Evaluated articles

eLife Assessment

This valuable proof-of-concept study tests and validates a novel magnetic resonance-based method - proton-observed proton-edited MRS - for tracking glucose metabolism in the brain beyond simple substrate uptake, without the need for specialist hardware typically restricted to research settings. The approach offers a promising way to assess excitation/inhibition balance by detecting labelled glucose metabolites. The pre-clinical data in mouse models provide convincing support for the authors' hypothesis. The evidence in the human brain is incomplete: the results would require further optimisation of the experimental set-up and validation in a larger group of volunteers. This work will be of broad interest to researchers studying psychiatric, neurodevelopmental, and related brain disorders.

eLife Assessment

There is a significant need for improved understanding of the neural circuit mechanisms for learning and memory dysfunction in Alzheimers disease. In this valuable study, Zheng and colleagues compare neural coding between wild-type and App knock-in rats experiencing different contexts. Solid evidence of a difference emerges when "spatial" and "temporal" neural coding dynamics are considered separately. However, the lack of a link between neural coding and behaviorally measured learning, and minor issues with the analyses, are limiting factors of the evidence and the significance of the work.

eLife Assessment

This important study demonstrates that pyroglutamylation of peptide ligands alters G protein-coupled receptor (GPCR) activation in a subtype-specific manner and proposes a novel mechanism whereby the posttranslational modification steers the distal conformation of the peptide within the orthosteric binding site. The strength of the evidence supporting receptor-specific functional effects is convincing, but the strength of the evidence supporting the proposed structural mechanism is incomplete. This study will be of interest to pharmacologists and cell biologists interested in posttranslational modifications (PTMs) and activation mechanisms of GPCRs.

eLife Assessment

This important paper studies how adiposity affects brain development in the ABCD study. Major findings include: (1) central adiposity indices (BRI, WHtR) show stronger cross-sectional associations with cognition than BMI, partially mediated by frontotemporal cortical morphology; (2) the rate of adiposity accrual, rather than static adiposity at either timepoint, predicts follow-up cognition and altered (attenuated) cortical thinning; and (3) among overweight/obese adolescents, central fat reduction is accompanied by accelerated cortical thinning and catch-up in inhibitory control. The strength of evidence is solid, with the main limitation related to only looking at the cerebral cortex rather than examining the whole brain. The subgroup observation that fat reduction may be accompanied by normalization of both cortical trajectories and inhibitory control is potentially clinically meaningful, suggesting reversibility rather than fixed deficit, and would be of broad interest if it withstands more rigorous analysis.

eLife Assessment

This in vitro study provides important evidence that the mitochondrial intermembrane space protein HAX1 functions as a direct activating cofactor of the AAA+ chaperone CLPB, resolving a longstanding question arising from the strong genetic, proteomic, and disease associations between these proteins. The convincing work advances our understanding of mitochondrial proteostasis by demonstrating that HAX1 promotes CLPB oligomerization and will potentially even enable the generation of small molecules that mimic the function of HAX1 in CLPB activation. The study will be of general interest to biochemists working on chaperones and/or mitochondrial biology.

eLife Assessment

This valuable study provides a detailed three-dimensional characterization of primary cilia organization in the postnatal mouse growth plate, revealing reproducible spatial patterns in ciliation, ciliary length, and orientation. The evidence supporting these descriptive findings is solid, based on high-quality quantitative imaging and complementary genetic, mechanical, and transcriptomic approaches. However, evidence for the broader mechanistic conclusions is incomplete, particularly regarding whether ciliary orientation is uncoupled from basal-body and cell orientation and whether its stability under altered mechanical loading reflects a cell-intrinsic program. The study provides a helpful foundation for understanding primary cilia organization and mechanobiology in the growing skeleton, while the mechanisms underlying these observations remain to be established.

eLife Assessment

This valuable study investigates the action of a floral homeotic transcription factor in different cell types. The results provide solid evidence that PhDEF shows more extensive binding and regulatory effects in the epidermis than in the mesophyll, supporting the conclusion that cell-layer context influences homeotic gene function. While there are some limitations, they do not undermine the principal observation of layer-dependent PhDEF activity, but the interpretation of the data is complicated by uncertainties in cell-type assignment and composition in the scRNA-seq data, the cell-type-enriched rather than strictly cell-type-specific nature of the ChIP-seq data, and differences in developmental stage between the single-cell and ChIP-seq experiments. The work will be of interest to developmental biologists studying transcriptional regulation and cell identity.

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

eLife Assessment

This is a potentially valuable study in the area of connectomics, comparing across species to obtain a uniform synaptic density of ~1 synapse per micron. While the methods add to the field, the datasets are limited and filtered, and the role of cell-type on spacing is passed over. Additionally, some of the analyses could be tightened; hence, overall, the findings remain incomplete.

eLife Assessment

This valuable study provides a very large data set of motor unit recordings in people with multiple sclerosis and, as such, could impact both foundational and clinical studies of the neuromuscular system. The study reports increased variability in firing rate profiles across participants and suggests that this observation reflects differences in the excitatory, inhibitory, and neuromodulatory drive reaching motor neurons. The descriptive finding is solid, but the link to specific neural mechanisms is incomplete as it depends heavily on assumptions related to its model-based framework.

