Evaluated articles

Gene dosage imbalance disrupts systemic metabolism in the Dp16 Down syndrome mouse model

1. Fangluo Chen
2. Muzna Saqib
3. Christy M Nguyen
4. Dylan C Sarver
5. Y Eugene Yu
6. Susan Aja
7. Marcus M Seldin
8. G William Wong

• Curated by eLife

  eLife Assessment

  This article describes the comprehensive metabolic phenotype of a mouse model of Down Syndrome, together with supporting transcriptomic, metabolomic, and biochemical data. While the work is largely descriptive, the evidence presented is convincing and highlights similarities and differences in male and female mice. This is a valuable study that provides essential groundwork for the further genetic dissection of dosage-sensitive genes causing metabolic dysregulation in Down Syndrome.

Reviewed by eLife

A pilot study for whole proteome tagging in C. elegans

1. Matthew Eroglu
2. Oliver Hobert

• Curated by eLife

  eLife Assessment

  The nematode C. elegans is an ideal model in which to achieve the ambitious goal of a genome-wide atlas of protein expression and localization. In this paper, the authors explore the utility of a new and efficient method for labeling proteins with fluorescent tags, evaluating its potential to be the basis for a larger, genome-wide effort that is likely to be very useful for the community. While the evidence for the method itself is solid, carrying out this project at a large scale will require significant additional feasibility studies.

Reviewed by eLife

NAD boosting mediated by CD38 inhibition drives reversal of a pathological vicious cycle of intracrine activity and inflammation in eyelid meibomian gland dysfunction

1. Yuki Hamada
2. Takehide Sakamoto
3. Daisuke Yarimizu
4. Hikari Uehara
5. Xinyan Shao
6. Tom Macpherson
7. Emi Hasegawa
8. Masao Doi

• Curated by eLife

  eLife Assessment

  The authors provide valuable data linking NAD+ dependent HSD3b6 gene expression in the eyelid to a vicious cycle involving decreased steroidogenesis and AR signaling, pro-inflammatory cytokine release, inflammation, CD38 activation, and further NAD+ decline, which induces meibomian gland atrophy leading to dry eye disease. Overall, the presented work provides evidence for the pathologic relationship between a pro-inflammatory environment, intracrine activity, and the NAD+ cofactor. However, the current study does not clearly establish the proposed intracrine mechanism and may largely reflect systemic hormonal effects resulting from the global Had3b6 knockout, leading to an incomplete narrative.

Reviewed by eLife

Fully computational design of PAM-relaxed Staphylococcus aureus Cas9 with expanded targeting capability using UniDesign

1. Youcai Xiong
2. Li-Kuang Tsai
3. Jun Zhou
4. Shuang Chen
5. Xiaofeng Xia
6. Jifeng Zhang
7. Y Eugene Chen
8. Jie Xu
9. Xiaoqiang Huang

• Curated by eLife

  eLife Assessment

  This important study demonstrates the power of the UniDesign computational framework in prospectively engineering a PAM-relaxed Staphylococcus aureus Cas9 variant with editing performance comparable to evolution-derived counterparts. The authors responded promptly and thoroughly to reviewer concerns and strengthened the manuscript with additional experimental validation, providing compelling evidence through expanded biochemical characterization across multiple human cell types, comprehensive deep-sequencing analyses, and direct comparisons with established variants that illuminate the mechanistic basis of PAM specificity remodeling and Cas9 optimization. By establishing computational design as a rigorous and viable alternative to directed evolution for CRISPR systems, this work will be of broad interest to the protein engineering, genome engineering, synthetic biology, and computational protein design communities.

Reviewed by eLife

During an inflammatory response, zebrafish tnfa and tnfb are expressed by different cell types and have distinct expression kinetics

1. Kaylee SE van Dijk
2. Christina Begon-Pescia
3. Boudewijn A de Bruin
4. Resul Özbilgiç
5. Philip M Elks
6. Mai E Nguyen-Chi
7. Maria Forlenza

• Curated by eLife

  eLife Assessment

  This study provides a valuable contribution to the field of zebrafish immunology by demonstrating that the two TNF paralogs tnfa and tnfb show distinct cellular sources and temporal expression patterns during inflammation. These findings are potentially significant because they suggest regulatory divergence and functional specialization within the TNF signaling system in teleosts. While the evidence supporting differential expression is convincing, the work remains largely observational and would benefit from functional experiments and deeper mechanistic insight to determine whether these differences translate into distinct roles in inflammatory signaling. This work will be of interest to immunologists interested in inflammatory cytokine evolution and immune regulation in vertebrates.

