Evaluated articles

eLife Assessment

This fundamental study uses the Drosophila mushroom body as a model to understand the molecular machinery that controls the temporal specification of neuronal cell types. With convincing experimental evidence, the authors make the finding that the Pipsqueak domain-containing transcription factor Eip93F plays a central role in specifying a later-born neuronal subtype while repressing gene expression programs for earlier subtypes.

eLife Assessment

This manuscript reports valuable results on the role of MDC1 and Treacle in DSB repair in rDNA repeats. It has been previously established that MDC1 is replaced by Treacle as the main adaptor in the nucleolar DNA damage response. This work provides convincing evidence that MDC1 is required for the recruitment of RAD51 and BRCA1 to DSBs in rDNA. The work involves multiple MDC1 knockout models and establishes that RFN8-RNF168 act downstream of MDC1 in the recruitment of the HR machinery to nucleolar DSBs.

eLife Assessment

In this important work, the authors present a new transformer-based neural network designed to isolate and quantify higher-order epistasis in protein sequences. They provide solid evidence that higher-order epistasis can play key roles in protein function. This work will be of interest to the communities interested in modeling biological sequence data and understanding mutational effects.

eLife Assessment

This manuscript uses adaptive-bandit simulations to describe the dynamics of the Pseudomonas-derived chephalosporinase PDC-3 β-lactamase and its mutants to better understand antibiotic resistance. The finding, that clinically observed mutations alter the flexibility of the Ω- and R2-loops, reshaping the cavity of the active site, is valuable to the field. The evidence is considered incomplete, however, with the need for analysis to demonstrate equilibrium weighting of adaptive trajectories and related measures of statistical significance.

eLife Assessment

This manuscript employs cryo-EM, mutational analysis, and biochemical assays to explore the molecular basis by which glutamine promotes filamentation and regulates the activity of human glutamine synthetase (hGS) by stabilizing interactions between hGS decamers. The studies supporting this mechanism are solid, but could be improved by providing more clarity and by addressing methodological issues in the cryoEM data processing workflow. This work will be of particular interest and useful to groups interested in understanding the molecular basis of nutrient sensing, cellular metabolism, and structural regulation of enzyme activity.

eLife Assessment

This valuable study re-evaluates a published simulation model on the role of heterozygote advantage in shaping MHC diversity. By modifying key modeling assumptions, the author argues that the original conclusions depend on a narrow and potentially unrealistic parameter range. While the work is in principle solid, the robustness of this claim is viewed differently by the reviewers. The manuscript further proposes an alternative modeling framework in which expansion of the MHC gene family allows homozygotes to outperform heterozygotes, thereby challenging the idea that heterozygote advantage alone can account for high allelic diversity at MHC loci. The topic is highly relevant for eco-immunology and evolutionary genetics, although it is not clear yet how well the model generalizes to other genes with different patterns of haplotype diversity in the population and different degrees of heterozygous advantage.

eLife Assessment

This important study shows how hunger alters avoidance of harmful heat in C. elegans by reconfiguring the activity of key sensory neurons. The evidence is convincing, with well-designed behavioural, genetic, and imaging experiments that support the main conclusions. The work will be of interest to neuroscientists studying how internal states shape sensory processing and behaviour across species.

eLife Assessment

This study employed state-of-the-art quantitative imaging and genomics approaches to address a fundamental question regarding the establishment of Polycomb domains during Drosophila embryogenesis. The critical developmental stage was pinpointed to the maternal-to-zygotic transition, rather than earlier stages, providing clarification for the field. The roles of two factors, Zelda and GAGA-factor, were investigated, which reveal that Zelda, but not GAGA-factor, contributes to this process. These compelling findings have implications for chromatin and developmental biology.

eLife Assessment

This useful study examines the contribution of synaptotagmin 1 and synaptotagmin 7 to metabolite antigen presentation to mucosal-associated invariant T (MAIT) cells; it begins to address a critical gap in our understanding of the antigen presentation mechanisms of these cells. Strengths of the study include the use of Mtb to study the dynamics of antigen presentation to MAIT cells instead of a synthetic antigen. The strength of the evidence to support the conclusion is solid.

eLife Assessment

This valuable study analyzes aging-related chromatin changes through the lens of intra-chromosomal gene correlation length, which is a novel computational metric that captures spatial correlations in gene expression along the chromosome. The authors propose that this metric reflects chromatin structure and can serve as a proxy for its changes during aging. While currently the strength of evidence is somewhat incomplete, if revised with further supporting data, this work will provide a systems-level understanding of aging and genome regulation, which is predicted to have a substantive impact on the field.

