Evaluated articles

eLife Assessment

This set of studies provides important knowledge for the role of zona incerta neurons in motivation and food-seeking in mice. The evidence supporting the findings is convincing, with the use of multiple approaches and nice behavioral procedures to provide converging lines of evidence. Additional analyses and data from the current studies would further strengthen the evidence. This work will be of interest to those interested in motivation and its brain substrates.

eLife Assessment

This study demonstrates a critical role of the glycolipid membrane protein insertase (MPIase) in the twin-arginine translocation (Tat) pathway, a protein translocation system that is conserved across all domains of life. The successful reconstitution of the bacterial Tat system in both bacteria-derived and artificial liposomes provides solid experimental evidence that MPIase has a broader role in membrane protein translocation than previously recognized. By revealing the essential function of a nonproteinaceous membrane component in catalyzing a core cellular process, this work offers fundamental insights into the molecular mechanisms of protein translocation.

eLife Assessment

The authors provide convincing evidence that, during early mouse embryogenesis, distal visceral endoderm cells migrate in a coordinated, intermittent start-and-stop manner along an axis that correlates with the asymmetric morphology of the ectoplacental cone. This fundamental finding is supported by high-quality live imaging and quantitative image analysis, while computational modelling suggests that the observed intermittent behavior may be explained by the movement of a cohesive cell group through a viscoelastic tissue, rather than by fluctuations in DVE migration velocity itself.

eLife Assessment

This is an important study establishing the mechanistic principles how NUP98-KDM5A phase separates together with H3K4me3 chromatin in leukemia. Methods are sound and results are convincing, providing a framework to understand gene expression changes in leukemia patients.

eLife Assessment

In this important study, the authors describe the mechanisms by which CDK4/6 overexpression mediates resistance to Osimertinib in EGFR mutant lung cancer models. Their data show that CD4/6 overexpressing cells had increased replicative stress and genomic instability. The evidence is solid, but inclusion of some additional experiments would make this stronger.

eLife Assessment

This study presents a potentially important structure-interaction model describing recognition of polymyxin antibiotics by the human transporter hPepT2 and applies these insights to guide the rational design of potent polymyxin B analogues with reduced nephrotoxicity. The conclusions are supported by compelling evidence, integrating molecular dynamics simulations, transporter mutagenesis, uptake assays, protein expression analyses, antibacterial testing, and mouse nephrotoxicity studies, although some mechanistic interpretations remain limited by altered transporter expression and the absence of direct structural validation.

eLife Assessment

This valuable study provides solid evidence that N6 methylation of A74 by METTL3 is required for efficient translation directed by the SARS-CoV-2 5′UTR in uninfected cells, likely by limiting access of protein factors to the 5′UTR that are necessary for efficient translation. These findings advance our understanding of the role of RNA modification in coronavirus replication and m6A-mediated regulation of gene expression more broadly, while further supporting METTL3 as a potential anticoronaviral therapeutic target. However, the evidence that m6A acts by destabilizing the third stem-loop (SL3) of the 5′UTR remains incomplete. The impact of the study would be strengthened by biochemical analyses directly assessing structural changes in the 5′UTR induced by A74 methylation.

eLife Assessment

This is a valuable study on the metabolic adaptations upon succinate dehydrogenase loss in cancer cells. If confirmed, this study will offer some therapeutic vulnerabilities in treating SDH-deficient cancer. However, the evidence supporting the authors' claim is incomplete and would benefit from additional experimental evidence. This study will be of broad interest for cancer biologists focusing on metabolism.

eLife Assessment

This valuable study documents, for the first time, the degree of preference for contralateral versus ipsilateral forelimb movements in the motor cortex of mice, revealing subtly distinct profiles across cortical areas, with the orofacial region showing comparatively little limb selectivity relative to the forelimb motor areas. The experiments and analyses are, in general, solid and well-designed, and the data support the paper's conclusions.