Reviewed by eLife

Chromatin priming and Hunchback recruitment integrate spatial and temporal cues in Drosophila neuroblasts

1. Ayanthi Bhattacharya
2. Hemalatha Rao
3. Sonia Q Sen

• Curated by eLife

  eLife assessment

  The study provides an important advance towards understanding how spatial and temporal transcriptional programs are integrated to regulate lineage-specific chromatin and enhancer activation. The functional evidence is currently incomplete, but the current data provide a solid correlative and conceptual foundation. Functional experiments directly linking Gsb occupancy to chromatin state and regulation of some lineage-specific targets would further strengthen the causal interpretation of the model. Clarifying the scope of conclusions and explicitly acknowledging the technical limitations of current chromatin assays would provide a more balanced interpretation of the manuscript.

Reviewed by eLife

Large-scale synthetic data enable digital twins of human excitable cells

1. Pei-Chi Yang
2. Mao-Tsuen Jeng
3. Deborah K Lieu
4. Regan L Smithers
5. Gonzalo Hernandez-Hernandez
6. L Fernando Santana
7. Colleen E Clancy

• Curated by eLife

  eLife assessment:

  This important study presents a novel and technically robust framework that combines deep learning and optimized patch‑clamp protocols to infer biophysical parameters and generate electrophysiology‑based digital twins, with the inclusion of convincing experimental data being a clear strength; there is methodological innovation and potential impact for understanding cellular heterogeneity, drug response, and arrhythmia risk prediction. Concerns remain about clarity and validation, particularly regarding the biological meaning of the modeled heterogeneity, the selection and sufficiency of large synthetic training populations, and the robustness and uniqueness of inferred parameter sets. Most notably, key translational claims (e.g., replacing large‑scale wet experiments and predicting rare arrhythmic events) lack direct experimental validation and head‑to‑head comparisons with conventional protocols. Overall, while the approach is promising and timely, stronger biological grounding, clearer framing, and additional experimental validation are needed to support the manuscript's broad claims.

Reviewed by eLife

The spike tip protein of bacteriophage T4

1. Yves Mattenberger
2. Ekaterina S Knyazhanskaya
3. Mikhail M Shneider
4. Sergey A Buth
5. Sergey Nazarov
6. William P Robins
7. Petr G Leiman
8. Dominique Belin

• Curated by eLife

  eLife Assessment

  This important study by Mattenburger et al. employs structural biology, biochemistry, and genetics to advance understanding of how bacteriophage contractile injection systems mediate host recognition and DNA delivery, yielding a remarkable 1.15 A crystal structure of the T4 spike tip complex (gp5-gp5.4). The compelling evidence presented demonstrates that the spike tip protein gp5.4 is essential for phage fitness and successful infection of Escherichia coli strains bearing truncated lipopolysaccharide; however, direct proof regarding interaction with the cell wall or its components is lacking. The study further provides biochemical evidence that the analogous spike tip protein from phage P2 (GpV) is translocated into the host periplasm during infection, together establishing the spike tip as a critical and active component of the phage infection machinery.

Reviewed by eLife

Single Domain Antibody Inhibitors Target the Coiled Coil Arms of the Bacillus subtilis SMC complex

1. Ophélie Gosselin
2. Michael Taschner
3. Lea M Huber-Hürlimann
4. Markus A Seeger
5. Stephan Gruber

• Curated by eLife

  eLife Assessment

  This important study introduces an innovative synthetic nanobody approach to probe the function of the bacterial SMC complex. The authors provide convincing evidence that these nanobodies target the coiled-coil region of the SMC subunit and demonstrate that this region is critical for SMC function in vivo. Overall, the work is significant for the fields of genome organization, SMC protein biology, synthetic biology, and bacterial cell biology.

  [Editors' note: this paper was reviewed by Review Commons.]