eLife Assessment

This study establishes the fast-developing tuxedo sea urchin, Mespilia globulus, as a genome-enabled experimental model. With the tools and methods described here, the authors provide a valuable platform with particular potential for developmental biology and physiology as well as comparative studies. The evidence supporting the principal claims of experimental tractability and quality of genomic resources is solid, although fuller documentation, e.g., of husbandry, aquarium-stock provenance and genetic diversity as well as gene-editing efficiency and imaging set up, would strengthen the work. This work will be of particular interest to developmental and evolutionary biologists.

eLife Assessment

The study presents a valuable dataset and analysis on two sympatric Mediterranean clingfishes which will be of interest to the fields of evolutionary genomics, population genetics and comparative phylogeography, and especially to marine biologists working on population connectivity. The comparative design provides solid evidence that contemporary connectivity is more predictable across species than deeper phylogeographic and demographic history. The analysis of the genomic data, which is still incomplete, would benefit from further work and clarification, particularly regarding the evidence for parallel genomic divergence.

eLife Assessment

This valuable study identifies the IL1R1-IRAK4 axis as a mediator of inflammation-associated ovarian cancer implantation. The evidence is convincing, supported by complementary genetic and pharmacological approaches across multiple in vivo models. These findings advance our understanding of how inflammatory signaling shapes metastatic niche formation and highlight IRAK4 as a potential therapeutic target.

eLife Assessment

This study presents a useful approach to analyzing brain responses to transcranial focused ultrasound (tFUS), and potentially to neuromodulation-evoked activity more generally. By applying ideas from physics, it reveals changes in brain activity that measures of signal strength alone do not capture. The authors report a surprising non-monotonic relationship between irreversibility and stimulation dose, and a relationship between baseline irreversibility and susceptibility during stimulation. The evidence for the central interpretation remains incomplete, however: it is not yet clear that these changes reflect genuine reorganization of brain activity rather than artifacts of the calcium-recording method or an unaccounted-for side effect of the stimulation itself.

eLife Assessment

In this important study, Abdelnaby and colleagues systematically examine the four native Orai channel isoforms (Orai1α, Orai1β, Orai2, and Orai3) and find that all can couple to NFAT1/4 activation, with NFAT responses largely scaling with the magnitude of Ca2+ influx (Orai1β > Orai1α >> Orai2 > Orai3). The study shows that in primary CD4⁺ T cells, Orai1α and Orai1β are functionally redundant, restoring SOCE, NFAT activation, cytokine production, and highly similar transcriptional programs. Human genetic data further show that selective loss of Orai1α does not cause CRAC channelopathy and instead slightly enhances SOCE and NFAT activation. Overall, the findings are significant, and the strength of the evidence supporting the conclusions is convincing.

eLife Assessment

The work provides a valuable analytical and technical framework for relating spatial microRNA patterns to therapeutic response and features of the tumor immune environment in a BRCA1-associated model of triple-negative breast cancer. The evidence supporting the main conclusions is solid, although additional validation and statistical analyses would strengthen claims regarding biomarker performance and the specific contribution of spatial measurements.

eLife Assessment

This important study shows that neural responses to visual input during active vision are more closely aligned with self-generated eye movements than with fixation onset. The evidence for neural responses being more aligned to saccade-related events than fixation-related events is convincing, but the evidence for the more novel finding that neural responses are most closely aligned to peak saccade curvature is currently incomplete. This work will be of interest to visual perception and sensory processing researchers.

eLife Assessment

The manuscript presents a primary important finding, namely that microbial riboflavin-derived MR1 ligands are pharmacological activators of human MAIT cells and that MR1 ligand stimulation enhances MAIT-mediated tumor killing across multiple tumor models. While the evidence presented is generally solid, there are some limitations of the in vitro and in vivo models used, as well as some overstatements about the broader applicability of the research, which should be revised.

eLife Assessment

This study shows that partial cone photoreceptor loss induces pathway-specific circuit remodeling in the mouse retina, with alpha OFF-sustained and OFF-transient retinal ganglion cells adapting differently through changes in their pre- and postsynaptic circuits. The results are valuable because they provide a key understanding of the diversity of circuit remodeling in retinal degeneration. The data are convincing, although clearer reporting of the numbers of independent animals and retinas, a more rigorous distinction between compensation and circuit change, and discussion of the functional consequences would strengthen the mechanistic insights.

eLife Assessment

This study presents valuable findings regarding the role of the P2X7 receptor in retinoic acid signaling-mediated retinal remodeling following photoreceptor degeneration. However, the evidence supporting the main conclusions is currently incomplete, as key comparisons are confounded by differences in genetic background, and the cellular source of receptor expression is not sufficiently resolved. While the work offers mechanistic insights of interest to researchers studying retinal degeneration, additional experimental controls are needed to fully support the authors' claims.

eLife Assessment

This important work considerably advances our understanding of the nature of ongoing thought across individuals and across task contexts. Using a combination of fMRI brain data and experience sampling, they find that activation of the MDN leads to greater stability of deliberate task-focused thoughts during task performance. The evidence supporting the claims is convincing and both analytically strong and creative, offering a novel approach to capture thought stability and its relationship to independent brain maps. The findings will be of broad interest to cognitive scientists and neuroimagers.