eLife Assessment

This important study addresses how the molecular identity of a single neuron specifies its hard-wired synaptic connectivity, using repeated single-cell RNA sequencing of identified Drosophila sensory neurons together with functional perturbation of candidate cell-surface molecules. It demonstrates remarkably low transcriptomic variability across animals for the same identified neuron, defines a tractable set of differentially expressed cell-surface molecules that distinguish mechanosensory from chemosensory neurons, and links several of these molecules to axonal targeting and circuit function. The evidence is solid, with the single-neuron transcriptomic datasets and Dscam isoform repertoires offering a lasting resource for the field, though clearer articulation of the experimental logic, additional controls in the RNAi screen, and a more complete characterization of the neuronal re-wiring would further strengthen the central claims.

eLife Assessment

This study investigates the role of Interleukin-2-inducible T cell kinase (ITK) deficiency in autoimmune lung injury using a pristane-induced pulmonary hemorrhage (PH) model, suggesting that ITK-deficient regulatory T cells (Tregs) restrict severe tissue pathology. The work represents a valuable addition to the fields of autoimmunity, inflammation, and T-cell biology in the lung. However, the experimental evidence supporting the underlying cellular and molecular mechanisms and the integration of foundational background literature to provide the necessary context are incomplete.

eLife Assessment

This important study by Otgonbaatar and colleagues employs advanced live microscopy, optogenetics, and an endogenous fluorescent timer system to investigate short- and long-term stabilization dynamics of β-catenin/Armadillo (Arm) during Drosophila development. The authors identify an unexpected and functionally relevant enrichment of stabilized junctional Arm in leading-edge cells during dorsal closure, providing evidence for a stabilization mechanism that appears independent of canonical Wingless signaling. These findings are significant because they expand current understanding of β-catenin/Arm beyond its canonical signaling functions and suggest a role in tissue mechanics and force transmission during dorsal closure. The proposed model represents a key advance in the field, but the strength of evidence is currently incomplete: the main conclusions regarding Wingless independence, JNK-mediated regulation, and the mechanical role of stabilized Arm are only partially supported by the available data and would benefit from further experimental testing and corroboration.

eLife Assessment

This useful study investigates how plasticity and homeostatic adaptation can lead to the emergence of synchronization patterns associated with different sleep phases. The ideas are novel and interesting, but the evidence at present remains incomplete. Further work is needed to determine whether the reported states persist for larger system sizes, longer integration times, and how robust the results are to different initial conditions.

eLife Assessment

The report by Liu and colleagues provides a valuable analysis of environmental adaptation across diverse lineages of the grass Phragmites australis differing by their level of ploidy. The analysis reports solid evidence that lineages with distinct levels of ploidy occupy different climate niches. The use in tandem of regional survey and common garden experiment represents a convincing approach to suggest a correlation between ploidy and climate adaptation. This manuscript will be of interest to a broad community of ecological genomicists interested in how structural variation in gene dosage potentially affects the pattern of adaptation.

eLife Assessment

This important study combines peptide engineering, molecular docking, and functional assays to define the molecular basis of ligand recognition and activation of the human Y4 receptor and to identify three novel small-molecule agonists. The evidence supporting the conclusions is convincing, with complementary experimental and computational approaches providing strong support for the proposed receptor-ligand interactions. While concentration-response analyses of the small-molecule agonists and additional structural or mutagenesis studies would further strengthen the work, these are not essential to support the main conclusions. The work will be of interest to researchers studying GPCR pharmacology, structural biology, and ligand discovery.

eLife Assessment

This study presents a valuable metagenomic analysis of the gut microbiome in sickle cell disease (SCD) patients, revealing associations between bacteriophage, host immunity, and SCD pathophysiology. While these data are interesting and helpful for hypothesis generation, they are deemed incomplete; additional experiments would be needed to test causality and to provide mechanistic insight. Despite these limitations, this work will be of broad interest to researchers studying SCD, immunology, phage biology, and the microbiome, adding to the small but growing literature suggesting a microbial component to SCD.