Evaluated articles

eLife Assessment

This important study advances our understanding of vertebrate forelimb development, specifically the contribution of Hox genes to zebrafish pectoral fin formation. The authors have employed a robust and extensive genetic approach to tackle a key and unresolved question. The findings are overall convincing and will be of broad interest to developmental and evolutionary biologists.

eLife Assessment

This valuable study aims to advance the toolkit of small molecules used for approaches to targeted protein degradation for research and therapeutic applications. The authors provide solid data demonstrating the use of a high-throughput screen of small molecules to target a specific E3 ligase, KLHDC2 (Kelch-like homology domain containing protein 2); the resulting compounds then form the basis for new PROTAC (proteolysis targeting chimera) reagents. The strength of the work lies in expanding the PROTAC reagent inventory. The current work would be strengthened further by confirming that the PROTAC's activity is dependent on KLHDC2 and by a more thorough examination of off-target effects in cellular applications.

eLife Assessment

This study presents the important finding that lysosomal damage triggers inflammatory signaling through ubiquitination and the TAB-TAK1-IKK-NF-kB axis. The data obtained from the unbiased transcriptomic and proteomic analyses are convincing and provide invaluable information to the field. Although further experiments will be required to clarify how TAB2/3 are recruited after various types of lysosome damage, this work will be of interest to researchers in the fields of organelle biology and inflammation.

eLife Assessment

Antibodies that selectively bind distinct amyloid-beta variants are vital tools for Alzheimer's disease research. This valuable manuscript aims to delineate the epitope specificity in a panel of anti-amyloid-beta antibodies, including some with clinical relevance. The experiments were rigorously conducted, employing an interesting combination of established and state-of-the-art methodologies, yielding convincing findings.

eLife Assessment

This study presents important findings on the role of Slit-Robo signaling in cardiac innervation. The evidence supporting the main claims of the authors is convincing. The use of several mouse models including constitutive and cell type specific knockout models make the findings more robust. The scope of the presented studies is fitting, as they primarily focus on evaluating the phenotypic changes in cardiac innervation following the loss of various Slit or Robo genes

eLife Assessment

This valuable study examines the role of map3k1, a MAP3K family member that has both kinase and ubiquitin ligase domains, in the differentiation of progenitors in the flatworm Planaria. The convincing analyses demonstrate that map3k1 acts within progenitors to restrict their premature differentiation and to prevent formation of teratomas. This work would be of interest to researchers in the fields of regeneration, developmental biology, and aging.

eLife Assessment

This study demonstrates the application of END-seq, originally developed to study genomewide DNA double-strand breaks, to telomere biology; the work packs a punch, concisely demonstrating the utility of this approach and the new insights that can be gained. The authors confirm that telomeres in telomerase-positive cells terminate with 5'-ATC in a Pot1-dependent manner, and demonstrate that this principle holds true in telomerase-negative ALT cells as well. S1-END-seq is similarly developed for telomeres, showing that ALT cells harbor several regions of ssDNA. The study is well-executed and convincing, the new insights are fundamental and compelling, and the optimized END-seq approaches will be widely utilized. The work will prompt additional studies that the reviewers look forward to, including combining telomeric END-seq with long-read sequencing to address the distribution and origin of variant telomere repeats and ssDNA along telomeres in ALT and telomerase-positive settings.

eLife Assessment

This important study describes newly identified light-gated ion channel homologs (channelrhodopsins, ChRs) in several protist species, with a primary focus on the biophysical characterization of ChRs of ancyromonads. The authors employed a powerful combination of bioinformatics, manual and automated patch-clamp electrophysiology, absorption spectroscopy, and flash photolysis. Additionally, they evaluated the applicability of the newly discovered anion-conducting ChRs in cortical neurons of mouse brain slices and in living C. elegans worms. The evidence supporting most of the claims is compelling, and this work will be of interest to the microbial rhodopsin community and neuro- and cardioscientists utilizing optogenetics in their research.

eLife Assessment

This valuable study employs transition-metal FRET (tmFRET) and time-correlated single-photon counting to investigate allosteric conformational changes in both isolated cyclic nucleotide-binding domains (CNBDs) and full-length bacterial CNG channels, demonstrating that transmembrane domains stabilize CNBDs in their active state. By comparing isolated CNBD constructs with full-length channels, the authors reveal how allosteric networks couple domain movements to gating energetics, providing insights into ion channel regulation mechanisms. The rigorous methodology and compelling quantitative analysis establish a framework for applying tmFRET to study conformational dynamics in diverse protein systems.

