Evaluated articles

eLife Assessment

This study presents a useful finding on the effects of arginine vasopressin (AVP) on islet cells in pancreatic tissue slices, using technically sophisticated spatio-temporal calcium recordings to confirm that AVP influences α and β cells differently depending on glucose concentrations. While the study’s methods – particularly the calcium imaging techniques and peptide ligand design targeting V1b receptors – are strong, the reviewers were concerned about several aspects of the experimental design. The results on β-cell responses are incomplete and insufficient to support the manuscript’s claims, especially due to the high variability of islet responses and lack of mechanistic and functional (hormone release) data. There are also concerns about the possibility of off-target effects and suboptimal receptor specificity: the study would be significantly strengthened by inclusion of signaling pathway interrogation, hormone output assays, genetic validation (e.g., β cell-specific deletion of V1br), and receptor localization. The work will still be of interest to researchers studying islet physiology in the context of health and diabetes.

eLife Assessment

By performing a chemical screen of an FDA-approved library of small molecules against a leucine-dependent Mtb strain, this work discovered that semapimod inhibits Mtb growth by impairing leucine import. The work is useful because it connects leucine uptake with the cell wall lipids in Mtb; however, it remains incomplete as the evidence supporting semapimod's ability to target leucine uptake needs more substantial proof. The work requires significant experimental evidence to identify leucine transporter(s) and determine how PDIM participates in leucine uptake.

eLife Assessment

This study presents an alternative to conventional and UV-based tetramers, which are easy to use and reliable for the identification of antigen-specific CD8 T cells. The authors demonstrate that tetramers for HLA alleles A0301, A1101, B0702, and C0702 can be subjected to specific temperatures that facilitate peptide exchange, whilst maintaining structural integrity. Whilst the strength of the evidence is currently incomplete, further development and validation of this approach is likely to provide a useful alternative to generating reagents for examining T cell specificities.

eLife Assessment

This useful study shows a protective role of type 1 IFN during Mycobacterium tuberculosis infection. It shows that the type 1 IFN response in human skin TST inversely correlates with TB severity, suggesting its protective role. Considering that type I IFN is usually shown to be pro-pathogenic, the higher vulnerability of zebrafish larvae lacking stat2 to M marinum infection is a strong result. However, the conclusion that IFN-I is protective during mycobacterial infection remains indirect and incomplete; the study requires additional mechanistic insights and validation.

eLife Assessment

Engineering of adeno-associated virus (AAV) replication proteins may provide new insights into Parvoviral replication. The authors created a useful collection of Rep protein variants with changes that alter the amino acid sequence, but these did not lead to clear improvements in how the virus worked. Instead, their screen showed that changes that do not alter the protein ("synonymous" mutations) and changes to the promoter were more common. As it stands the results are incomplete due to potential issues with the screening design. We encourage a more complete characterization, which may enhance the translational potential of the approach.

eLife Assessment

Endothelial cell-specific loss of TGF-beta signaling in mice leads to CNS vascular defects, specifically impairing retinal development and promoting immune cell infiltration. The data are solid, showing that loss of TGF-beta signaling triggers vascular inflammation and attracts immune cells specific to CNS vasculature, but there are issues with the single-nucleus RNA sequencing of immune cells. These findings are valuable, highlighting TGF-beta's role in maintaining vascular-immune homeostasis and its therapeutic potential in neurovascular inflammatory diseases.

eLife Assessment

This study presents an important finding linking the bacterial metabolite trimethylamine and its receptor to circadian rhythms and olfaction. The current evidence supporting the claims of the authors is convincing, although further data and improvements to the presentation would further increase the impact of these results. This work will be of broad interest to researchers interested in nutrition, microbial metabolism, circadian rhythms, and host-microbiome interactions.

eLife Assessment

This valuable study addresses the role of sphingolipid metabolism in maintaining endolysosomal membrane integrity and its impact on tau pathology in Caenorhabditis elegans and human cell culture models. The methods are solid and the proposed mechanisms are conceivable. However, the current evidence is incomplete and could be strengthened, due to reliance on imaging data and insufficient biochemical validation. The work will be of broad interest to cell biologists and biologists working on Alzheimer's disease and related proteinopathies.

eLife Assessment

This important study provides converging results from complementary neuroimaging and behavioral experiments to identify human brain regions involved in representing regular geometric shapes. Geometric shape concepts are universally present across diverse human cultures and possibly essential for unique human capabilities such as numerical cognition and symbolic reasoning, and identifying the brain networks involved in geometric shape representation is of broad interest to researchers studying human visual perception, reasoning, and cognitive development. The provided experimental evidence regarding the presence of geometric shape regularity representation in dorsal parietal and prefrontal cortex is solid, but the claimed link with mathematical reasoning, the influence of experimental tasks, and the role of experience in driving geometric shape representation in both humans and artificial vision models require further elucidation.

