Evaluated articles

eLife Assessment

The manuscript by Ross, Miscik, and others describes an intriguing series of observations made when investigating the requirement for podxl during hepatic development in zebrafish. Understanding how genetic compensation pathways are involved in gene function is an important question. However, there is incomplete evidence provided in the manuscript at this point to conclude that discrepancies between observed phenotypes are due to genetic compensation.

eLife Assessment

In this important study, the authors set out to determine the molecular interactions between the AQP2 from Trypanosoma brucei (TbAQP2) and the trypanocidal drugs pentamidine and melarsoprol in order to clarify the origins of clinically observed drug resistance and facilitate future drug design. Using cryo-EM, molecular dynamics simulations, and lysis assays, the authors present a solid theory for how drug resistance mutations in TbAQP2 prevent drug uptake. Overall, even though a few methodological issues still need minor clarification, this study will be of interest to those working on aquaporins and the development of drugs targeting aquaporins.

eLife assessment

This valuable manuscript presents findings supported by solid data to identify a surprising glia-exclusive function for betapix in vascular integrity and angiogenesis. The manuscript also describes the optimisation of a modified CRISPR-based Zwitch approach to generate conditional knockouts in zebrafish.

eLife Assessment

This useful study provides a spatial transcriptomic analysis of the mouse adrenal gland that could have implications for future research and applications. The authors present solid results that allow the dissection of the cell signalling pathways and cellular composition of different zones of the adrenal glands in the mouse model; they propose new zone-specific gene markers and specific intra- and inter-zonal signaling pathways based on receptor-ligand expression patterns. Their web tool is user-friendly and will be helpful for adrenal scientists; however, the validation of crucial results of the large dataset is necessary. There are also several contradictory results/interpretations, and the opportunity to dissect the sexually dimorphic gene expression pattern and mouse-human interspecies differences is a missed opportunity.

eLife Assessment

This important study explores the role of SIRT2 in regulating Japanese encephalitis virus replication and disease progression in rodent models. The findings presented are novel as sirtuins are known for their roles in aging, metabolism, and cell survival, but have not been studied in the context of viral infections until recently. The evidence supporting the claims is solid, although additional experiments to further characterize the clinical outcomes and directly test the link between acetylated NF-kB and SIRT2 expression would have strengthened the study. The work will be of interest to biologists studying viruses, sirtuins, and inflammation.

eLife Assessment

This valuable study tested whether several months of dolutegravir intensification alters the size of the HIV reservoir as well as immune activation in individuals already on suppressive ART. While the general study approach is appropriate and the paper is well written, the evidence supporting the claims of the authors is incomplete. The title of the paper is only partially supported by the data, based on specific issues with the study design and analysis plan highlighted by Reviewer 1. Specifically, the primary study outcomes were not clearly described a priori, the plausibility of a biologic effect is uncertain based on lack of a consistent effect across participants, and sample size is small. Given a possible observed partial effect and relevant hypothesis, this approach warrants study in a larger trial.

eLife Assessment

Tropical single-island endemic bird populations are particularly vulnerable to climate change. The authors investigate genetic evidence of how such species dealt with climate changes in the past as a possible predictor for how they will respond to change in the future, which could provide an important example for the fields of conservation genetics and island biogeography. The authors' integration of genomics and habitat modeling is commendable, but we find that the support for their conclusions is incomplete: at times, the results presented appear to contradict each other, the authors do not fully account for key variables, and the limited taxonomic scope may cause problematic biases for the conclusions.

eLife Assessment

This study presents valuable findings on the relationship between nutrient availability and NAD/NADH levels, which in turn regulate biomass production in cancer cells. The authors provide solid evidence to support their claims, offering insight into why it is difficult to predict which nutrients limit cancer cell growth: both cell type and nutrient availability together determine the oxidative capacity that constrains the synthesis of various metabolic intermediates. The manuscript will be of interest to researchers working in cancer and cell metabolism.

eLife Assessment

Weiss et al. provide important new insights and convincing evidence to further our mechanistic understanding of how antigen presentation shapes skin persistence of CD8+ TRM. Using a mouse model for inducible genetic ablation of transforming growth factor beta receptor 3 (TGFBR3) in CD8+ T cells, they demonstrate TGFBR3's role in regulating CD8+ TRM persistence in skin. Furthermore, they show that the strength of T cell receptor (TCR) engagement upon initial CD8+ TRM skin seeding has a positive influence on subsequent TRM expansion following a secondary antigen-reencounter. Together, these mechanisms add to our understanding of how the skin CD8+ T cell repertoire is dynamically responsive to topical antigen.

eLife Assessment

This study presents a useful framework to extract the individuality index to predict subjects' behavior in the target tasks. However, the evidence supporting such a framework is somewhat incomplete and would benefit from overall framing and clarity on its approaches. Overall, this study would be of interest to cognitive and AI researchers who work on cognitive models in general.

