eLife Assessment

This important study addresses a topic that is frequently discussed in the literature but is under-assessed, namely correlations among genome size, repeat content, and pathogenicity in fungi. Contrary to previous assertions, the authors found that repeat content is not associated with pathogenicity. Rather, pathogenic lifestyle was found to be better explained by the number of protein-coding genes, with other genomic features associated with insect association status. The results are considered solid, although there remain concerns about potential biases stemming from the underlying data quality of the analyzed genomes.

eLife Assessment

This potentially valuable work aimed at a better understanding of the mechanisms of response and resistance to androgen deprivation therapy in prostate cancer using genetically engineered mouse models. A key observation relates to the timing of TNF blockage therapy and the concept of a "TNF switch." The solid data were collected using conventional approaches and the conclusions are mostly justified, particularly with the inclusion of more detailed statistics in the revision. The work will be of interest to the prostate cancer research community.

eLife Assessment

This useful study uses a combination of experimental and modeling approaches to investigate the role of actomyosin in epithelial invagination during Ciona siphon tube morphogenesis. Several types of solid quantitative analyses are presented, yet the evidence supporting the central claim of bidirectional translocation of actomyosin remains incomplete. Since epithelial invagination contributes to the morphogenesis of many developing organs, this work has the potential to appeal to both cell biologists and developmental biologists.

eLife Assessment

This important study presents a technically rigorous and carefully controlled analysis of the signalling potential of cancer-associated gain-of-function Notch alleles. The work is clearly presented, and the experiments are robust, comprehensive, and well-controlled. While some data primarily establish the system or report negative findings, the comparative approach in a well-characterized model provides convincing mechanistic evidence for how these Notch variants function. This study will be of interest to researchers in both developmental and cancer biology.

eLife Assessment

This study investigates the influence of genomic information and timing of vaccine strain selection on the accuracy of influenza A/H3N2 forecasting. The authors utilised appropriate statistical methods and have provided convincing evidence, which amounts to an important contribution to the evidence base. Substantial revisions have been made to the manuscript and issues of concern have been clarified, with the necessary study limitations appropriately discussed.

eLife Assessment

This manuscript reports on an FLIM-based calcium biosensor, G-CaFLITS. It represents an important contribution to the field of genetically-encoded fluorescent biosensors, and will serve as a practical tool for the FLIM imaging community. The paper provides convincing evidence of G-CaFLITS's photophysical properties and its advantages over previous biosensors such as Tq-Ca-FLITS. Although the benefits of G-Ca-FLITS over Tq-Ca-FLITS are limited by the relatively small wavelength shift, it presents some advantages in terms of compatibility with available instrumentation and brightness consistency.

eLife Assessment

The manuscript by Mancl et al. provides important mechanistic insights into the conformational dynamics of Insulin Degrading Enzyme (IDE), a zinc metalloprotease involved in the clearance of amyloid peptides. In the revised version, the authors have substantially expanded their analysis by incorporating time-resolved cryo-EM and coarse-grained molecular dynamics simulations, which reveal an insulin-induced allosteric transition and transient β-sheet interactions underlying IDE's unfoldase activity. Supported by a convincing combination of cryo-EM, SEC-SAXS, enzymatic assays, and both all-atom and coarse-grained simulations, this work refines our understanding of IDE's functional cycle and offers a structural framework for developing substrate-selective modulators of M16 metalloproteases.

eLife Assessment

This study represents a valuable addition to the catalog of mitochondrial proteins. With the use of methodology based on the bi-genomic split-GFP technology, the authors generate convincing data, including dually localized proteins and topological information, under various growth conditions in yeast. The study represents a key basis for further functional and/or mechanistic studies on mitochondrial protein biogenesis.

eLife Assessment

During the development of the unicellular eukaryote Dictyostelium discoideum, cells aggregate into mounds, forming protrusions or tips, which then become the front of migrating slugs and the top of fruiting bodies. This valuable study identifies adenosine deaminase-related growth factor (ADGF) as a key regulator of tip formation and convincingly shows that ADGF catalyses the conversion of adenosine to ammonia, allowing ammonia to initiate tip formation, and then elucidates pathways upstream and downstream of ADGF. The authors discuss the intriguing possibility that mammalian ADGF may also similarly regulate development.

eLife Assessment

This valuable study describes an interesting infection phenotype that differs between adult male and female zebrafish. The authors present data indicating that male-biased expression of Cyp17a2 mediates viral infection through STING and USP8 activity regulation. The authors present solid evidence linking this factor to direct and indirect antiviral outcomes through ubiquitination pathways. These findings raise interesting questions about immune mechanisms that underlie sex dimorphism and the selective pressures that might shape it.

eLife Assessment

This important study reports the development of the first tankyrase degrader and demonstrates its enhanced ability to inhibit β-catenin signaling compared to conventional tankyrase inhibitors. The evidence supporting the conclusions is comprehensive and convincing, based on rigorous biochemical and cellular analyses. The findings will be of broad interest to researchers studying Wnt signaling, protein degradation, and cancer biology.

eLife Assessment

This important study provides a theoretical framework for quantifying privacy risk from publicly shared genome-wide association summary statistics. The findings reveal the conditions under which genotype reconstruction may become feasible, challenging long-held assumptions about personal data safety. While the evidence is solid, supported by clear mathematical derivations and simulations, validation on large empirical datasets would further strengthen the claims.

eLife Assessment

The manuscript by Shukla et al. provides important mechanistic insights into kinesin-1 autoinhibition and cargo-mediated activation. Using a convincing combination of protein engineering, computational modeling, biophysical assays, HDX-MS, and electron microscopy, the authors reveal how cargo binding induces an allosteric transition that propagates to the motor domains and enhances MAP7 binding. Despite limitations arising from conformational heterogeneity and structural resolution, the study presents a unified mechanism for kinesin-1 activation that will be of broad interest to the motor protein, structural biology, and cell biology communities.

eLife Assessment

This important study describes a new link between nutrient signaling and chromosome regulation, providing compelling evidence that reduced activity in the central nutrient-sensing pathway governed by TORC1 improves chromosome stability and alters gene expression in S. pombe through effects on cohesin. While the biological importance of this newly described circuit is not yet fully known, and some data would benefit from further clarification, the overall body of evidence supports the main conclusions.