eLife Assessment

This study presents a valuable quantitative framework for analyzing transcription dynamics data for enhancers and genes expressed in the early Drosophila embryo. By analyzing existing data across both synthetic reporters and an endogenous gene (eve), this work provides evidence that spatial gene expression patterns within the embryo are largely determined by "activity time" - the time during which a gene is bursting. The methods and evidence are solid and should be of broad interest to researchers in developmental biology and quantitative gene regulation, but the study would be significantly enhanced by clarifying the novelty of the findings relative to prior work and presenting a rigorous benchmarking of their algorithm against previously used algorithms.

eLife Assessment

This study presents a new toolbox for Representational Similarity Analysis, representing a valuable contribution to the neuroscience community. The authors offer a well-integrated platform that brings together a range of state-of-the-art methodological advances within a convincing framework, with strong potential to enable more rigorous and insightful analyses of neural data across multiple subfields.

eLife Assessment

The authors describe the important finding that the Legionella-containing vacuole is surrounded by a dense ubiquitin "cloud" that is highly resistant to detergent extraction. The study provides compelling evidence that this structure is generated through a combination of canonical ubiquitination mediated by the SidC Legionella ligase and phosphoribosyl-ubiquitination mediated by the SidE family of Legionella ligases. These findings provide insight into how Legionella remodels the host vacuolar environment through complex ubiquitin modifications.

eLife Assessment

This work, combining behavioural genetics and calcium imaging, provides evidence for a form of learning in Drosophila that derives solely from direct or (optogenetically induced) phantom experience of punishment or reward. Flies that experience foot-shock alone show a subsequent decrease in avoidance to all odorants, together with increased odor-evoked activation of reward-encoding dopaminergic neurons that innervate the mushroom body. Phantom reward, delivered via optogenetic activation of reward-encoding dopaminergic neurons, increases subsequent odour-avoidance. While the findings are valuable to the field, there are aspects of the work that are incomplete, and some of the conclusions and terminology are also not completely justified; three major issues include : (a) the use of the term "priming" to describe this form of learning seems inappropriate and inconsistent with the accepted definition of this term; (b) a key 1998 publication with an initial description of this behavioural phenomenon needs to be cited and presented as context; and (c) the work on reward induced increase in odor-aversion seems relatively preliminary.

eLife Assessment

This is a valuable study describing transcriptome-based pheochromocytoma and paraganglioma (PPGL) subtypes and exploring the mutations, immune correlates and disease progression of cases in each subtype. The cohort is a reasonable size and a second cohort is included from the Cancer Genome Atlas (TCGA). One of the key premises of the study is that identification of driver mutations in PPGL is not complete and that compromises characterisation for prognostic purposes. This is a solid starting point on which to base characterisation using different methods.

eLife Assessment

This valuable study explores the role of the chromatin regulator ATAD2 in mouse spermatogenesis. The data convincingly demonstrate that ATAD2 is essential for proper chromatin remodeling in haploid spermatids, influencing gene accessibility, H3.3-mediated transcription, and histone eviction. Using Atad2 knockout (KO) mice, the authors link ATAD2 to the DNA-replication-independent incorporation of sperm-specific proteins like protamines and histone H3.3. Although the findings highlight chromatin abnormalities and impaired in vitro fertilization in KO mice, natural fertility remains unaffected, suggesting possible in vivo compensatory mechanisms. Future experiments will be needed to tease out the precise molecular role of ATAD2 in spermatogenesis. This work will be of interest to the epigenetics and developmental fields.

eLife Assessment

This study provides valuable insights with convincing evidence detailing altered tactile perception in a mouse model of ASD (Fmr1 mice), paralleling sensory abnormalities in Fragile X and autism. Its main strength lies in the use of a novel and quantitative tactile categorization task and the careful dissection of behavioral performance across training and difficulty levels, suggesting that deficits may stem from an interaction between sensory and cognitive processes. The behavioral experiments are well executed and set the stage for subsequent mechanistic, causal, and computational approaches. The work is relevant to those interested in autism, cognition, and/or sensory processing.

eLife Assessment

This work demonstrates an objective way to select parameter values for a quadratic integrate-and-fire model so that its bifurcation diagram matches a specific target diagram, generated from the Wang-Buzsaki model. The method is useful for the field and is presented with convincing evidence. The method is currently limited in its ability to be applied to data, but improves our mathematical tools to treat a rarely studied type of bifurcation.

eLife Assessment

This study presents a valuable finding on whether executive resources mediate the impact of language predictability in reading in the context of aging. The evidence is solid in the investigation of prediction in reading, with one caveat that the text materials used could be biased against the aging population. The work will be of interest to cognitive neuroscientists working on reading, language comprehension, and executive control.

eLife Assessment

This study used a conditional knockout mouse line to remove Ptbp1 in retinal progenitors and demonstrated that its deletion has no effect on retinal neurogenesis or cell fate specification, thereby challenging the prevailing view of Ptbp1 as a master regulator of neuronal fate. The data are convincing, supported by transcriptomic analysis, histology, and proliferation assays. This study is important, and the broader implications for other CNS regions warrant further investigation.