous analysis are required to present a complete study.

eLife Assessment

In this potentially important study, the authors conducted extensive atomistic and coarse-grained simulations as well as a lattice Monte Carlo analysis to probe the driving force and functional impact of supercomplex formation in the inner mitochondrial membrane. The study highlighted the importance of membrane mechanics to the supercomplex formation and revealed differences in structural and dynamical features of the protein components upon complex formation. In its current form, the analysis is considered incomplete, especially concerning the contributions of membrane mechanics and allosteric coupling of key regions.

eLife Assessment

This manuscript presents a valuable finding on the impact of FRMD8 loss on tumor progression and the resistance to tamoxifen therapy. The author conducted systematic experiments to explore the role of FRMD8 in breast cancer and its potential regulatory mechanisms, confirming that FRMD8 affects tamoxifen resistance and convincingly validating this hypothesis through a series of experiments.

eLife Assessment

In this valuable manuscript, the authors propose that the lysosomal protein LAPTM4B plays a role in suppressing the TGF-β/SMAD signaling pathway and suggest that enhancing LAPTM4B function could be a potential therapeutic strategy for alleviating bleomycin-induced lung fibrosis. The findings will be of interest to the lung disease field, and the data presented to support the authors' conclusions is solid. However, it remains unclear whether the suppressive effect of LAPTM4b on idiopathic pulmonary fibrosis is mediated by Nedd4l.

eLife Assessment

This valuable study describes how a single effector of the Type Six Secretion System (T6SS) has two distinct enzymatic functions that together may contribute to bacterial survival and dynamics in a community and provide potential for developing new antimicrobial compounds. The authors have deployed a range of methods in biochemistry, microbiology, and microscopy, generating solid data that support the main assertions. While the manuscript could benefit from additional clarifying experiments and a more detailed discussion of the methods, it will appeal to those studying T6SS, particularly those interested in effectors and bacterial enzymes.

eLife Assessment

This work provides a potentially valuable framework for understanding the primary causes of disease. However, the evidence supporting the utility of the approach is incomplete given the reliance on strong assumptions about the underlying causal mechanisms.

eLife Assessment

In this work, the authors propose that astrocytic aquaporin 4 (AQP4) is the main pathway for tonic water efflux, without which astrocytes undergo cell swelling. These findings are important, because they shed light on key molecular mechanisms implicated with the regulation of brain water homeostasis. The authors use a broad set of experimental tools (e.g., acute brain slices, in vivo recording, and diffusion-weighted MRI) but the evidence remains incomplete without ruling out non-specific effects of TGN-020, and without evidence that changes in sulforhodamine B fluorescence can be used as reliable readouts of cell volume dynamics.

eLife Assessment

The authors utilized single-cell RNA-seq profiling of non-small cell lung cancer (NSCLC) patient tumor samples to generate useful insights into the determinants of immune checkpoint inhibitor (ICI) responsiveness in NSCLC patients. While some of the findings add weight to the current literature, the analysis is incomplete due to the small cohort size and heterogeneous population which has limited their ability to draw statistically supported conclusion after adjusting for multiple hypothesis testing, as well as the lack of functional characterization of the findings. This study would benefit from external cohorts to both validate the findings and justify the statistical analysis undertaken.

eLife Assessment

This comprehensive and compelling study presents a robust, cost-effective method for expanding pluripotent stem cells. The authors have identified a media condition that maintains iPSCs in suspension cultures by inhibiting the PKCβ and Wnt signaling pathways. The manuscript is important for the pluripotent stem cell field as it seeks robust and economical approaches to expand iPSCs at scale for high throughput screens and preclinical studies. While the authors have tested their media and protocol on a few lines, given the variability of iPSCs, further testing across more cell lines and in different laboratory settings will be crucial to evaluate its reproducibility.

eLife Assessment

This valuable study reports machine learning models derived from large-scale data to predict the risk of post-stroke epilepsy. The evidence supporting the conclusions is convincing, although there are some validation issues (lack of cross-validation, possible bias in external validation results). The study may be of interest in the field of clinical neurology

eLife Assessment

This important study provides interesting insights into the mechanisms of action of adjuvants. It shows that adjuvants, MPLA and CpG especially, modulate the peptide repertoires presented on the surface of antigen presenting cells, and surprisingly, adjuvant favored the presentation of low-stability peptides rather than high-stability peptides by antigen presenting cells. As a result, the low stability peptide presented in adjuvant groups elicits T cell response effectively. Evidence in support of these conclusions is solid, and this paper would be of interest to vaccinologists and immunologists.

