Evaluated articles

eLife Assessment

This valuable study investigates the role of dinucleoside polyphosphates in regulating the cGAS-STING-TBK1 axis of innate immunity. The data collected using multiple biochemical and cellular assays, plus X-ray crystallography, are solid, but testing additional polyphosphates and using NUDT2KO cells will further strengthen the main conclusion. This paper will be broadly relevant to those studying various innate immune pathways.

eLife Assessment

This valuable study applies a hidden Markov model to freezing, ultrasonic vocalizations, and lever pressing in male rats to ask whether fear extinction restores normal behavior or only suppresses defensive responding. The evidence is incomplete because the model states are not related back to raw behavior or group manipulations, and the states are not tested as predictors of relapse. The work will be of interest to researchers studying fear extinction and computational approaches to behavior.

eLife Assessment

This valuable study substantially improves the phylogenetic framework for Kinetoplastea through greatly expanded sampling of free-living neobodonids; the phylogenomic analyses provide convincing evidence that neobodonids are paraphyletic and establish a substantially revised framework for deep relationships within Metakinetoplastina. The work forms the foundation for future comparative studies of kinetoplastid evolution and systematics, although its implications for the origins of parasitism should not be overstated. An 18S rRNA phylogeny documenting the placement of the newly sampled strains within previously recognized neobodonid lineages and/or confirmation of the principal topology using a well-documented phylogenomic set of marker genes would further strengthen the study. The work will be of particular interest to researchers studying protist evolution and the evolutionary context of trypanosomatids.

eLife Assessment

This important study uses coarse-grained molecular simulations to investigate how phosphorylation and small-molecule ligands reshape the interactions underlying condensation and multidomain assembly of HDAC6. The findings provide mechanistic insights into how modifications of intrinsically disordered regions and ligand binding may regulate protein condensation. The evidence is solid: although the simulations broadly agree with previous experimental observations, concerns about model robustness and sampling in full-length assemblies limit support for the proposed mechanism and its pharmacological implications.

eLife Assessment

This useful study presents Penumbria, a method for segmenting cells in three-dimensional microscopy images, released with publicly available code and documentation. The implementation is technically sound, and the reported performance gains would be a welcome contribution; the advance is incremental, since regression on distances to boundaries is already widespread in the field. The evidence is incomplete: the main text does not state which setting it used for the main competing method, and the setting used is the one that handles data of this kind poorly, so the central claim of better accuracy is unsettled; current leading methods are missing from the comparison; and five architectural and training choices are combined without attributing the gains to any of them. Every evaluation dataset labels nuclei, so the work should present itself as nuclei segmentation; describing and completing the comparisons, and attributing the gains, would raise the strength of evidence.

eLife Assessment

This study provides important novel insight into how Wnt/beta-catenin signaling may regulate the responsiveness of blood vessels in the brain and retina to vascular endothelial growth factor, with potential relevance to Wnt surrogate therapies aimed at restoring vascular barriers. Solid evidence that Wnt/beta-catenin signaling changes the protein abundance and relative balance of two vascular endothelial growth factor receptors in brain blood vessels is provided by informative genetic mosaic experiments; in the retina, however, regulation of VEGFR2 was difficult to establish because expression by neighboring cells obscured its detection in blood vessels. Physiological implications are discussed, but evidence remains incomplete because the observed changes in receptor abundance were not directly linked to altered signaling or vascular function in living animals. A second mechanism, in which Wnt/beta-catenin signaling suppresses signaling through VEGFR2 with little or no change in receptor abundance, was inferred from reporter experiments in cell-based systems.

eLife Assessment

This important study used several genome-wide approaches to compare dormancy in S. pombe spores and killifish diapause embryos. The findings include a trade-off between longevity and heat resistance in yeast spores and, in both these systems, a relatively higher expression of ribosomal-protein mRNAs but not proteins. While the evidence for the findings is overall solid, some interpretations should still be tempered. The large-scale datasets provide an excellent resource for future research in the dormancy field.

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

eLife Assessment

This is an important study with implications for signal transduction, breast cancer, and metastasis research. The study uses cell lines from the innovative HER2BOW model mouse to compare and contrast properties of mouse mammary tumors induced by wt-HER2, dex16-HER2, and p95-HER2. The study involves mechanistic approaches that are convincing for distinguishing signaling from dex16-HER2 and p95-HER2; this will be of interest to the cancer field.

eLife Assessment

This important paper introduces a generalisable tissue-clearing method to study human anatomy and the organisation of complex tissues and organs. The evidence for its broad applicability is compelling, based on results from 15 diverse human tissues, including highly heterogeneous specimens, with successful labelling using five antibodies and five fluorescent dyes. The method has broad potential applications across multiple disciplines.