eLife Assessment

Mitochondrial DNA (mtDNA) exhibits a degree of resistance to mutagenesis under genotoxic stress, and this study on the mitochondrial Transcription Factor A (TFAM) presents valuable data concerning the possible mechanisms involved. The presented data are solid, technically rigorous, and consistent with established literature findings. The experiments are well-executed, providing reliable evidence on the change of TFAM-DNA interactions following UVC irradiation. However, the evidence is inadequate to support the primary claims.

eLife Assessment

This study investigates the folding and unfolding behavior of the doubly knotted protein TrmD-Tm1570, providing insight into the molecular mechanisms underlying protein knotting. The findings reveal multiple unfolding pathways and suggest that the formation of double knots may require chaperone assistance, offering valuable insights into topologically complex proteins. The evidence is solid, supported by consistent agreement between simulation and experiment, though some aspects of the presentation and experimental scope could be clarified or expanded.

eLife Assessment

This study used a conditional knockout mouse line to remove Ptbp1 in retinal progenitors and demonstrated that its deletion has no effect on retinal neurogenesis or cell fate specification, thereby challenging the prevailing view of Ptbp1 as a master regulator of neuronal fate. The data are convincing, supported by transcriptomic analysis, histology, and proliferation assays. This study is important, and the broader implications for other CNS regions warrant further investigation.

eLife Assessment

This study demonstrates the cartilage-protective effects of osteoactivin in inflammatory experimental models. The work offers valuable insights advancing current knowledge regarding regulation of joint inflammation and tissue degeneration. The evidence provided is compelling and suggests that osteoactivin may serve as a promising therapeutic target for inflammatory joint diseases.

eLife Assessment

This important work provides mechanistic insights into the development of cardiac arrhythmia and establishes a new experimental use case for optogenetics in studying cardiac electrophysiology. The agreement between computational models and experimental observations provides a convincing level of evidence that wave train-induced pacemaker activity can originate in continuously depolarized tissue, with the limitation that there may be differences between depolarization arising from constant optogenetic stimulation, as opposed to pathophysiological tissue depolarization. Future experiments in vivo and in other tissue preparations would extend the generality of these findings.

eLife Assessment

The authors investigate arrestin2-mediated CCR5 endocytosis in the context of clathrin and AP2 contributions. Using an extensive set of NMR experiments, and supported by microscopy and other biophysical assays, the authors provide compelling data on the roles of AP2 and clathrin in CCR5 endocytosis. This important work will appeal to an audience beyond those studying chemokine receptors, including those studying GPCR regulation and trafficking. The distinct role of AP2 and not clathrin will be of particular interest to those studying GPCR internalization mechanisms.

eLife Assessment

In this manuscript Taujale et al describe an interdisciplinary approach to mine the human channelome and further discover orthologues across diverse organisms. Further, this work provides evidence that supports a role for conserved residues in CALHM channel gating. Overall this important work presents findings that can be helpful to the ion channel community, as well as to those interested in improved methods for mining sequence space for their protein of interest. However, further validation of the improvements their approach shows over previous approaches is needed, making this a solid contribution to the literature in this field.

eLife Assessment

Antibodies that selectively bind distinct amyloid-beta variants are vital tools for Alzheimer's disease research. This valuable manuscript aims to delineate the epitope specificity in a panel of anti-amyloid-beta antibodies, including some with clinical relevance. The experiments were rigorously conducted, employing an interesting combination of established and state-of-the-art methodologies, yielding convincing findings.

eLife Assessment

This valuable work provides new insights into the role of lysine acetylation of alpha-synuclein, the protein involved in Parkinson's Disease. The evidence is mostly solid, but the claims around the potential disease relevance based on seeding assays and structural work need to be toned down, or else supported by additional experimental evidence. Overall, the work will be of interest to researchers in the fields of protein biophysics and post-translational modifications, as well as Parkinson's Disease.

eLife Assessment

This study seeks to expand the understanding of insulin and glucose responses in the brain, specifically by implicating a family of protein kinases responsive to insulin. The significance of the study to the field is valuable, given this study is very emblematic of the new field of interoception (Brain-Body physiology). The evidence supporting the conclusions about brain glucose utilization is convincing and is relevant to many age-related diseases, such as Alzheimer's disorder.

eLife Assessment

This study provides valuable data on the role of Hsd17b7, a gene involved in cholesterol biosynthesis, as a potential regulator of mechanosensory hair cell function. The authors used both zebrafish and the HEI cell line to examine the effects of deletion of Hsd17b7 on hair cell function and survival. While the results do show a reduction in hair cells in the lateral line neuromasts of Hsd17b7 mutant fish, the reduction was limited. The findings are considered incomplete, with additional experiments required to confirm the conclusions.

eLife Assessment

Zebra finches are a prominent model system for vocal learning and auditory system function, yet little is known about the functional development of the auditory system. Here, the authors convincingly show that newly hatched zebra finches lack detectable auditory brainstem responses and that auditory neural signals emerge only days after hatching, challenging influential claims of prenatal acoustic communication in altricial birds. This important work clarifies the developmental timeline for auditory communication and highlights the value of neuroscientific methods for validating and complementing behavioral ecological studies of animal perception.

eLife Assessment

This study provides evidence for distinct neurotransmitter release modalities between two subclasses of dopaminergic neurons in the olfactory bulb. Specifically, it demonstrates dendritic neurotransmitter release in anaxonic neurons and axonal release in axon-bearing neurons. The presence of GABAergic self-inhibition in anaxonic neurons further underscores the functional divergence between these subtypes. Overall, the manuscript presents solid evidence and offers biologically important insights into the organization and function of dopaminergic circuits within the olfactory bulb.

eLife Assessment

This important theoretical study shows that active hexatic topological defects in epithelia enable collective cell flows. Within the general limitations of coarse-grained hydrodynamic models in fully capturing cell-scale behavior, the study provides compelling evidence supporting its conclusions. These findings will be of interest to both biophysicists studying collective cell behaviors and biologists investigating epithelial flows during development.