eLife Assessment

This manuscript makes important contributions to the methodology commonly used to assess representational structures in human and animal brain activity recorded using various techniques (especially fMRI). The evidence in the form of mathematical analysis and simulations is solid. The impact of this contribution could be improved by extending the simulations to assess the effects of violations of explicit and implicit assumptions.

eLife Assessment

This is an important study that combines replications of findings and novel detailed MRI investigations to assess the impact of environmental enrichment and maternal behavior on mice brain structure at different stages of development. The results and evidence supporting the conclusions are convincing, but in detail, the interpretation is challenging, in particular due to inter-individual and inter-litter variability. The extent to which maternal care mediates the impact of enrichment on brain development during the perinatal period also remains unclear because behavior was observed only during short periods, and the performed analyses are still incomplete. This study will nevertheless be of significant interest to neuroscientists and researchers interested in neurodevelopment in relation to environmental factors because of its in-depth use of MRI to study brain plasticity in mice.

eLife Assessment

In this valuable study, Taber et al used a battery of biophysical and structural approaches to characterize the impact of erythrocytosis-related mutations in prolyl hydroxylase domain protein 2 (PHD2). The authors show that PHD2 mutant proteins are destabilized, thus supporting the tenet that dysregulation of PHD2/hypoxia induced factor (HIF) axis underpins erythrocytosis, while providing incomplete evidence that N-terminal ODD prolyl hydroxylation of HIF is indispensable for these phenotypes. Notwithstanding that this study was found to be of broad interest for a variety of fields focusing on oxygen sensing in homeostasis and pathological states, resolving inconsistencies in the biophysical analysis (e.g., NMR, SEC, and BLI/MST) was thought to be warranted to further corroborate the proposed model.

eLife Assessment

Based on several lines of interesting data, the authors conclude that FMRP, though associated with stalled ribosomes, does not determine the position on the mRNAs at which ribosomes stall. Although this conclusion would be valuable if clearly established, the current set of data are incomplete and it is unclear if the methodologies applied in this paper are fully adequate to address this gap.

eLife Assessment

In their study, Neiswender et al. provide important insights into how BicD2 variants linked to spinal muscular atrophy alter dynein activity and cargo specificity. While the findings suggest disease-relevant changes in BicD2's binding partners, the evidence connecting these changes to disease mechanisms remains incomplete and would benefit from further experimental validation. The work lays a strong foundation for future research, but could be strengthened by deeper functional analysis of key interactions, such as the BicD2/HOPS complex.

eLife Assessment

In this study, the authors investigate the role of ZMAT3, a p53 target gene, in tumor suppression and RNA splicing regulation. Using quantitative proteomics, the authors uncover that ZMAT3 knockout leads to upregulation of HKDC1, a gene linked to mitochondrial respiration, and that ZMAT3 suppresses HKDC1 expression by inhibiting c-JUN-mediated transcription. This set of convincing evidence reveals a fundamental mechanism by which ZMAT3 contributes to p53-driven tumor suppression by regulating mitochondrial respiration.

eLife Assessment

This is a useful study in the role of CHI3L1 in Kupffer cells, the macrophages of the liver, showing that CHI3L1 alters glucose regulation in obesity. Specifically, Chi3l1 protects glucose-dependent Kupffer cells during Metabolic dysfunction-associated steatotic liver disease (MASLD) by inhibiting glucose uptake, preventing metabolic stress and death. These data are compelling, yet require further validation.

eLife Assessment

This study establishes bathy phytochromes, a unique class of bacterial photoreceptors that respond to near-infrared light (NIR), as important tools for bacterial optogenetics. NIR light is a key control signal in optogenetics due to its deep tissue penetration and the ability to combine with existing red- and blue-light sensitive systems, but thus far, NIR-activated proteins have been poorly characterized. The strength of the evidence is solid overall, with comprehensive in vitro characterization, modular design strategies, and validation across different hosts. There are some questions that remain – such as the rationale for linker choices, characterization of growth and performance relative to controls, and the physiological significance of color blind effects at alkaline pH – but overall, this study should advance the fields of optogenetics and photobiology and inspire future work.

eLife Assessment

This valuable manuscript provides convincing evidence that BK and CaV1.3 channels can co-localize as ensembles early in the biosynthetic pathway, including in the ER and Golgi. The findings, supported by a range of imaging and proximity assays, offer insights into channel organization in both heterologous and endogenous systems. However, mechanistic questions remain unresolved, particularly regarding the specificity of mRNA co-localization, the dynamics of ensemble trafficking, and the functional significance of pre-assembly at the plasma membrane. While the data broadly support the central claims, certain conclusions would benefit from more restrained interpretation and additional clarification to enhance the manuscript's impact and rigor.

eLife Assessment

This study provides valuable insights into a new toxin-antidote element in C. elegans, the first naturally occurring unlinked toxin-antidote system where endogenous small RNA pathways post-transcriptionally suppress the toxin. The strength of evidence is solid, using a combination of genomic and experimental methods. Enthusiasm, however, is tempered by its reliance on meta-analysis of existing data sets and limited experimental evaluation.