eLife Assessment

This important work explores the modulation of pain by intense stress. The authors employed a series of cutting-edge techniques and provided convincing evidence suggesting that the dorsal lateral septum-> lateral hypothalamus-> rostral ventromedial medulla circuit is responsible for mediating stress-induced analgesia. This work will be of interest to neuroscientists interested in the neural circuits of behavior, and scientists interested in stress or pain.

eLife Assessment

This study uses C. elegans, a poikilothermic ("cold-blooded") animal, to investigate the interesting question of how cells and organisms adapt to prolonged exposure to cold temperature. The study employed ribosome profiling and RNAseq analyses and provides a useful inventory of genes changed in cold adapted nematodes. However, the overall conclusions that 1) translation is ongoing at a low rate and 2) IRE mediated transcriptional changes play a significant role in cold adaptation are incompletely supported by the evidence provided. The authors are encouraged to conduct additional bioinformatic analyses and rewrite the manuscript to more accurately reflect the evidence provided.

eLife Assessment

This important study develops a high throughput version of expansion microscopy that can be performed in 96-well plates. The engineered technology is convincing and compatible with standard microplates and automated microscopes and thus will be of broad interest. The application to hiPCS-derived cardiomyocytes treated with doxorubicin provides a solid proof-of-concept demonstrating the potential for high-throughput analysis.

eLife Assessment

This useful study examines relationships between tumor mutational burden and the response to immunotherapy, using new data sets along with publicly available data sets. The authors conclude that tumor mutational burden cut-offs are unreliable proxies for predicting the response to therapy, underpinned by solid evidence, but with several caveats and assumptions that leave the central question subject to further inquiry. In summary, this is an interesting study that adds to a growing body of work investigating the particular conditions governing the effectiveness of immunotherapy.

eLife assessment

This work presents a valuable new approach for self-supervised segmentation for fluorescence microscopy data, which could eliminate time-consuming data labeling and speed up quantitative analysis. The experimental evidence supplied is currently incomplete as the comparison with other methods is only done on a single dataset, lacks common metrics, and could not be easily reproduced for other sample data listed in the manuscript.

eLife Assessment

This valuable study combines agent-based modelling and in vivo experiments in medaka embryos to provide new insights into the role of the thymic niche in T cell development. The modelling yields some interesting findings regarding the importance of thymic epithelial cells, for some of which the evidence is incomplete. This study would be of interest to oncologists, immunologists, and mathematical modelers.

eLife Assessment

In this valuable study, the authors attempt to reconstruct the evolutionary history of a large and widespread group of freshwater fishes (Nemacheilidae) across Eurasia since the early Eocene, based on molecular phylogenetic analysis with very comprehensive samplings including 471 specimens belonging to 250 living species. The authors infer that range expansions of the family were facilitated by tectonic connections, favourable climatic conditions, and orogenic processes, adding to our understanding of the effects of climatic change on biodiversity during the Cenozoic. The molecular evidence is overall solid, but the calibration points from the fossil records used in the analysis have not been clearly demonstrated or cited; the different dates for the calibration points might impact the discussion on the evolutionary history relating to past climatic changes.

eLife Assessment

This study focuses on the regulation of GLP-1 in enteroendocrine L cells and how this may be stimulated by the mechanogated ion channel Piezo1 and the CaMKKbeta-CaMKIV-mTORC1 signaling pathway. The work is innovative and is considered valuable, as the hypothesis that is being tested may have significant mechanistic and translational implications. Data to support the proposed mechanism were considered incomplete, yet data to support the overall physiological characterization were considered solid.

eLife Assessment

This study investigates the role of Hox genes in determining the position of the forelimb bud using experimental loss- and gain-of-function approaches in chicken embryos, concluding that Hox4 and Hox5 provide permissive signals for forelimb formation throughout the neck region, while the final forelimb position is determined by the instructive signals of Hox6/7 in the lateral plate mesoderm. These results could potentially be fundamental to our understanding of Hox patterning. However, the evidence supporting these conclusions is incomplete; while the gain-of-function experiments are well supported, the loss-of-function experiments using dominant-negative constructs lack sufficient controls, and could be the result of an experimental artifact.