eLife Assessment

This important work attempts to understand observed variability in oral shedding of SARS-CoV-2 and suggests that routine clinical factors are not determinative. The evidence supporting the conclusion is solid though the limited clinical heterogeneity of the included cohorts, the lack of COVID vaccination, and the absence of comprehensive viral load data for model training, makes the results difficult to generalize to contemporaneous COVID-19 conditions. This study may be of interest to virologists, public health officials and clinicians.

eLife Assessment

The findings of this study are valuable as it demonstrates that when treatment is initiated during acute infection, HIV specific CD8 T cell responses are maintained long term and continued proliferative capacity of these cells may play a role in reducing HIV DNA levels. The evidence supporting the conclusions are solid with rigorous and advanced methodology used with the major limitations being that the findings are association level and do not meet strict criteria for causality. The work is of interest to the HIV cure field and suggests that enhancing early HIV specific CD8 T cell responses should be considered in the design of interventional cure strategies.

eLife Assessment

This manuscript provides evidence that mouse germline cysts develop an asymmetric Golgi, ER, and microtubule-associated structure, referred to as Visham, which in many ways resembles the fusome of Drosophila germline cysts. This is an important study that provides new evidence that fusome-like structures exist in germ cell cysts across species. While most of the data are solid, several instances remain in which conclusions regarding the dynamics and function of Visham should be restated, or additional experimental evidence should be provided to more fully support the authors' interpretations.

eLife Assessment

The authors combine experiments and mathematical modeling to determine how the infectivity of human cytomegalovirus scales with the viral concentration in the inoculum, i.e., considering the multiplicity of infection (MOI). They propose and test different model assumptions to explain a mechanism termed "apparent cooperativity" of virions based on an observed super-linear increase in the number of infected cells with increasing inocula. The authors present a solid study showing valuable findings for virologists and quantitative scientists working on the analysis and interpretation of viral infection dynamics. Some of the presented aspects would benefit from additional clarification.

eLife Assessment

This manuscript reports on the application of ribosome profiling (EZRA-seq and eRF1-seq) combined with massively parallel reporter assays to identify and characterize a GA-rich element associated with ribosome pausing during translation termination. While the development of eRF1-seq is useful and the identification of GA-rich elements upstream of stop codons is convincing, the level of support for other claims is inadequate. Specifically, the evidence that GA-rich sequences upstream of stop codons can base-pair with the 3′ end of 18S rRNA to prolong ribosome dwell time, and the evidence that Rps26 interferes with this interaction to regulate translation termination, are not adequate.

eLife Assessment

The authors investigated the epigenetic mechanisms regulating the differentiation of circulating monocytes that infiltrate the CNS and adopt microglia-like characteristics. The work is useful to the field, as the contribution of circulating myeloid cell-derived microglia remains controversial. However, the evidence presented is inadequate as the analyses are based on a very limited set of genes, which does not sufficiently support the authors' central claims.

eLife Assessment

This study presents a role for heparin sulfate in SARS-CoV-2 entry that runs counter to prevailing data in the field. If the conclusions were firmly supported by the data, the work would be a significant contribution to the field. While the use of diverse cellular models, virological tools, and robust microscopy approaches constitutes a useful data set, the proposed model remains incomplete and requires clarification of entry mechanisms, host factors, and viral variant-specific fusion pathways to substantiate it against established entry models.

eLife Assessment

This work details the finding that in at least one of the subunits of the heterohexameric chaperone complex Pfdn5 has additional functions beyond its contribution to cytoskeletal protein folding in Drosophila. The authors provide convincing evidence that it is a hitherto unknown microtubule associated protein in addition to regulating microtubule organization and levels of tubulin monomers. The important findings show that Pfdn5 loss exaggerates pathological manifestations of mutant human Tau bearing FTDP-17 linked mutations in Drosophila, while its overexpression suppresses them, suggesting that the latter may constitute a future therapeutic approach.

eLife Assessment

In this valuable study, the authors used an elegant genetic approach to delete EED at the post-neural crest induction stage. The usage of the single-cell RNA-seq analysis method is extremely suitable to determine changes in the cell type-specific gene expression during development. Results backed by solid evidence demonstrate that Eed is required for craniofacial osteoblast differentiation and mesenchymal proliferation after the induction of the neural crest.

eLife Assessment

This useful study explores the role of RAP2A in asymmetric cell division (ACD) regulation in glioblastoma stem cells (GSCs), drawing parallels to Drosophila ACD mechanisms and proposing that an imbalance toward symmetric divisions drives tumor progression. While findings on RAP2A's role in GSC expansion are promising, and the reviewers found the study innovative and technically solid, the study relies on neurosphere models without in vivo confirmation and will therefore need to be further validated in the future.

eLife Assessment

This important study reveals that connexin43 (Cx43) hemichannels are directly activated by CO₂ through a conserved carbamylation motif, extending a mechanism previously described for β-connexins to α-connexins. The evidence is convincing, supported by complementary biochemical and electrophysiological analyses showing CO₂-induced hemichannel opening and ATP release in cultured cells and hippocampal slices. These findings advance our understanding of connexin regulation by metabolic gases and will be of broad interest to researchers studying cell communication, neural signaling, and gasotransmitter biology.

eLife Assessment

The authors develop an important microfluidic microvascular model called "Vessel-on-Chip", which they use to study Neisseria meningitidis interactions within this in vitro vascular system. Compelling evidence shows that the fabricated channels are lined by endothelial cells, and these can be colonized by N. meningitidis that in turn triggers neutrophil recruitment. This model has advantages over the human skin xenograft mouse model, which requires complex surgical techniques, however, it also carries limitations in that only endothelial cells and supplied specific immune cells in the microfluidics are present, while true vasculature contains a number of other cell types including smooth muscle cells, pericytes, and components of the immune system.

