Evaluated articles

eLife Assessment

This important study provides convincing evidence that glucosylceramide synthase (GlcT), a rate-limiting enzyme for glycosphingolipid (GSL) production, plays a role in the differentiation of intestinal cells. Mutations in GlcT compromise Notch signaling in the Drosophila intestinal stem cell lineage, resulting in the formation of enteroendocrine tumors. Further data suggest that a homolog of glucosylceramide synthase also influences Notch signaling in the mammalian intestine. While the outstanding strengths of the initial genetic and downstream pathway analyses are noted, there are minor weaknesses in the data regarding the potential role of this pathway in Delta trafficking. Nevertheless, this study opens the way for future mechanistic studies addressing how specific lipids modulate Notch signalling activity.

eLife Assessment

TrASPr is an important contribution that leverages transformer models focused on regulatory regions to enhance predictions of tissue-specific splicing events. The revisions strengthen the manuscript by clarifying methodology and expanding analyses across exon and intron sizes, and the evidence supporting TrASPr's predictive performance is compelling. This work will be of interest to researchers in computational genomics and RNA biology, offering an improved model for splicing prediction and a promising approach to RNA sequence design.

eLife Assessment

Fleming et al sought to better understand DNAJC7's function in motor neurons as mutations in this gene have been associated with amyotrophic lateral sclerosis (ALS). Using iPSC-derived motor neurons, interactome, and transcriptomic data, they provide solid evidence that loss-of-function mutations in DNAJC7 disrupt RNA binding proteins and resistance to proteasomal stress. These important findings advance our understanding of DNAJC7 in motor neurons while providing clues to how its loss may be causal for ALS; nonetheless, the experiments were performed with a single iPSC line, while at least 3 are deemed to be required to validate the results. Furthermore, the mechanistic evidence is still incomplete with respect to how DNAJC7 mutations lead to HSF1 impaired activity, and whether it is direct or not.

eLife Assessment

This study presents valuable findings on the regulation of survival and maintenance of brain-resident immune cells called microglia. Using compelling and sophisticated genetic tools, the authors demonstrate a gene dosage-dependent mechanism using which microglia are eliminated. This research on cell competition and survival will be of broad interest to the cell biology community.

eLife assessment

Using intracellular in vitro and in vivo recordings and a deep learning approach, this study shows that mouse dentate gyrus mossy cells (MCs) and CA3 pyramidal cells process information from an important electrophysiological hall mark of hippocampus, sharp wave-ripples (SWRs). The innovative use of deep learning to predict SWR waveforms from MC membrane potentials represents an interesting methodological advance. While the key findings are potentially fundamental, some of the evidence is currently incomplete and should be revised to better support the findings.

eLife Assessment

The authors have generated important resources such as a reference dataset of early primate development by utilizing single-cell transcriptomic technology together with induced pluripotent stem cells (iPSCs) from four primate species: humans, orangutans, cynomolgus macaques, and rhesus macaques. By analyzing marker gene expression and cell types across species during undirected differentiation of iPSCs, the authors provide solid evidence that the transferability of marker genes decreases as the evolutionary distance between species increases. This work demonstrates the extended usage of iPSCs for broader fields, which will benefit several scientific communities including anthropology, comparative biology, and evolutionary biology.

eLife Assessment

This study provides a valuable contribution to spatial transcriptomics by introducing MerQuaCo, a computational tool for standardizing quality control in image-based spatial transcriptomics datasets. The tool addresses the lack of consensus in the field and provides robust metrics to identify and quantify common imperfections in datasets. The work is supported by an impressive dataset and compelling analyses, and will be of significant interest to researchers focused on data reproducibility and downstream analysis reliability in spatial transcriptomics.

eLife Assessment

This study provides an important method to model the statistical biases of hypermutations during the affinity maturation of antibodies. The authors show convincingly that their model outperforms previous methods with fewer parameters; this is made possible by the use of machine learning to expand the context dependence of the mutation bias. They also show that models learned from nonsynonymous mutations and from out-of-frame sequences are different, prompting new questions about germinal center function. Strengths of the study include an open-access tool for using the model, a careful curation of existing datasets, and a rigorous benchmark; it is also shown that current machine-learning methods are currently limited by the availability of data, which explains the only modest gain in model performance afforded by modern machine learning.

