Evaluated articles

eLife Assessment

This is an important study that identifies the developmental time window during which re-expression of TCF4 mutated in Pitt-Hopkins syndrome, can rescue phenotypic features of brain function in a TCF4 knockout mouse. The study presents compelling data using a viral transgenic intersection approach to show that TCF4 expression is required early in perinatal life. These findings have implications for the timing of possible gene therapy in people with Pitt-Hopkins-associated TCF4 mutations.

eLife Assessment

This important work substantially advances our understanding of the role of synaptotagmin-7 (Syt7) in short-term plasticity at cortical glutamatergic synapses. The evidence supporting the conclusions is convincing, with rigorous and elegant quantal-level iGluSnFR imaging and failure-based analyses at single boutons. The work will be of broad interest to synaptic physiologists and molecular biologists.

eLife Assessment

This study proposes a cross-species transcriptomic framework to predict vaccine reactogenicity, with implications for preclinical vaccine safety assessment. The findings show that mouse muscle transcriptomic signatures capture conserved inflammatory programs and can identify highly reactogenic formulations, with supportive but limited evidence for finer discrimination among licensed human vaccines. Overall, the work establishes a valuable foundation for translational biomarkers of reactogenicity, although the strength of evidence for broad cross-species predictive performance remains incomplete and would benefit from further validation.

eLife Assessment

The study presents a valuable finding on the ubiquitin-dependent regulatory loop in which proapoptotic Bim is targeted to the E3 ubiquitin ligase Cul5-Wsb2-mediated degradation through its sequestration by BCL2 proteins. The conclusions are supported by incomplete evidence and would benefit from additional experiments addressing both the mechanistic understanding and the physiological/cancer-related significance of the study.

eLife Assessment

This important study provides mechanistic evidence that tea-adapted two-spotted spider mite overcomes green tea catechin defenses via the horizontally transferred dioxygenase TkDOG15, supporting a two-step adaptation model, combining enzyme refinement and inducible upregulation. The evidence is convincing because multi-omics signals converge with functional validation (RNAi knockdown and recombinant enzyme assays) and well-controlled behavioral/toxicity assays to link TkDOG15 activity and expression to survival and feeding on tea.

eLife Assessment

This structural biology study provides insights into the assembly of the GID/CTLH E3 ligase complex. The multi-subunit complex forms unique, ring-shaped assemblies and the findings presented here describe a "specificity code" that regulates formation of subunit interfaces. The data supporting the conclusions are convincing, both in thoroughness and rigor. This study will be valuable to biochemists, structural biologists, and could lay foundation for novel designed protein assemblies.

eLife Assessment

This convincing study examines a novel interaction of RAB5 with VPS34 complex II. Structural data are combined with site-directed mutagenesis, sequence analysis, biochemistry, yeast mutant analysis, and prior data on RAB1-VPS34 and RAB5-VPS34 interactions to provide a new perspective on how RAB GTPases recruit related but distinct VPS34 complexes to different organelles. The judgment is that this work represents a fundamental advance in our understanding of VPS34 localization and regulation.

eLife Assessment

This important study presents a convincing methodological approach to probe the structural features of the full-length human Hv1 channel as a purified protein. The method is supported by rigorous biochemical assays and spectral FRET analysis, which will interest biophysicists and physiologists studying Hv1 and other ion channels and membrane proteins. Overall, the work introduces an interesting labeling strategy and provides a methodology that is of value in investigating hHV1 in particular and can be extended to other ion channels. The authors also provide preliminary observations regarding conformational changes induced by zinc.

eLife Assessment

Li et al. present an important and innovative study linking developmental changes in sleep to ecological context in Drosophila mojavensis, and propose that sleep at one stage of an animal's life might anticipate needs at a future stage. The results fit well with this model, but are correlative in nature. The work is convincing, scientifically rigorous, and effectively bridges sleep biology and evolutionary ecology, opening promising new directions for the field.

eLife Assessment

This study provides useful insights regarding the alterations of sleep architecture in a knock-in mouse model of Alzheimer's Disease (AD). These include age-related hyperactivity that is typically associated with increased arousal, a normal homeostatic response to sleep loss, and a stronger AD-like phenotype in females. Although the analyses are robust, evidence for the proposed mechanisms underlying abnormal sleep architecture is incomplete. Overall, the study may have a focused impact on the sleep and AD fields.