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

eLife Assessment

This important study characterises the morphogenesis of cortical folding in the ferret and human cerebral cortex using complementary physical and computational modelling. Notably, these approaches are applied to charting, in the ferret model, known abnormalities of cortical folding in humans. The study finds convincing evidence that variation in cortical thickness and expansion account for deviations in morphology, and supports these findings using cutting-edge approaches from both physical gel models and numerical simulations. The study will be of broad interest to the field of developmental neuroscience.

eLife Assessment

This study thoroughly assesses tactile acuity on women's breasts, for which no dependable data currently exists. The study provides two important contributions, by convincingly showing that tactile acuity on the breast is poor in comparison to other body parts, and that acuity is worst in larger breasts, indicating that the number of tactile sensors is fixed. However, further arguments concerning the role of the nipple in spatial localisation are not well supported by the current evidence, therefore diluting the overall contribution of the study. This study will be of interest to the broader community of touch, as well as those interested in breast reconstruction and sexual function.

eLife Assessment

This valuable study reports that EEG recordings of the earliest stage of information processing in the human visual cortex can be used to predict subsequent choice responses. The findings provide novel, solid evidence for integrative processing in low-level sensory cortices, though the exact nature of the neural signals measured here requires some clarification. While some conceptual issues need to be addressed, the paper is likely to be of interest to neuroscientists interested in the contribution of early sensory signals to decision-making.

eLife Assessment

This study shows that excitatory cholecystokinin (CCK)-expressing neurons in hippocampal area CA3 influence hippocampal-dependent memory using multiple methods to manipulate excitatory CCK-expressing CA3 neurons selectively. The work is valuable because most past studies of CCK-expressing neurons have focused on those neurons that co-express CCK and GABA. Currently, the strength of evidence is incomplete; however, if additional evidence were to be presented that the methods were selective, the evaluation would potentially be higher.

eLife Assessment

This study integrates large-scale behavioral, genetic, and molecular analyses in animal models to investigate morphine response. Utilizing high-quality, time-series Quantitative Trait Loci (QTL) mapping, the work provides compelling evidential support for novel, time-dependent genetic interactions (epistasis). A fundamental result of this rigorous analysis is the discovery of a novel Oprm1-Fgf12-MAPK signaling pathway, which offers new insights into the mechanisms of opioid sensitivity.

eLife Assessment

This important study presents JABS, an open-source platform that integrates hardware and user-friendly software for standardized mouse behavioral phenotyping. The work has practical implications for improving reproducibility and accessibility in behavioral neuroscience, especially for linking behavior to genetics across diverse mouse strains. The strength of evidence is convincing, with comprehensive validation of the platform's components and enthusiastic reviewer support.

eLife Assessment

In this 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 major contribution from membrane mechanics to the supercomplex formation and revealed interesting differences in structural and dynamical features of the protein components upon complex formation. Upon revision, the analysis is considered solid, although the magnitude of estimated membrane deformation energies seem somewhat large. Overall, the study is thorough, creative and the impact on the field of bioenergetics is expected to be significant.

eLife Assessment

This study provides important findings on the understanding of circannual timing in mammals, for which iodothyronine deiodinases (DIOs) have been suggested to be of critical importance, yet functional genetic evidence has been missing. The authors convincingly implicate dio3, the major inactivator of the biologically active thyroid hormone T3, in circannual timing in Djungarian hamsters, using a combination of correlative and gene knock-out experiments; thus this provides key insights into the evolution and function of animal annual timing mechanisms.

eLife Assessment

The results in this study are useful because they begin to establish a causal link between physical activity and the cellular mechanisms of regeneration. The evidence presented is largely solid, supporting the conclusion that exercise-induced changes in the extracellular matrix disrupt regeneration; however, some claims are incomplete, requiring additional controls and a clearer distinction between the effects of mechanical loading and mechanical injury to the blastema. The work will be of interest to researchers in regenerative medicine.

eLife Assessment

This important work characterizes layers of neuropeptidergic modulations that collectively regulate the intake of sugar in a hunger state-dependent manner. Combinations of genetic, physiological, and behavioral approaches present convincing evidence that neurons that release Hugin and Allatostatin A are in an active state in sated flies, leading to suppression of sugar feeding behavior by reducing the sensitivity of sugar-sensitive gustatory neurons that express Gr5a. They also demonstrate that neurons that release Neuromedin U, a vertebrate homolog of Hugin, have common physiological properties as the fly Hugin neurons, revealing a similar function of evolutionarily conserved peptides across animal phyla.

eLife Assessment

This important study extends the previous interesting work of this group to address the potentially different control of movement and posture. Through experiments in which stroke participants used a robotic manipulandum, the authors provide solid evidence supporting a lack of a relation between the resting force postural bias they measure (closely related to the flexor synergy in stroke) and kinematic deficits during movement. Based on these results, the authors propose a conceptual framework that differentially weights the two main descending pathways (corticospinal tract and reticulospinal tract) for neurologically intact and stroke patients.

eLife Assessment

This study investigates how people adapt their speech when auditory feedback is altered. The analyses are rigorous and the work makes a valuable contribution by extending methods from limb motor control to speech. However, because the paradigm does not directly measure sensory error, the evidence for the proposed mechanism of sensorimotor learning is incomplete. The findings are best viewed as evidence for how prior motor adjustments influence subsequent behaviour, highlighting the need for future studies to more precisely separate sensory and motor contributions to adaptation.

eLife Assessment

This study extends prior work on head bristle mechanosensation by delivering a synaptic-resolution map of second-order partners that preserves somatotopy and highlights a cholinergic pathway linking sensory input to grooming circuits, providing a valuable resource for the field. The reconstructions and quantitative connectivity analyses provide solid support the main anatomical claims, while causal sufficiency for the behavioral sequence remains inferential and could be strengthened by a simple rank-order test relating wiring to the known grooming hierarchy.

eLife Assessment

This timely and fundamental study introduces a human iPSC-based co-culture system that models Kupffer cell-hepatocyte interactions and aims to recapitulate liver-specific immune-parenchymal dynamics. Direct contact between iMacs and iHeps promotes mutual tissue-specific maturation, with iHeps downregulating fetal genes while iMacs acquire a Kupffer cell-like profile. This convincing in vitro model holds significant promise and is a leap forward; future experimental understanding will enhance its translational impact.

eLife Assessment

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

eLife Assessment

This manuscript provides a single-cell transcriptomic atlas for AML (222 samples comprising 748,679 cells) integrating data from multiple studies. They use this dataset to investigate t(8;21) AML, and they reconstruct the Gene Regulatory Network and enhancer Gene Regulatory Network, which allowed identification of interesting targets. This aggregation is important and can help infer differences in genetic regulatory modules based on the age of disease onset. Their compelling effort may help explain age-related variations in prognosis and disease development in subtype-specific manner.

