Evaluated articles

eLife Assessment

The authors present an important set of data implicating ETFDH as an epigenetically suppressed gene in cancer with tumor suppressive functions. The evidence is solid, with the authors demonstrating that ETFDH suppression results in accumulation of amino acids that impact metabolism via hyperactive mTORC1.

eLife Assessment

This study offers valuable insights into the role of post-translational modifiers, specifically SUMO2ylation at K81 in p66Shc, and its impact on endothelial function through reactive oxygen species. A series of compelling experiments demonstrated that lysine 81 of p66Shc is the site of SUMO2 conjugation, which is crucial for mitochondrial localization and essential for S36 phosphorylation, leading to specific pathological effects. The combination of cell overexpression and animal studies provides solid data supporting this mechanistic link.

eLife Assessment

This study provides important insights into the regulation of neuroblast lifespan and proliferation in the Drosophila mushroom body, identifying Krüppel (Kr) as a key transcription factor promoting timely termination of these neuroblasts by repressing Imp expression, and proposes an antagonistic role of Krüppel homolog 1 (Kr-h1), whose overexpression leads to prolonged mushroom body neuroblast proliferation and tumor-like expansion. The findings are impactful for researchers interested in temporal patterning and neural development, and the methods and data analysis are solid, however, the precise regulatory interactions between Kr and Kr-h1 and their modes of action remain incompletely tested. Further experiments would be required to fully elucidate the mechanistic interplay between the factors involved.

eLife Assessment

The findings in this manuscript are important because they demonstrate the key role of metabolism in insect development. The data were collected and analyzed using solid and validated methodologies, but the evidence is incomplete, as the extent of the involvement of AOX activity in vivo and in physiological conditions is not addressed. This manuscript will be of interest for the fields of mitochondrial bioenergetics, metabolism and development.

eLife Assessment

This important study advances our understanding of vertebrate forelimb development, specifically the contribution of Hox genes to zebrafish pectoral fin formation. While there are reservations about some of the descriptions and interpretations of the data, the results are mostly convincing. The authors have employed a robust and extensive genetic approach to tackle a key and unresolved question. The findings 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 activated, 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 mostly robust findings. While the data regarding antibody sequence preferences for distinct amyloid-beta regions and aggregation states are convincing, a thorough revision of the manuscript would help to highlight the key results.

eLife Assessment

This study presents a valuable finding on the role of Slit-Robo signaling in cardiac innervation. The evidence supporting the main claims of the authors is solid. 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 somewhat limited, 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 genome-wide 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, the new insights are fundamental and compelling, and the optimized END-seq approaches will be widely utilized. The interest of the paper could be heightened by deepening the discussion of potential biases in telomere representation, the origin of the ssDNA captured in ALT cells, and the occurrence of variant telomere repeats in the cell lines studied.

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 convincing and this work will be of interest to the microbial rhodopsin community and neuro- and cardioscientists utilizing optogenetics in their research.

eLife Assessment

This useful work employs transition-metal FRET (tmFRET) to study the cyclic nucleotide binding domain (CNBD) of a bacterial ion channel. The authors employ lifetime measurements of fluorescence to extend their own prior study and observe distance changes within the CNBD domains of a full-length channel; they base these measurements on changes in lifetimes due to tmFRET between a metal at an introduced chelator site and a fluorescent non-canonical amino acid at another site within the channel sequence. This allows the authors to show that coupling of the CNBDs to the rest of the channel stabilizes the CNBDs in their active state relative to an isolated CNBD construct. The data are compelling and of high quality, and support the authors' conclusions.

eLife Assessment

The first part of this manuscript describes an interdisciplinary approach to mine the human channelome and discover further ion channel orthologues across diverse organisms. Although the findings and data curation enabled by the new approach are valuable to the ion channel community, as well as to those interested in improved methods for mining sequence space for their protein of interest, this part of the work is incomplete because critical methodological information is missing. Further validation of the improvements this approach shows over others is needed. The second part of the manuscript utilizes the approach described in the first part to delineate co-conserved amino acid patterns in CALHM channels, but the evidence provided to support the role of the identified residues in channel gating is currently inadequate.

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 important study is a first report investigating the boundary formation between sensory and non-sensory tissues of the inner ear, which has broad relevance to the developmental field in general. All three reviewers thought the results and data analyses presented are solid. However, the causal relationship between the morphological evidence and the role of Lmx1a is not well supported by the results. The mechanism linking Lmx1a to ROCK is also incomplete, considering ROCK is involved in so many processes.

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, structural, and cellular approaches, the authors show that covalent inhibitors with inverse agonist activities modulate receptor conformation to permit co-binding with additional ligands, leading to a finely tuned transcriptional response. The data support a model of proximal, bi-directional allostery that challenges traditional views of nuclear receptor regulation. These findings will be of broad interest to researchers in structural biology, transcriptional control, and drug discovery.

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 is potentially compelling, but a clearer justification of the methods and analyses is needed to fully support the main claims.

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.