eLife Assessment

This important study provides insights into the role of maternal behavior in the learning and ontogeny of vocalization, finding evidence that the maternal behavior of sac-winged bats (Saccopteryx bilineata) can influence the learned territorial songs of their pups. The behavioral analyses are solid, although a more comprehensive and quantitative description of the babblings and the female displays would have strengthened the study. The work will interest biologists and neuroscientists studying vocal learning and its evolution.

eLife Assessment

These are valuable findings for those interested in how neural signals reflect auditory speech streams, and in understanding the roles of prediction, attention, and eye movements in this tracking. However, the evidence as it stands is incomplete. Further details are needed on how the observed quantities relate to the relevant theoretical claims and mathematical models. Moreover, additional motivation is required for several analytical choices.

eLife Assessment

This study provides convincing evidence that the Kinesin protein family member KIF7 regulates the development of the cerebral cortex and its connectivity and the specificity of Sonic Hedgehog signaling by controlling the details of Gli repressor vs activator functions. This study provides important new insights into general aspects of cortical development.

eLife Assessment

This is an important study demonstrating that cholecystokinin is a key modulator of auditory thalamocortical plasticity during development and in young adults but not aged mice, though the cortical application of this neuropeptide in older animals appears to go some way to restoring this age-dependent loss in plasticity. A strength of this work is the use of multiple experimental approaches, which together provide convincing support for the proposed involvement of cholecystokinin. Nevertheless, the specificity of the electrical and optical stimulation experiments requires further validation and some key details are missing in the presentation and discussion of these findings. This work is likely to be influential in opening up a new avenue of investigation into the roles of neuropeptides in sensory plasticity.

eLife Assessment

This important study highlights the key role of the gut-liver axis mediated by LPS in causing hepatic steatosis. The authors provide solid evidence, in vivo, in vitro, and in silico, for the role of acyloxyacyl hydrolase in mediating this effect using KO mice subjected to MASD-inducing diets. The findings are significant for the liver research community and others interested in the gut-liver axis.

eLife Assessment

This important study provides solid in-vivo evidence that CCR4 regulates the early inflammatory response during atherosclerotic plaque formation. The authors propose that altered T-cell response plays a role in this process, shedding light on mechanisms that may be of interest to medical biologists, biochemists, cell biologists, and immunologists. Further in vivo validation, mechanistic studies, and discussion of results in vitro suggested would be helpful to cement the significance and implications of these findings.

eLife Assessment

Wittkamp et al. investigated the spatiotemporal dynamics of expectation of pain using an original fMRI-EEG approach. The methods are solid and the evidence for a substantially different neural representation between the anticipatory and the actual pain period is convincing. These important findings are discussed within a general framework that encompasses their research questions, hypotheses, and analysis of results. Although the choice of conditions and their influence on the results might accept different interpretations, the manuscript is strong and contributes beneficial insights to the field.

eLife Assessment

This valuable study provides convincing evidence that white matter diffusion imaging of the right superior longitudinal fasciculus might help to develop a predictive biomarker of chronic back pain chronicity. The results are based on a discovery-replication approach with different cohorts, but the sample size is limited. The findings will interest researchers interested in the brain mechanisms of chronic pain and in developing brain-based biomarkers of chronic pain.

eLife Assessment

By combining psychophysics and computational modelling based on the Theory of Visual Attention, this study examines the mechanisms underlying self-prioritization by revealing the influence of self-associations on early attentional selection. While the findings are important, the experimental evidence is incomplete. The relationship between consciousness (awareness) and attention, the potential contamination by arousal, the inconsistent and unexpected results, and the distinguishing between social and perceptual tasks need to be addressed or improved. The work will be of interest to researchers in psychology, cognitive science, and neuroscience.

eLife Assessment

This study describes a useful technique to improve imaging depth using confocal microscopy for imaging large, cleared samples. It is as yet unclear if their proposed technique presents a significant advance to the field since their comparisons to existing techniques remain incomplete. However, the work will be of broad interest to many researchers in different fields.