eLife Assessment

The use of DNA tethers is an important advance for studying how motor proteins respond to load. The authors use a convincing methodology to investigate the detachment and reattachment kinetics of kinesin-1, 2, and 3 motors against loads oriented parallel to the microtubule. As the manuscript stands, the conclusions drawn from the experiments, as well as the overall interpretation of the results, are incompletely supported by the presented data, and the novelty over previous reports appears less clear.

eLife Assessment

This study provides a valuable insight into how the medial and lateral entorhinal cortices interact through distinct excitatory and inhibitory pathways. Using anatomical tracing, optogenetics, and electrophysiology, the authors show that glutamatergic medial entorhinal neurons provide broad excitatory input to lateral entorhinal, while long-range SST+ interneurons deliver selective inhibition to layer I. These findings reveal a novel layer- and cell-type-specific organization of medial to lateral entorhinal connectivity with implications for spatial and episodic memory. The work is solid, but validation of injection specificity and viral spread is needed to fully confirm the anatomical interpretations; with these clarifications, this will be a significant contribution to understanding entorhinal-hippocampal circuit organization.

eLife Assessment

This valuable clinical trial compares the impact of dolutegravir intensification on longitudinal measures of total HIV DNA and day 84 measures of intact HIV DNA. The trial was well-designed, and the paper is easy to read and provides hypothesis generation-level evidence that treatment intensification might decrease intact HIV DNA level in some people after 3 months. The findings are solid, with significant limitations being that study endpoints and hypotheses were not precisely defined prior to the trial, and that effect size is limited and inconsistent across trial participants.

eLife Assessment

Using a transposon sequencing (TN-seq) approach, the authors identified key genetic determinants of drug tolerance in Mycobacterium abscessus. Given that M. abscessus is inherently resistant to multiple antibiotics, this valuable study makes a significant contribution by uncovering how antibiotic tolerance is linked to reactive oxygen species (ROS) in this non-tuberculous mycobacterial (NTM) species. The solid findings further strengthen the growing evidence that ROS play a central role in the mechanism of antibiotic action and tolerance in mycobacteria. However, the manuscript would benefit from improved clarity of presentation and corrections in the reference section.

eLife Assessment

The study presents important findings regarding the incidence and clinical impact of a mutation in a cardiac muscle protein and its association with the development of atrial fibrillation. The authors provide convincing evidence of electrophysiological disturbances in cells with this mutation and of its association with atrial fibrillation, which would be of interest to cardiologists. Evidence supporting the conclusion that this mutation causes atrial fibrillation would benefit from more rigorous electrophysiologic approaches.

eLife Assessment

This study provides valuable insights into the role of the NF-kB and IKK signaling pathways in γδ T cell development and survival, using robust genetic mouse models. While the research is methodologically sound, some conclusions require further evidence, with incomplete analyses, particularly regarding cell-intrinsic effects and mechanistic details. Overall, the findings are significant for immunologists interested in innate-like T cell biology and advancing the understanding of γδ T cell differentiation and maintenance.

eLife Assessment

This study is useful because it challenges the widely accepted notion that muscle stem cell numbers decline with aging, providing novel insights into population heterogeneity and the identification of new surface markers for geriatric MuSCs. However, the evidence is considered incomplete due to insufficient quantitative comparisons of absolute cell numbers, limited analysis of age groups (particularly the lack of "aged" mice as opposed to geriatric), and the need for further functional and mechanistic validation of key subpopulations. Additional concerns that require clarification include the lack of statistical rigor in some experiments, the presentation of supporting data not being complete, and the overextension of claims relating to senescence and new marker validation. Overall, while the findings advance understanding of MuSC aging, the conclusions drawn by the authors should be strengthened with expanded experiments and more rigorous data analysis.

eLife Assessment

This useful paper examined the mechanism of planar cell polarity (PCP) using Drosophila pupal wing, investigating how 'cellular level', 'molecular level' and 'tissue level' mechanisms intersect to establish PCP. This represents progress for the field and the conclusions are mostly backed up by solid data. Whereas the manuscript is sound overall, remaining concerns could be addressed by textual clarification of the concepts used in the manuscript.

[Editors' note: this paper was reviewed by Review Commons and revised by the authors.]

eLife assessment

This important study provides novel evidence that navigational experiences can shape perceptual scene representations. The evidence presented is incomplete and would benefit from clearer explanations of the experiment design and careful discussion of alternative interpretations such as contextual associations or familiarity. The work will be of interest to cognitive psychologists and neuroscientists working on perception and navigation.

[Editors’ note: A revised version of this work has been published in the Journal of Cognitive Neuroscience (DOI: https://doi.org/10.1162/JOCN.a.2409).]

eLife Assessment

The reviewers have found that this manuscript is a valuable contribution, and the evidence in support of its conclusions is mostly solid. It provides novel insights and raises interesting possibilities about the functions of an understudied histone modification within the nucleosome core; however, the data are mostly descriptive and correlative, and although this has value, it is not totally persuasive. Short of additional non-genomic experiments, a more detailed analysis of the genomic data and perhaps additional data would strengthen the conclusions. The manuscript crucially needs further antibody validation to raise confidence in the data.

eLife Assessment

This study provides fundamental insights into eukaryotic phosphate homeostasis by demonstrating how yeast vacuoles dynamically regulate cytosolic phosphate levels. The conclusions are convincing, supported by an elegant combination of in vitro assays and in vivo measurements. This study will be of interest to cell biologists, particularly for those who are working in the field of phosphate metabolism.

eLife Assessment

The mechanistic basis for the potential health benefits of NAD⁺ precursors remains incompletely understood. This manuscript provides a useful assessment of the role of SIRT1 in mediating the effects of NMN in mice fed a high-fat diet. The study addresses a key question, though some of the conclusions appear only partially supported by the presented data.

eLife assessment

The authors identify a novel, conserved link between glycolytic flux and sulfur amino acid metabolism that governs fungal morphological differentiation independently of the cAMP-PKA pathway. This represents an important conceptual advance in understanding metabolic control of development and virulence. While the evidence supporting this connection is compelling, the mechanistic basis of how glycolysis regulates the Met30/Met4 axis requires further experimental clarification.

eLife Assessment

This valuable work investigates the role of protein N-glycosylation in regulating T-cell activation and function and suggests that B4GALT1 is a potential target for tumor immunotherapy. The strength of evidence is solid, and further mechanistic validation could be provided.