eLife Assessment

This fundamental study combines in vitro reconstitution experiments and molecular dynamics simulations to elucidate how membrane lipids are transported from the outer to the inner membrane of mitochondria. The authors provide convincing evidence that a positive membrane curvature is critical for membrane lipid extraction. The work will be of broad interest to cell biologists and biochemists.

eLife Assessment

This study identifies 53BP1 as an interaction partner of GMCL1 (a likely CUL3 substrate receptor). The study seeks to link this finding to regulation of the mitotic surveillance pathway and paclitaxel resistance in cancer. The evidence for these claims is currently inadequate; concerns include the use of cell lines that have been reported to lack the mitotic surveillance pathway, insufficient consideration of paclitaxel mechanisms of action, and an overinterpretation of correlative results.

eLife Assessment

This study presents valuable findings that advance our understanding of mural cell dynamics and vascular pathology in a zebrafish model of cerebral small vessel disease. The authors provide compelling evidence that partial loss of foxf2 function leads to progressive, cell-intrinsic defects in pericytes and associated endothelial abnormalities across the lifespan, leveraging powerful in vivo imaging and genetic tools. The strength of evidence could be further improved by additional mechanistic insight and quantitative or lineage-tracing analyses to clarify how pericyte number and identity are affected in the mutant model.

eLife Assessment

The authors present a computational pipeline for the identification of endogenous allosteric modulators of GPCRs, with experimental validation performed in a yeast system. This approach is valuable for a broad audience, including GPCR structural biologists, molecular pharmacologists, and computational biophysicists. However, the rigor of the computational methods needs to be strengthened to provide stronger evidence for the study's conclusions, which is currently incomplete. The authors should justify their methodological choices and provide greater detail and clarity regarding each computational layer of the pipeline.

eLife Assessment

This valuable study expands the inventory of polyadenylated RNAs cleaved by the double-stranded RNA endonuclease Rnt1 in budding yeast, using solid methodology based on high-throughput sequencing. Previous studies had anecdotally discovered mRNA substrates, and this global characterization is comprehensive with multiple complementary controls. However, the study would be stronger with a deeper investigation into the biological function of Rnt1, as well as experiments directly probing the interaction between Rnt1 and its putative substrates.

eLife Assessment

Complex traits are influenced by genes and the environment, but especially the latter is difficult to pin down. This important study uses C. elegans to demonstrate that non-genetic differences in gene expression, partly influenced by the environment, correlate with individual differences in two reproductive traits. This supports the use of gene expression data as a key intermediate for understanding complex traits. The clever study design makes for compelling evidence, which is further strengthened by experimental confirmation that identified differentially expressed genes indeed influence these traits.

eLife Assessment

This useful study presents the potentially interesting concept that LRRK2 regulates cellular BMP levels and their release via extracellular vesicles, with GCase activity further modulating this process in mutant LRRK2-expressing cells. However, the evidence supporting the conclusions remains incomplete, and certain statistical analyses are inadequate. This work would be of interest to cell biologists working on Parkinson's disease.

eLife Assessment

This manuscript introduces a useful protein-stability-based fitness model for simulating protein evolution and unifying non-neutral models of molecular evolution with phylogenetic models. The model is applied to four viral proteins that are of structural and functional importance. The justification of some hypotheses regarding fitness is incomplete, as well as the evidence for the model's predictive power, since it shows little improvement over neutral models in predicting protein evolution.

eLife Assessment

This study presents a valuable assessment of increased similarity in visual appearance combined with an increased chemical difference between two butterfly species in sympatry compared with differences between three populations of one of the two species in allopatry. While the evidence is solid, its interpretation in terms of evolutionary responses to shared predators (visual signals) and avoiding between-species mating (chemical signals) is overstated due to the lack of direct experimental evidence.

eLife Assessment

This study presents a valuable advance for the analysis of gene expression variation at the level of individual cells by introducing a novel reference-free framework that can detect splicing, fusion, editing, immune-receptor diversity and repeated elements in sequencing data. The evidence supporting these claims is solid, with rigorous validation on simulated datasets and extensive analysis of full-length single-cell sequencing data demonstrating improved performance over existing methods. This work will be of particular interest to researchers developing methods for high-resolution transcriptome analysis and to those studying cellular heterogeneity in health and disease.

eLife Assessment

This important study investigated whether the nuclear receptor Nur77 is regulated by a non-canonical mechanism of ligand-induced disruption of its interaction with RXRg, similar to the family member Nurr1. The overall evidence is solid, but additional mechanisms that have not been fully explored in this study might contribute as well. This manuscript will be of interest to scientists focusing on mechanisms of transcriptional regulation.