Evaluated articles

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 solid evidence that N-terminal ODD prolyl hydroxylation of HIF is indispensable for these phenotypes. These findings were found to be of interest for researchers focusing on oxygen sensing in homeostasis and pathological states.

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. The authors present convincing evidence that disease-associated mutations lead to interactome changes, supported by additional validation of the BicD2/HOPS complex and discussion of their functional implications. This well-executed study offers invaluable datasets and a strong foundation for future exploration of disease mechanisms.

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 important study establishes bathy phytochromes, a unique class of bacterial photoreceptors that respond to near-infrared light (NIR), as versatile 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 evidence is convincing, with comprehensive in vitro characterization, modular design strategies, and validation across different hosts, supporting the versatility and potential for these tools in biotechnological applications. This study should advance the fields of optogenetics and photobiology and inspire future work.

eLife Assessment

This fundamental manuscript provides compelling evidence that BK and CaV1.3 channels can co-localize as ensembles early in the biosynthetic pathway, including within 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. The data substantiate the central claims, while highlighting intriguing mechanistic questions for future studies: the determinants of mRNA co-localization, the temporal dynamics of ensemble trafficking, and the physiological implications of pre-assembly for channel function at the plasma membrane.

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.

eLife Assessment

This valuable study identifies asymmetric dimethylarginine (ADMA) modification of histones as a potential key determinant of the initial genomic binding of Rhino, a Drosophila-specific chromatin protein essential for piRNA cluster specification. The authors provide correlative genomic and imaging data to support their model, although functional validation of the proposed mechanism remains incomplete. Testing the redundancy between dART4 and dART1, which together could affect the prominent piRNA loci, in addition to the minor ones investigated in the manuscript, may change our assessment.

eLife Assessment

This important study uses long-term behavioural observations to understand the factors that influence female-on-female aggression in gorilla social groups. The evidence supporting the claims is convincing, as it includes novel methods of assessing aggression and considers other potential factors. The work will be of interest to broad biologists working on the social interactions of animals.

eLife Assessment

This important study combines imaginative and innovative experiments with a finite element modelling to demonstrate the relevance of poroelasticity in the mechanical properties of cells across physiologically relevant time and length scales. The authors present convincing evidence that cytosolic flows and pressure gradients can persist in cells with permeable membranes, generating spatially segregated influx and outflux zones. These findings are of interest to the cell biology and biophysics communities.

eLife Assessment

This study makes a novel and valuable contribution by adapting step selection functions, traditionally used in animal ecology, to explore human movement and environmental risk exposure in urban slums, offering a promising framework for spatial epidemiology, particularly regarding leptospirosis. The integration of GPS telemetry with environmental data and the stratification by gender and serostatus are notable strengths that enhance the study's relevance for public health applications. The strength of evidence is compelling.

eLife Assessment

Alignment and sequencing errors are a major concern in molecular evolution, and this valuable study represents a welcome improvement for genome-wide scans of positive selection. This new method seems to perform well and is generally convincing, although the evidence could be made more direct and more complete through additional simulations to determine the extent to which alignment errors are being properly captured.

eLife Assessment

In this valuable study, the authors provide a simple yet elegant approach to identifying therapeutic targets that synergize to prevent therapeutic resistance in ovarian cancer using cell lines, data-independent acquisition proteomics, and bioinformatic analysis. The authors convincingly identify several combinations of pharmaceuticals that were able to overcome or prevent therapeutic resistance in culture models of ovarian cancer, a disease with an unmet diagnostic and therapeutic need. However, the extent to which these findings may extend to more complex models of ovarian cancer remains unclear.

eLife Assessment

This manuscript reports an important finding for understanding the molecular mechanisms of mutagenesis, carcinogenesis, and senescence. It follows a previous report showing that the Werner syndrome protein WRN and its interacting protein WRNIP1 are indispensable for translesion DNA synthesis (TLS) by Y-family DNA polymerases (Pols). The manuscript provides convincing evidence that WRN and WRNIP1 ATPases, in addition to the previously reported role of the WRN 3'>5' exonuclease activity, are essential for promoting the fidelity of replication through DNA lesions by Y-family Pols in human cells.

eLife Assessment

This is a valuable study that suggests that HPV-human DNA junctions can be identified from cfDNA in women with cervical cancer and that detection of these junctions is indicative of recurrence. The evidence supporting the conclusions is incomplete, in part because the numbers of reads identifying breakpoints in tumor samples or in circulating cell-free serum samples are not provided. More quantitative analysis will be required to confirm that the breakpoints represented in cell-free DNA can be used as a surrogate to monitor the recurrence of cervical cancer cells, and additional patient studies would also be needed to strengthen the study. This work will be of interest to those who study and treat cervical cancer as well as other HPV-related malignancies.

eLife Assessment

This Research Advance manuscript further elucidates the roles of SMC5/6 loader proteins and associated factors in the silencing of extrachromosomal circular DNA by the SMC5/6 complex. While the findings are largely in line with expectations, they are valuable, representing a meaningful advance beyond the recent study from the same laboratories (PMC9708086), validating the previous model that distinct SMC5/6 subcomplexes, SIMC1-SLF2 and SLF1/2, separately control its transcriptional repression and DNA repair activities on extrachromosomal DNA. Solid evidence is presented for a role for SIMC1/SLF2 in localization of the SMC5/6 complex to plasmid DNA, and the distinct requirements as compared to recruitment of SMC5/6 to chromosomal DNA lesions.

eLife Assessment

The findings of this study are valuable as it demonstrates that when treatment is initiated during acute infection, HIV specific CD8 T cell responses are maintained long term and continued proliferative capacity of these cells may play a role in reducing HIV DNA levels. The evidence supporting the conclusions are solid with rigorous and advanced methodology used with the major limitations being that the findings are association level and do not meet strict criteria for causality. The work is of interest to the HIV cure field and suggests that enhancing early HIV specific CD8 T cell responses should be considered in the design of interventional cure strategies.

eLife Assessment

The authors conducted a valuable study that investigates a molecular pathway mediating the transformation of a cell aggregate into a sheet known as the nucleus laminaris, a crucial site for auditory processing. While the study offers a comprehensive view of the sequence of developmental events and suggests possible roles for FGF signaling, the transcription factor Mafb, and the cell surface adhesive molecule Cadherin-23 in this process, the current data were considered incomplete.

eLife Assessment

This is a valuable and rigorous study that addresses the question of what determines the spatial organization of endocytic zones at synapses. The authors use compelling approaches, in both Drosophila and rodent model systems, to define the role of activity and active zone structure on the organization of the peri-active zone. While the findings are primarily negative, they are carefully executed and contribute to the field by refining existing models of presynaptic organization.