Baldwin contends that Black English is a legitimate language forged by historical necessity and bound to power and identity, and that contempt for it is contempt for Black experience.

Angle most relevant to my theme: Language as power/identity vs. “neutral standard.”

Alvarez, Wan, and Lee advocate a translingual orientation that treats students as “language architects,” offering concrete strategies to bring full language resources into academic writing.

Angle most relevant to my theme: Pedagogy that legitimizes multilingual voice and challenges monolingual standards.

Young argues that teachers should teach and value code meshing—blending dialects and languages within the same text—and reject a single “standard” as the only acceptable academic or professional English.

Angle most relevant to my theme: Language plurality as both pedagogy and justice.

Heller argues that Bambara’s use of AAVE in “The Lesson” constructs realism, affirms Black identity, and equips the narrator to critique inequality and resist dominant norms.

Angle most relevant to my theme: Vernacular as a tool of critique and agency.

Jenkins argues that mastering Standard American English is essential for professional success and is not inherently discriminatory.

Angle most relevant to my theme: SAE as pragmatic, workplace-driven convention for cross-audience communication.

eLife Assessment

This study presents SegPore, a valuable new method for processing direct RNA nanopore sequencing data, which improves the segmentation of raw signals into individual bases and boosts the accuracy of modified base detection. The evidence presented to benchmark SegPore is solid, and the authors provide a fully documented implementation of the method. SegPore will be of particular interest to researchers studying RNA modifications.

eLife Assessment

This valuable study provides insights into the role of Pten mutations in SHH-medulloblastoma, by using mouse models to resolve the effects of heterozygous vs homozygous mutations on proliferation and cell death throughout tumorigenesis. The experiments presented are convincing, with rigorous quantifications and orthogonal experimentation provided throughout, and the models employing sporadic oncogene induction, rather than EGL-wide genetic modifications, represent an advancement in experimental design. However, the study remains limited, such that the biological conclusions do not extend greatly from those in the extant literature. This could be addressed with additional experimentation focused on cell cycle kinetic changes at early stages, as well as greater characterization of macrophage phenotypes (e.g., microglia vs circulating monocytes). The work will be of interest to medical biologists studying general cancer mechanisms, as the function of Pten may be similar across tumor types.

eLife Assessment

Pinho et al use in vivo calcium imaging and chemogenetic approaches to examine the involvement of hippocampal sub-regions across the different stages of a sensory preconditioning task in mice. They find evidence for sensory preconditioning in male mice. They also find that, in these mice, CaMKII-positive neurons in the dorsal hippocampus encode the audio-visual association that forms in stage 1 of the task. The evidence in support of these findings is convincing. The important study will be of interest to researchers in the fields of learning and memory and/or hippocampus function.

eLife Assessment

This Research Advance manuscript further elucidates the roles of SMC5/6 loader proteins and associated factors in the silencing of extrachromosomal circular DNA by the SMC5/6 complex. While the findings are largely in line with expectations, they are valuable, representing a meaningful advance beyond the recent study from the same laboratories (PMC9708086), validating the previous model that distinct SMC5/6 subcomplexes, SIMC1-SLF2 and SLF1/2, separately control its transcriptional repression and DNA repair activities on extrachromosomal DNA. Solid evidence is presented for a role for SIMC1/SLF2 in localization of the SMC5/6 complex to plasmid DNA, and the distinct requirements as compared to recruitment of SMC5/6 to chromosomal DNA lesions.

eLife Assessment

This paper provides potentially valuable insight into why memory consolidation may differ between children (5-7 years of age) and adults. The work hints at developmental differences in neural engagement during the retrieval of recent and remote memories. However, there are several major concerns with the analyses not alleviated by included controls, and as such the evidence supporting the authors' main claims remains incomplete.

eLife Assessment

This study presents fundamental insights into overcoming resistance in hormone receptor-positive breast cancer by demonstrating that sustained CDK4/6 inhibitor treatment, either alone or in combination with CDK2 inhibitors, significantly suppresses the growth of drug-resistant cancer cells. The findings are supported by compelling evidence from both in vitro cell line experiments and in vivo mouse models, highlighting the therapeutic potential of maintaining CDK4/6 inhibitors beyond disease progression. Additionally, the identification of cyclin E overexpression as a key driver of resistance offers a target that will be of value for future therapeutic strategies, potentially improving outcomes for patients with advanced breast cancer.

eLife Assessment

The study provides important mechanistic insight into the transcriptional control of γδT17 development, elegantly demonstrating how HEB and Id3 act sequentially and cooperatively to regulate γδT17 cell specification and maturation. The study provides compelling evidence that advances the understanding of E-Id protein dynamics in thymic T cell specification. The work is comprehensive, technically rigorous, and conceptually clear, and will be of interest to immunologists, developmental biologists, and those studying the molecular underpinnings of physiological outcomes.

eLife Assessment

This useful manuscript reports findings indicating that cell cycle progression and cytokinesis both play a role in the transition of early to late neural stem cell fates. The imaging data are solid and mostly support the conclusions. However, experimental details are missing, the method of quantitation could be improved, and orthogonal approaches are needed to confirm the findings, which are based on loss-of-function approaches and are not sufficient to support some of the authors' conclusions. Lastly, there is no investigation of the underlying mechanism linking the cell cycle or cytokinesis to the changes (or lack thereof) of early and late NSC fates.

eLife Assessment

The manuscript by Hensley and Yildez studies the mechanical behavior of kinesin under conditions where the z-component of the applied force is minimized. The important study shows that much of the mechanical information gleaned from the traditional "one bead" with attached kinesin approach was probably profoundly influenced by the direction of the applied force. The data are convincing, but in some cases the amount of data collected appears to be smaller than optimal.

eLife Assessment

This important manuscript presents a thorough analysis of the evolution of Major Histocompatibility Complex gene families across primates. A key strength of this analysis is the use of state-of-the-art phylogenetic methods to estimate rates of gene gain and loss, accounting for the notorious difficulty to properly assemble MHC genomic regions. Overall the evidence for the authors' conclusions – that there is considerable diversity in how MHC diversity is deployed across species – is compelling.