eLife Assessment

In this manuscript Taujale et al describe an interdisciplinary approach to mine the human channelome and further discover orthologues across diverse organisms. Further, this work provides evidence that supports a role for conserved residues in CALHM channel gating. Overall this important work presents findings that can be helpful to the ion channel community, as well as to those interested in improved methods for mining sequence space for their protein of interest. However, further validation of the improvements their approach shows over previous approaches is needed, making this a solid contribution to the literature in this field.

eLife Assessment

This useful study describes a physical mechanism for the emergence of spiral patterns in the outer epithelial layer of the mammalian cornea independent of pre-patterning or guidance cues, using an agent-based model of self-propelled particles with alignment. The model is well constructed, however the central premise of the manuscript, that the spiral patterning of epithelial corneal cells occurs without guidance cues, is incomplete and not fully supported. Several significant questions remain unanswered, such as the role of the corneal curvature or the importance of topological defects. Furthermore, comparison between the model and data are qualitative at best for the moment.

eLife Assessment

This is an important study describing the morphological changes during boundary formation between sensory and non-sensory tissues of the inner ear. The authors provided solid evidence that a transcription factor, Lmx1a and ROCK-dependent actinomyosin are key for border formation in the inner ear. However, future studies will be needed to investigate the direct relationships among boundary formation, Lmx1a and ROCK. This work will be of interest to developmental biologists interested in boundary formation.

eLife Assessment

This manuscript presents a fundamental advance in our understanding of nuclear receptor pharmacology by expanding on previous work demonstrating dual ligand occupancy in the peroxisome proliferator-activated receptor-gamma (PPARγ). Using a compelling combination of biophysical, biochemical, and cellular approaches, the authors show that covalent inverse agonists with enhanced efficacy shift the receptor conformation toward a transcriptionally repressive state that limits orthosteric ligand co-binding more effectively. This revised manuscript further strengthens support for a proximal, bidirectional allosteric model of dual ligand occupancy by sharpening the distinction between prior and new findings, adding clear conceptual figures, and strengthening statistical rigor.

eLife Assessment

This is a fundamental discovery revealing two independent IFNγ-induced pathways that restrict bacterial motility: one GBP1-dependent and the other GVIN1-dependent. The findings are supported by compelling evidence. While the paper is already very strong, there are a few points that could be addressed editorially or through the addition of a few key experiments.

eLife Assessment

This valuable study presents an analysis of evolutionary conservation in intrinsically disordered regions, identified as key drivers of phase separation, leveraging a protein language model. The strength of evidence presented is convincing overall, though the theoretical grounding could benefit from further development.

eLife Assessment

In this valuable study, the authors demonstrate that TCF7L2 plays a role in the pathogenesis of cachexia in a mouse model of GI cancer. The results are solid, although future studies will need further mechanistic analyses. These data will be interesting to cancer biologists, especially those trying to understand late-stage complications such as cachexia and wasting, a major cause of cancer morbidity and mortality.

eLife Assessment

This study exploring the role of TRPV1 signaling in recruiting macrophages and promoting angiogenesis during tympanic membrane wound healing presents useful findings. However, the strength of evidence supporting the central claims is incomplete, as the mechanistic links between TRPV1 activation and immune cell recruitment remain largely correlative and rely heavily on previously published datasets without sufficient functional validation. The work will be of interest to researchers studying wound healing and sensory-immune interactions, though substantial revisions are needed to support its broader significance.

eLife Assessment

This high-N, multi-task study offers a comprehensive examination of rhythmicity in behavioral performance during listening. It presents a valuable set of findings that reveal task- and ear-specific effects, challenging the notion of a universal rhythmicity in auditory perception. The evidence is solid and the work is likely to be of significant interest to behavioral and cognitive scientists focused on perception and neural oscillations.

eLife Assessment

This revised manuscript provides fundamental findings on how the mouse barrel cortex connects to the dorsolateral striatum, uncovering that inputs from discrete whisker cortical columns are convergent and SPN-specific, but topographically organized at the population level. The evidence supporting this claim is compelling, demonstrating that SPNs uniquely integrate sparse input from variable stretches across the barrel cortex. The study would be of interest to basal ganglia and sensory-motor integration researchers.

eLife Assessment

This fundamental study demonstrates that lipid binding can regulate the dimerization state of the SARS-CoV2 Orf9b protein. The data from biophysical and cellular experiments along with mathematical modeling are compelling. This paper is broadly relevant to those studying coupled equilibria across all aspects of biology.