eLife Assessment

Using an unbiased approach, this important study discovered a role of Ezh2 in the differentiation of granule neuron precursors, the cell of origin for Shh group of medulloblastoma. Furthermore, the authors also provided solid evidence that combined inhibition of Ezh2 and CDK4/6 likely represents a promising strategy for the treatment of this subgroup of MB. Validation of these findings using the FDA-approved Ezh2 inhibitor is needed to further strengthen this preclinical study.

eLife Assessment

This study presents valuable findings suggesting that the late maturation of prefrontal cortex-based control processes enhances conceptual learning by allowing a period of less-constrained knowledge acquisition. The authors provide convincing computational evidence that delayed semantic control promotes learning without compromising representation integrity, with the strongest benefits emerging when control connections target intermediate layers of the model. However, the model's narrow scope raises concerns about scalability to more complex, real-world learning environments, and the meta-analysis, while supporting the developmental trajectory, does not directly test the model's specific predictions regarding task outcomes or error patterns.

eLife Assessment

The study presents important findings regarding the incidence and clinical impact of a mutation in a cardiac muscle protein and its association with the development of atrial fibrillation. The authors provide convincing evidence of electrophysiological disturbances in cells with this mutation and of its association with atrial fibrillation, which would be of interest to cardiologists. Evidence supporting the conclusion that this mutation causes atrial fibrillation would benefit from more rigorous electrophysiologic approaches.

eLife Assessment

This important study analyzes the effect of heat treatment on phage-bacterial interactions and convincingly shows that prior heat exposure alters the bacterial cell envelope, enhancing persistence and bacterial survival when exposed to lytic phages. The study will interest researchers working on antibiotic resistance, tolerance, and phage therapy.

eLife Assessment

This is an important study that examines the impact of Streptococcus pneumoniae genetics on its in vitro growth kinetics, aiming to identify potential targets for vaccines and therapeutics. The study identified significant variations in growth characteristics among capsular serotypes and lineages, linked to phylogeny and high heritability, but genome-wide association studies did not reveal specific genomic loci associated with growth features independent of the genetic background. The evidence supporting these findings is convincing.

eLife Assessment

This study establishes the methodology (machine vision and gaze pose estimation) and behavioral apparatus for examining social interactions between pairs of marmoset monkeys. Their results enable unrestrained social interactions under more rigorous conditions with detailed quantification of position and gaze. It has been difficult to study social interactions using artificial stimuli, as opposed to genuine interactions between unrestrained animals. This study makes an important contribution to studying social neuroscience within a laboratory setting; the approach is novel and well-executed, backed by convincing evidence.

eLife Assessment

This important study examines the relationship between cognition and mental health and investigates how brain, genetics, and environmental measures mediate that relationship. The methods and results are compelling and well-executed. Overall, this study will be of interest in the field of population neuroscience and in studies of mental health.

eLife Assessment

This important study examined orientation representations along the visual hierarchy during perception and working memory. The authors provide results suggesting that during working memory there is a gradient where representations are more categorical in nature later in the visual hierarchy. The evidence presented is solid, most notably a match between behavioral data, though minor weakness can be attributed to the tasks and behaviors not being designed to address this question. The findings should be of interest to a relatively broad audience, namely those interested in the relationship between sensory coding and memory.

eLife Assessment

The songbird vocal motor nucleus HVC contains cells that project to the basal ganglia, the auditory system, or to downstream vocal motor structures. In this fundamental study, the authors conduct optogenetic circuit mapping to clarify how four distinct inputs to HVC act on these distinct HVC cell types. They provide compelling evidence that all long range projections engage inhibitory circuits in HVC and can also exhibit cell-type specific preferences in monosynaptic input strength. Understanding HVC at this microcircuit level is critical for constraining models of song learning and production.

eLife Assessment

This important manuscript proposes a dual behavioral/computational approach to assess emotional regulation in humans. The authors present solid evidence for the idea that emotional distancing (as routinely used in clinical interventions for e.g. mood and anxiety disorders) enhances emotional control.