eLife Assessment

This important study demonstrates that some degree of spatial tuning (e.g., place cells) and ability to decode spatial location emerges in sufficiently complex systems trained to process visual information. This intriguing observation challenges existing approaches and findings used in the study of spatial navigation. However, the strength of evidence regarding the nature and quality of spatial tuning, its compatibility with experimental data, and the overall interpretation of the study remains incomplete. This work will be of interest to the research community of spatial navigation.

eLife Assessment

This important study uses an original method to address the longstanding question of why reaching movements are often biased. The combination of a wide range of experimental conditions and computational modeling is a strength. Solid evidence is presented in support of the main claim that most of the biases in 2-D movement planning originate in misalignment between visuo-proprioceptive reference frames.

eLife Assessment

This study provides solid evidence that odor fear conditioning biases olfactory sensory neuron receptor choice in mice and that this bias is detectable in the next generation. The authors use rigorous histological and behavioral analyses, including unsupervised behavioral quantification, to support the conclusion that odor-specific sensory representations can be shaped by experience and partially transmitted across generations. While the behavioral effects in offspring are modest and the mechanistic basis of inheritance remains unresolved, the study offers an important and carefully executed contribution to understanding experience-dependent sensory plasticity and its intergenerational consequences.

eLife Assessment

This useful study characterizes the evolution of medial prefrontal cortex activity during the learning of an odor-based choice task. The evidence provided is solid, providing quantification of functional classes of cells over the course of learning using the longitudinal calcium recordings in prefrontal cortex, and quantification of prefrontal sequences. However, the experimental design appears to provide limited evidence to support strong conclusions regarding pre-existing representations or the functional relevance of neural sequences. The study will be of interest to neuroscientists investigating learning and decision-making processes.

eLife Assessment

This study developed a novel continuous dot-motion decision-making task, in which participants can see another player's responses as well as their own, to measure perceptual performance and confidence judgments in a social context. The study is a valuable contribution to social decision-making primarily by introducing a new task and offering convincing evidence on how participants are impacted by others' decisions during continuous perceptual choices. The manuscript delivers clear evidence that participants judgements are driven by metacognitive confidence over simpler primary uncertainty.

eLife Assessment

This study provides a valuable genome-centric characterization of microbial communities across deep sediment cores from a Spartina patens salt marsh. The study provides claims on the metabolic capabilities of the deep sediment microbiome as well as on a burial microbial assembly process and functional complementarity at depth. However, some of these claims remain incomplete and would benefit from further supporting evidence. Overall, this work will be of interest to microbial ecologists working on wetlands.

eLife Assessment

The authors used a Bayesian modeling framework to fit behavior and serotonin neuron activity to reward history across multiple timescales. A key goal was to distinguish value coding from other influences, particularly thirst, by comparing model fits across neurons. Although the question and approach are valuable, several limitations of the current manuscript mean that support for the conclusions is incomplete.

eLife Assessment

This important study advances our understanding of vertebrate forelimb development, specifically the contribution of Hox genes to zebrafish pectoral fin formation. The authors have employed a robust and extensive genetic approach to tackle a key and unresolved question. The findings are overall convincing and will be of broad interest to developmental and evolutionary biologists.

eLife Assessment

By leveraging optical coherence tomography this study provides important insight into the deformation of human fingertip ridges when contacting raised features such as edges and contours. The study provides compelling evidence that such features tend to cause deformation and relative movement of what the authors term ridge flanks rather than bending of the ridges themselves.

eLife Assessment

The authors have performed a potentially valuable new kind of analysis in connectomics, mapping to an interesting developmental problem of synaptic input to sensory neurons. While the analysis itself is solid, the authors have drawn broader conclusions than are directly supported by the presented data. With more measured claims and greater clarity and explanations for the analysis, the study could potentially become stronger.

eLife Assessment

This study provides a valuable contribution to understanding how negative affect influences food-choice decision making in bulimia nervosa, using a mechanistic approach with a drift diffusion model (DDM) to examine the weighting of tastiness and healthiness attributes. The solid evidence is supported by a robust crossover design and rigorous statistical methods, although concerns about the interpretation of group differences across neutral and negative conditions limit the interpretability of the results.

eLife Assessment

This study provides an important advance in credibility-based learning research by demonstrating how feedback reliability can shape reward learning biases within a carefully controlled bandit task. The strength of the main findings, namely greater learning from credible feedback and robust computational modeling supported by strong parameter recovery and cross-fitting analyses, is compelling. The integration of reinforcement learning and Bayesian benchmark models is methodologically rigorous and well-executed, yielding reliable and interpretable results. The revised manuscript shows clear improvements in theoretical framing and transparency regarding limitations. While additional work is warranted to confirm the role of disinformation in amplifying positivity bias and to explore symptom-related variability or richer Bayesian comparators, this paper represents a high-quality and impactful contribution to the study of learning under uncertainty and misinformation.

eLife Assessment

This valuable study provides a large-scale EEG investigation into how visual deep neural networks (DNNs) and large language models (LLMs) differentially explain the temporal dynamics of visuo-semantic processing in the human brain. Although evidence convincingly shows that DNNs account for early perceptual responses, while LLMs capture later, low-frequency activity associated with semantic integration, the theoretical interpretation of LLM contributions and methodological aspects - including task engagement, justification of model choices, and dimensionality reduction - requires further clarification. The work will be of broad interest to fields of psychology, cognitive neuroscience, and artificial intelligence.

eLife Assessment

This valuable work defines a "learning proteome" for a C. elegans gustatory associative learning paradigm. These results provide the field with a new set of genes to further explore their roles in learning and memory, provide new tools for other labs to employ in their investigations of behavior, and molecular pathways revelant for C. elegans learning and memory. The methodological evidence and the quality of the dataset are convincing. The results will be of interest to neuroscientists and developmental biologists seeking to understand the self-assembly and operation of neural circuits for learning and memory.

