Evaluated articles

eLife Assessment

This study presents a useful application of trans-omic network analyses to existing human brain datasets, generating systems-level insights into metabolic dysregulation in Alzheimer's disease. Overall, the authors' analytical choices are solid, with appropriate use of existing data and methods, and with many of their results confirming previous findings. However, some of the authors' key claims, related to previously unknown details of regulatory relationships, are only partially supported due to limitations in dataset cell-type resolution and network robustness, as well as a lack of functional validation. This work will be of interest to cellular or systems neurobiologists studying Alzheimer's disease and could serve as a helpful starting point for future work.

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

eLife Assessment

This valuable study describes PXGS, a poly-transgene expression system that exploits the mutually exclusive splicing of Dscam variable exon 4 to enable conditional, simultaneous expression of up to 12 transgenes in Drosophila, addressing a longstanding limitation in which conditional co-expression has been restricted to a handful of genes. The approach is conceptually elegant and technically accessible, with potential applications spanning neuroscience, synthetic biology, and biomanufacturing across arthropod species. The evidence that Dscam exon 4 splicing is preserved in a UAS vector and that individual alternates can be replaced with functional transgenes is solid, and the in vivo axonal re-wiring application provides a convincing proof of principle. Quantitative characterization of expression levels, a direct demonstration of expression across all twelve positions, and additional imaging controls would further substantiate the system's utility and scope.

eLife Assessment

This study presents a valuable finding on linking the frequency of neural activity to cortical depths of blood flow in a naturalistic setting of participants listening to music. The presentation of evidence in the version of the original submission is incomplete, as further clarifications in methods and results, as well as performing additional analyses, would strengthen the study. The work will be of interest to cognitive neuroscientists working on multimodal recordings, auditory perception and music.

eLife Assessment

This study provides a useful anatomical resource by mapping the expression of four putative chemoreceptors in spinal cerebrospinal fluid-contacting neurons (CSF-cNs) of larval zebrafish. These descriptive findings offer an interesting entry point to explore how the nervous system senses signals within the spinal fluid microenvironment. The evidence supporting the spatial expression patterns of these receptors is convincing, utilizing high-resolution hybridization chain reaction (HCR) to validate previous transcriptomic data. However, the evidence remains incomplete regarding the actual functional roles of these receptors, as the study lacks protein-level validation, evidence of ligand availability in the CSF, or functional assays to demonstrate active chemoreception.

eLife Assessment

This work provides a reassessment of VBIT-4, a compound previously proposed to inhibit oligomerization of the crucial protein known as the mitochondrial voltage-dependent anion channel. Combining complementary experimental approaches with molecular dynamics simulations, the authors provide compelling evidence that VBIT-4 primarily disrupts lipid membranes and induces channel-independent cytotoxicity. The study has important implications for interpreting previous work using VBIT-4 as a probe of channel function and highlights the need to consider membrane-disruptive effects when evaluating drug mechanisms.

eLife Assessment

This valuable study provides novel evidence that congenital aphantasia is associated with structural differences in frontotemporal and cingulate systems, with relative sparing of early visual regions and major visual pathways. The multimodal structural imaging approach is carefully implemented and will be of interest to researchers studying mental imagery and aphantasia. However, the strength of evidence is incomplete because the data cannot adjudicate between alternative cognitive interpretations, and the multiple discovery streams make the findings better viewed as key exploratory evidence, rather than as establishing a definitive structural phenotype of aphantasia.

eLife Assessment

This useful study combines experiments and mathematical modeling to show that antibiotic protection provided by resistant cells can extend across both surface-associated and freely growing bacterial populations. Notably, they show that treatment efficacy depends on population composition and density. The evidence supporting the main conclusions is incomplete, primarily because the biofilm context is not adequately characterized and demonstrated, raising the concern that it might represent only an aggregate of cells on the surface (rather than a biofilm) under the studied experimental conditions.

eLife Assessment

This important study provides the first in vivo evidence that nonsense-mediated mRNA decay (NMD) in mature astrocytes regulates astrocyte function, synaptic plasticity, and anxiety-related behavior. Using a broad range of approaches, the authors show that conditional deletion of Upf2 alters astrocyte morphology and calcium signaling while impairing synaptic transmission and plasticity, providing solid support for the central conclusion that astrocytic NMD influences neural circuit function. Some key mechanistic claims remain incompletely supported, including whether phenotypes reflect astrocyte remodeling versus loss, the interpretation of synaptic engulfment data, the link between NMD targets and calcium signaling, and the extent to which calcium dysregulation explains the observed synaptic and behavioral effects.