eLife Assessment

This is a valuable study that aims to resolve the mechanistic details of the final steps of bacterial lipoprotein trafficking. The evidence supporting the conclusions is mostly solid but support for other claims is incomplete. This work will be of interest to biochemists and microbiologists studying the bacterial cell envelope and those aiming to develop novel antibacterial molecules.

eLife Assessment

This important study provides theoretical and experimental evidence that aliphatic-to-threonine substitutions in transmembrane domains improve the translocation properties of mitochondrial proteins from the cytosol to mitochondria. The authors provide convincing evidence that substitutions within hydrophobic transmembrane regions of mitochondrial proteins may have contributed to their evolutionary adaptation following the transfer of their genes from the mitochondria to the nucleus. This study will be of interest to biologists and biochemists working on mitochondrial protein import and mitochondrial evolution.

eLife Assessment

This study provides valuable new insights into the functional differentiation of human amygdala subnuclei during the observation of negative images and emotional reappraisal. The evidence is convincing, particularly regarding differences in the time course of evoked responses and their partial correspondence with broad anatomical subdivisions. The work will be of interest to researchers studying the amygdala, emotional processing, and emotion regulation.

eLife Assessment

This valuable study carefully assesses the anatomical organization of the adult zebrafish olfactory bulb using a densely reconstructed electron microscopy dataset. The data were generated using a previously acquired state-of-the-art serial block-face scanning electron microscopy dataset, followed by manual classification of cells into distinct anatomical groups. The analysis is a convincing application of careful expert neuroanatomical understanding that reveals key details of the cell class and connectivity in the olfactory bulb, with helpful detailed descriptions of why each cell class was distinguished.

eLife Assessment

By integrating RelB proximity labeling with targeted CRISPR screening, the authors identify several potential regulators of HIV latency and provide evidence implicating RelB, KAT7, and p300 in AZD5582-mediated HIV reactivation. While the study is important, the current work is incomplete, as it needs to establish physiological relevance. The findings require validation in primary latency models, and the unusually high basal RelB expression in the experimental system raises concerns about whether the observed effects accurately reflect endogenous mechanisms regulating HIV latency.

eLife Assessment

This valuable study introduces an innovative task and framework for examining whether movement vigor and reward-seeking behavior are governed by common or separate processes. The behavioral findings provide solid evidence that these behaviors can be differentially influenced by effort and delay, but support for the proposed model and its mechanistic claims remains incomplete, requiring more rigorous validation and analyses to address potential confounds. The work will be of interest to researchers studying motor control, decision-making, and effort-based behavior.

eLife Assessment

This useful study shows that neural activity before a conversational response contains information about the duration and timing of the subsequent turn. The evidence that this information originates from speech-production planning is incomplete. Because the analyzed EEG is recorded during processing of the partner's speech, and because that speech causally determines the subsequent response, production planning and comprehension/context are confounded in the current analyses. It would strengthen the production interpretation considerably if the authors could show that the relationship with forthcoming duration survives richer controls for the preceding turn, or ideally after accounting for EEG variance driven by the incoming speech.

eLife Assessment

This important study introduces Hetlearn, a novel learning algorithm that demonstrates that an ensemble of simple sub-learners with varying learning rates can effectively manage inference in complex, unstable environments. While the theoretical framework and its proposed application to parallel memory traces in the insect mushroom body are intriguing, the evidence supporting the core claims is currently incomplete. To fully validate the authors' conclusions, further exploration is needed to rigorously define the boundaries of the model's hyperparameter space, along with a deeper justification and clarification of its biological plausibility.

eLife Assessment

This important study identifies underappreciated experimental factors that influence α-synuclein amyloid polymorphism, with practical implications for the reproducibility of in vitro fibril preparations. Extensive cryo-EM analyses provide convincing evidence that protein purity, monomer preparation, and agitation conditions influence polymorph selection, including substantial effects from small amounts of an N-terminally truncated variant. The study provides a substantial resource for researchers studying amyloid assembly and synucleinopathies, although the proposed nucleation mechanisms need stronger kinetic support and reliable protocols for producing specific polymorphs require further development.

eLife Assessment

This study provides a valuable and comprehensive in vivo map of proteins in proximity to three vesicle-tethering complexes. The evidence supporting the overall proximity mapping is convincing. However, some aspects of the functional characterization of selected candidates remain incomplete.

eLife Assessment

The identification of a pleiotropic EPAS1 enhancer that influences adipocyte responses to hypoxia and thermogenic stimulation provides a valuable contribution to our understanding of high-altitude adaptation in Tibetans. The data are solid, although additional experiments would strengthen the link between ENH5 activity and the mechanisms underlying high-altitude adaptation.