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

eLife Assessment

This important study identifies a novel CRF-positive projection from the central amygdala and BNST to dorsal striatal cholinergic interneurons, revealing a previously unrecognized pathway by which stress signals modulate striatal function. The authors present strong and convincing evidence for the anatomical and functional connectivity of this circuit and demonstrate that alcohol disrupts CRF-mediated cholinergic activity, supporting its relevance to alcohol use disorder.

eLife Assessment

This study offers a valuable advance for neuroscience by extending a visualization tool that enables intuitive assessment of how dendritic and synaptic currents shape the output of neurons. The evidence supporting the tool's capabilities is convincing and solid, with well-documented code, algorithmic innovation, and application to hippocampal pyramidal neurons - although experimental confirmation of the predictions is not provided. The work will be of interest to computational and systems neuroscientists seeking accessible methods to examine dendritic computations.

eLife Assessment

This study presents valuable findings from a spatiotemporal analysis of arbovirus case notification data from 2013 to 2020 in Brazil, reporting associations between covariates representing potential drivers of arbovirus transmission and recorded incidence. The work is methodologically solid, though it is unclear how much explanatory power inclusion of the covariates adds. The findings will be of interest to researchers working on the epidemiology of arboviruses.

eLife Assessment

This important study investigates how the nervous system adapts to changes in body mechanics using a tendon transfer surgery that imposes a mismatch between muscle contraction and mechanical action. Using electromyography (EMG) to track muscle activity in two macaque monkeys, the authors conclude that there is a two-phase recovery process that reflects different underlying strategies. However, neither monkey's data includes a full set of EMG and kinematic measurements, and the two datasets are not sufficiently aligned with each other from a behavioural point of view; as a result, the evidence supporting the conclusions is solid but could be improved.

eLife Assessment

This paper contains valuable ideas for methodology concerned with the identification of genes associated with disease prognosis in a broad range of cancers. However, there are concerns that the statistical properties of MEMORY are incompletely investigated and described. Further, more precise details about the implementation of the method would increase the replicability of the findings by other researchers.

eLife Assessment

Davies et al. present a valuable study proposing that Shot can act as a molecular linker between microtubules and actin during dendrite pruning, suggesting an intriguing role in non-centrosomal microtubule organization. However, the experimental evidence is incomplete and does not robustly support these claims, and the lack of a cohesive model connecting the findings weakens the overall impact. While the data suggest that Shot, actin, and microtubule nucleation contribute to dendritic pruning, their precise interplay remains unresolved.

eLife Assessment

This study presents experiments suggesting intriguing mesoscale reorganization of functional connectivity across distributed cortical and subcortical circuits during learning. The approach is technically impressive and the results are potentially of valuable significance. However, in its current form, the strength of evidence is incomplete. More in-depth analyses and the acquisition of data from additional animals in the primary experiment could bolster these findings.

eLife Assessment

This study investigates how sleep loss and circadian disruption affect whole-organ metabolism in flies (Drosophila melanogaster) and reports that wild-type flies align metabolism in anticipation of diurnal rhythm, while mutant flies with impaired sleep or circadian function shift to reactive or misaligned metabolism. The integration of chamber-based flow-through respirometry with LC-MS metabolomics is innovative, and the significance of the findings is valuable. However, the strength of evidence needed to support the conclusions is incomplete based on concerns regarding the inappropriate use of constant darkness to disrupt circadian rhythms and the lack of details justifying the methods used to correlate respirometry data with whole-body metabolomics.

eLife Assessment

This important work presents technical and conceptual advances with the release of MorphoNet 2.0, a versatile and accessible platform for 3D+T segmentation and analysis. The authors provide compelling evidence across diverse datasets, and the clarity of the manuscript together with the software's usability broadens its impact. Although the strength of some improvements is hard to fully gauge given sample complexity, the tool is a significant step forward that will likely impact many biological imaging fields.

eLife Assessment

The study presents important insights into the regulation of muscle hypertrophy, regulated by Muscle Ankyrin Repeat Proteins (MARPs) and mTOR. The methods are overall solid and complementary, with only minor limitations. Overall, the findings will be of interest for both muscle-biology specialists and the broader mechanobiology community.

eLife Assessment

This important study examines the potential role of ARHGAP36 transcriptional regulation by FOXC1 in controlling sonic hedgehog signaling in human neuroblastoma. While there are many solid findings that strongly support this signaling pathway, there are some aspects of the study that are underdeveloped.

eLife Assessment

This study is important as it demonstrates that 4-aminoquinoline antimalarials antagonize artemisinin activity under physiologically relevant conditions. Using isogenic parasite lines and a chemical probe, the authors provide mechanistic insight and compelling evidence implicating PfCRT in this antagonism. However, some weaknesses have been identified that limit full interpretation of the findings, which are based solely on in vitro assays, though the results have implications that will be of importance in optimizing future antimalarial combination strategies.

eLife Assessment

This study presents vassi, a Python package that streamlines the preparation of training data for machine-learning-based classification of social behaviors in animal groups. This package is a valuable resource for researchers with computational expertise, implementing a framework for the detection of directed social interactions within a group and an interactive tool for reviewing and correcting behavior detections. However, the strength of evidence that the method is widely applicable remains incomplete, performance on benchmark dyadic datasets is comparable to existing approaches, and performance scores on collective behavioral datasets are low. While the package can analyze behavior in large groups of animals, it only outputs dyadic interactions within these groups and does not account for behaviors where more than two animals may be interacting.

Summary: The study shows that when students can use their full linguistic repertoires, participation rises and learners demonstrate more creativity and imagination in multilingual classrooms (p. 1). Why it matters: This frames translanguaging as both inclusive and academically productive.

eLife Assessment

This study provides useful insights into the ways in which germinal center B cell metabolism, particularly lipid metabolism, affects cellular responses. The authors use sophisticated mouse models to demonstrate that ether lipids are relevant for B cell homeostasis and efficient humoral responses. Although the data were collected from in vitro and in vivo experiments and analyzed using solid and validated methodology, more careful experiments and extensive revision of the manuscript will be required to strengthen the authors' conclusions.

eLife Assessment

This paper presents a computational method to infer from data a key feature of affinity maturation: the relationship between the affinity of B-cell receptors and their fitness. The approach, which is based on a simple population dynamics model but inferred using AI-powered Simulation-Based Inference, is novel and valuable. It exploits recently published data on replay experiments of affinity maturation. While the method is well-argued and the validation solid, the potential impact of the study is hindered by its complex presentation, which makes it hard to assess its claims reliably.