eLife Assessment

This fundamental manuscript describes a key role for the integrated stress response-regulated transcription factor CHOP in regulating liver biology in response to endoplasmic reticulum stress through both the downregulation of transcription factors involved in regulating hepatic identity and altering the capacity for integrated stress response and unfolded protein response signaling to induce protective signaling. The data supporting this model is convincing, but including some additional discussion on the mechanism and importance of the work in the context of the published literature would be helpful to better define the complex importance of CHOP signaling. This work will be of interest to a wide range of biologists interested in liver biology, stress-responsive signaling, and ER stress.

eLife Assessment

This is a valuable paper looking at nanoscale organization of the membrane associated periodic cytoskeleton in mouse sciatic nerve axons. Despite previous studies, the precise organisation of the structure remains unclear, especially in vivo, and this manuscript significantly adds to this knowledge with solid data. An unexpected observation is the presence of discrete nanoscale clusters, regularly distributed around sections of axons. However, the paper misses a description of these clusters along the longitudinal axis of the axons.

eLife Assessment

This useful study reports on lifespan extension in C. elegans males that carry a mutation in a gene for an insulin receptor; while the observations are striking, the strength of evidence is currently incomplete. The central claim of male-specificity is undermined by the absence of direct hermaphrodite healthspan comparisons, and the reliance on a single mutant allele leaves open the possibility that background mutations, rather than daf-2 loss-of-function, drive the phenotype. Methodological details critical for reproducibility are also lacking, particularly regarding male housing density, censoring of plate-leaving animals, and the adequacy of replication for the key epistasis experiment. The work could be substantially strengthened by a targeted set of additional experiments and fuller engagement with the existing literature on sex-specific aging in C. elegans.

eLife Assessment

Building on earlier studies, this manuscript reports a role for pol kappa in cisplatin resistance in the very specific scenarios of head and neck squamous cell carcinoma, providing evidence that the PIP box of Pol kappa is critical for cisplatin resistance in these cells. The findings are of a highly focused relevance and will be useful in the field, but the conclusions are limited to very specific cancer cells. Conclusions cannot be generalized to all cisplatin resistance mechanisms and cell types and are based on incomplete evidence that presents uncertainties and discrepancies that need to be resolved.

eLife Assessment

This is a potentially important study comparing LTP mechanisms between primates and rodents. The experimental methods have some possible confounds, and the power (replicates) and design of the statistical methods could be strengthened, hence the support for the central claims of species differences is currently incomplete.

eLife Assessment

This important study assessed the replicability of a selection of lab-based biomedical experiments in papers published by authors based in Brazil. The study adds a unique perspective to the literature on replication, and provides rich data on the approach taken, the outcomes, and the challenges involved in conducting large-scale crowd-sourced research. The evidence supporting the claims is convincing, but there is scope for clarifying the presentation of the results and extending the discussion section.

eLife Assessment

This study presents an important finding regarding the effect of Yoda molecules on PIEZO2 function, challenging the assumption that they selectively activate PIEZO1. The evidence supporting this claim is solid, but several methodological and conceptual issues need to be addressed. Overall, this work will be of broad interest to researchers working with PIEZO channels across various biological scales.

eLife Assessment

This important study investigates how surface stickiness shapes whisker mechanics and peripheral neural responses during active touch. The biomechanical evidence that surface stickiness alters whisker mechanics and stick-slip dynamics is compelling, supported by a large and high-quality 3D dataset, while the electrophysiological evidence is solid but limited by a small sample size and insufficient validation of the sticky stimuli. The work will be of broad interest to sensory neuroscientists studying active touch.

eLife Assessment

This study presents a useful compendium of triangulated single-cell eQTLs, Mendelian randomisation and colocalization of genetic signals in prostate cancer datasets. Biological interpretation in the context of the aging prostate gland, the tumour microenvironment and immune cell specificity is incomplete, so this study is a starting point for further study, and would require validation of the resulting putative causal genes.

eLife Assessment

This useful study explores how macrophage cell-cycle state may influence endocytosis, Mycobacterium tuberculosis uptake, and the intracellular stress experienced by bacteria. While the question is interesting and the experimental approach has promise, the evidence for the central claim that endocytic capacity is specifically regulated by cell-cycle stage is incomplete. The main concern is that fluorescence-based sorting and total-fluorescence measurements likely covary with cell size, so the reported phenotypes could reflect biomass accumulation or other cell-cycle-associated changes rather than endocytic capacity as the causal determinant. As a result, whilst the study raises a hypothesis that is of importance, additional controls are required before the proposed mechanism can be considered well supported.

eLife Assessment

This important submission from Ambler and colleagues brings new insights into how torpor conditions may confer resilience in cases of cardioprotection. It has novelty, which can be enhanced by additional in vivo support. The study is backed by solid evidence, and represents a unique interoceptive mechanism of interest.