eLife Assessment

This valuable study investigates how biologically plausible learning mechanisms can support assembly formation that encodes statistics of the environment, by enabling neural sampling that is based on within-assembly connectivity strength. It convincingly shows that assembly formation can emerge from predictive plasticity in excitatory synapses, while two types of plasticity in inhibitory synapses are required: inhibitory homeostatic (predictive) plasticity and inhibitory competitive (anti-predictive) plasticity.

eLife Assessment

This timely and important study used functional near-infrared spectroscopy hyperscanning to examine the neural correlates of how group identification influences collective behavior. The work provides incomplete evidence to indicate that the synchronization of brain activity between different people underlies collective performance and that changes in brain activity patterns within individuals may, in turn, underlie this between-person synchrony. This study will be of interest to researchers investigating the neuroscience of social behaviour.

eLife Assessment

This important study challenges conventional life-history theory by demonstrating that reproductive-survival trade-offs are minimal in birds, except when reproductive effort is experimentally exaggerated. The evidence is solid, drawing from a meta-analysis of over 30 bird species, and effectively separates the effects of individual quality from reproductive costs. The findings will be of broad interest to evolutionary biologists and ecologists studying life-history trade-offs and reproductive strategies.

eLife Assessment

The manuscript provides useful findings to explore the heterogeneity of hematopoietic stem cells and age-related myeloid-biased hematopoiesis. The results presented in this study are incomplete and additional data are necessary to bolster the conclusions. Certain aspects of the methods, experimental design, and data analyses remain inadequate and only partially support the central claims.

eLife Assessment

This valuable study investigates both online responses to, and offline replay of, visual motion sequences. Sophisticated EEG analyses provide solid evidence for both feature-specific and non-specific sequence representations, though the explanation of the statistical methods used is currently incomplete.

eLife Assessment

This important study advances our understanding of the role of dopamine in modulating pair bonding in mandarin voles by examining dopamine signaling within the nucleus accumbens across various social stimuli using state-of-the-art causal perturbations. The evidence supporting the findings is compelling, particularly cutting-edge approaches for measuring dopamine release as well as the activity of dopamine receptor populations during social bonding. However, statistical analyses were found to lack rigor and clarity, and the lack of complementary experiments in females was noted as a weakness. Additionally, the manuscript would be strengthened by placing findings within a broader framework, such as by highlighting similarities and/or differences between mandarin and prairie voles.

eLife Assessment

This manuscript offers valuable information on the combinatory effect of small molecules, CHIR99021 and A-485 (2C), during the reprogramming of mature cardiomyocytes into regenerative cardiac cells on stimulating cardiac cell regeneration. Although the study used several hESC lines and an in vivo model of myocardial injury to demonstrate the regenerative potential of cardiac cells, the manuscript is still incomplete as several concerns remain unanswered, including the lack of validation of the conclusions from scRNA-seq. It is still unclear how a small fraction of dedifferentiating cardiac cells can offer such broad effects on regeneration both in vitro and in vivo. If validated, this study might unlock potential therapeutic strategies for cardiac regeneration.

eLife Assessment

This valuable article represents a significant body of work that addresses some novel aspects of the biology of lung cancer, the overall influence of CHIP and its impacts on responses to therapy. While a high clonal hematopoiesis (CHIP) burden was previously linked with an inflammatory phenotype in other disease settings, the authors demonstrate with solid evidence that this is also true for lung cancer. CHIP is complex and more data will be required to substantiate more evidence with regard perhaps to specific mutations in certain situations and how this might influence therapy choices.

eLife Assessment

This work is of fundamental significance and has an exceptional level of evidence for a new population that protects against obesity-induced hypothalamic inflammation. This topic will attract attention from a broad base of readers, from hypothalamic neuroscientists to immunologists with an interest in metabolism.

eLife Assessment

This study presents the cryo-EM structures of two human biotin-dependent mitochondria carboxylases involved in various biological pathways, including the metabolism of certain amino acids, cholesterol, and odd chain fatty acids. The cryo-EM structures offer a valuable addition to the structural description of biotin-dependent carboxylases and provide solid evidence to support the major conclusions of this study. This paper would be of interest to biochemists and structural biologists working on biotin-dependent carboxylases.