eLife Assessment

This manuscript describing the phenotypes associated with loss and gain of RVCL-S documents important findings that have practical implications. Although the data and methods are solid and support many claims, there remain some concerns about mechanisms.

eLife Assessment

This manuscript reports high-resolution cryo-EM structures of a trimethylamine N-oxide demethylase and advances the hypothesis that the enzyme is bifunctional, coupling TMAO demethylation to formaldehyde capture via an enclosed intramolecular tunnel. The structural findings remain valuable, particularly the unusual oligomeric architecture and proposed conduit for a reactive intermediate. While the revision improves clarity and addresses several technical concerns, the central mechanistic framework remains incomplete, with persistent concerns regarding the proposed catalytic mechanism and metal dependence.

eLife Assessment

This important study provides a comprehensive comparison of the mechanisms through which different inhibitors affect the SARS-CoV-2 main protease, a pivotal antiviral drug target, and suggests a potentially broad-spectrum strategy to inhibit this critical viral enzyme by disrupting its dimerization states. However, whereas the biophysical analyses of the dimer stability are convincing, evidence supporting this new mode of mechanism to inhibit the main protease is incomplete and would benefit from a correlation of the biophysical observations with functional activity. With the functional validation part strengthened, this work would be of interest to biochemists and virologists working on anti-coronavirus drug discovery.

eLife Assessment

This study presents a potentially valuable exploration of the role of thalamic nuclei in language processing. The results will be of interest to researchers interested in the neurobiology of language. However, the evidence is incomplete to support robust conclusions at this point.

eLife Assessment

This study provides a useful contribution to understanding how wearable augmentation devices interact with human proprioception, using a longitudinal design over a single session. Results demonstrate that the perceptual representation of the biological finger and augmentation device changes across different phases of device exposure and use. The evidence supporting a representational change over time is solid, although it is still not clear whether these changes reflect three distinct phases of sensorimotor plasticity, as argued, versus 'washout' or adaptation effects. This work will be of interest to researchers studying body representation, sensorimotor learning, and human-technology interaction.

eLife Assessment

In this study, the authors identify EOLA1 as a novel mitochondrial protein required for mitochondrial translation and normal cardiac function. The characterization of the molecular role of EOLA1 is still incomplete, and additional controls will be necessary. Nevertheless, the identification of a novel factor critical for mitochondrial gene expression and oxidative phosphorylation will be useful for cell biologists working on mitochondrial dysfunction.

eLife Assessment

Stearns and Poletti present a technically impressive study that aims to uncover a deeper understanding of microsaccade function: their role in perceptual modulation and the associated temporal dynamics. The question is useful, and advances prior work by adding temporal granularity. However, the strength of the evidence is currently incomplete. Additional analysis is needed to control for the effects of endogenous attention and to demonstrate changes in perceptual performance.

eLife Assessment

This study provides important insights into how immune cells in the brain's protective layers behave under normal and disease-like conditions, revealing location-specific activity patterns that may shape inflammation and disorders such as migraine. The evidence is compelling and supported by advanced imaging approaches and rigorous analyses, although some conceptual and interpretational limitations temper the mechanistic depth. Overall, the work will be of broad interest and represents an invaluable contribution to the growing field linking immune and nervous system function.

eLife Assessment

This study provides valuable evidence that hepatic DHHC7-dependent palmitoylation is a physiologically relevant regulator of systemic metabolism, and that loss of DHHC7 disrupts Gαi palmitoylation, activates cAMP-PKA-CREB signaling, and increases hepatic transcription and secretion of Prg4. The identification of Prg4 as a hepatokine that is elevated in vivo, together with some in vitro evidence for its interaction with GPR146, represents a conceptually novel contribution to the field. However, the evidence linking these mechanisms to systemic lipolysis, liver-adipose tissue crosstalk, and whole-body metabolic physiology remains incomplete, as the phenotypic analyses rely on a limited set of experiments and do not yet fully support claims regarding adipose tissue dysfunction or altered lipid flux.

eLife Assessment

This important study introduces a pulsed laser phase plate that generates stable phase contrast in electron microscopy, offering a practical alternative to continuous-wave designs that suffer from optical instabilities and diffraction artifacts. The experimental results demonstrate a controllable and stable electron phase shift, and the evidence supporting the feasibility of this approach for phase-contrast electron microscopy is convincing. Clarifying the agreement between experiment and theory and further elaborating on possible applications would strengthen the manuscript.