Reviewed by eLife, Review Commons

Leveraging AI to explore structural contexts of post-translational modifications in drug binding

1. Kirill E. Medvedev
2. R. Dustin Schaeffer
3. Nick V. Grishin

Reviewed by eLife

In vitro reconstitutions suggest a general model for paradoxical activation of ARAF, BRAF, and CRAF by diverse RAF inhibitor types that does not rely on negative allostery

1. Emre Tkacik
2. Dong Man Jang
3. Kayla Boxer
4. Byung Hak Ha
5. Michael J Eck

• Curated by eLife

  eLife Assessment

  This paper's biochemical studies of the mechanisms underlying paradoxical activation of RAF family kinases by small-molecule inhibitors have uncovered some important new features of this process by establishing a role for the N-terminal acidic (NtA) motif and showing that CRAF and ARAF can also exhibit paradoxical activation. However, there are substantial criticisms that can be made regarding the data analysis and the evidence for the authors' new model that paradoxical activation does not rely on negative allostery is considered incomplete.

Reviewed by eLife

Single-cell co-mapping reveals relationship between chromatin state and gene expression in early zebrafish development

1. Vivek Bhardwaj
2. Alberto Griffa
3. Helena Viñas Gaza
4. Peter Zeller
5. Alexander van Oudenaarden

• Curated by eLife

  eLife Assessment

  In this valuable study, the authors examine transcription and chromatin dynamics during early zebrafish development by simultaneously profiling histone modifications and full-length transcriptomes in thousands of single cells, providing solid analysis that chromatin and transcriptional states are initially weakly correlated in early embryonic cells and become progressively more aligned as differentiation proceeds. The work also supports a model in which promoter-anchored cis-spreading of H3K27me3 contributes to stable gene silencing during development. Future functional perturbations and orthogonal validations will be needed to determine the causal contribution of Polycomb spreading to fate commitment. Overall, the dataset and accompanying analyses provide a robust resource and a quantitative framework for studying chromatin-transcription relationships during vertebrate embryogenesis.

  [Editors' note: this paper was reviewed by Review Commons.]

Reviewed by eLife, Review Commons

Engineering ATP Import in Yeast Uncovers a Synthetic Route to Extend Cellular Lifespan

1. Naci Oz
2. Hetian Su
3. Vedat Sari
4. Praveen Patnaik
5. Rohil Hameed
6. Jong Hee Song
7. Derek C Prosser
8. Vyacheslav M Labunskyy
9. Vadim N Gladyshev
10. Nan Hao
11. Alaattin Kaya

• Curated by eLife

  eLife Assessment

  This manuscript addresses an important and conceptually ambitious question by using a synthetic biology strategy to perturb ATP homeostasis in yeast and examine its causal relationship with lifespan. While the experimental approach and lifespan data are intriguing, the current evidence is incomplete and internally inconsistent, particularly regarding intracellular ATP measurements, transporter directionality, mitochondrial dependence, and the proposed mechanistic model. Substantial clarification, additional controls, and further experimentation will be necessary before the main conclusions can be considered robust and the biological significance of the findings can be fully assessed.

Reviewed by eLife

Inhibition of Slc17a7 expressing neurons in the basolateral amygdala which project to the nucleus accumbens shapes the fidelity of motivated behavior

1. William D Mercer
2. Iltan Aklan
3. Nathaniel E Connolly
4. Shivangi M Inamdar
5. Benjamin L Fisher
6. Chase M Larsson
7. Kyle H Flippo

• Curated by eLife

  eLife Assessment

  This useful study uses in vitro electrophysiology, projection-specific chemogenetics, and different behavioural tasks to investigate the role of Vglut1-expression in basolateral amygdala neurons projecting to the nucleus accumbens in aspects of motivated behaviour. Although the manuscript is clearly written, the strength of the evidence supporting claims about the role of this pathway is incomplete. Currently, the work may be of interest to some behavioural neuroscientists, but additional controls and further clarification of specific analyses would strengthen their broader significance.

Reviewed by eLife

Cortex-wide Dynamics of Internal Decisions About Behavioral Context

1. Joshua Calder-Travis
2. Ruud L van den Brink
3. Saanchi Thawani
4. Lars Schwabe
5. Tobias H Donner

• Curated by eLife

  eLife Assessment

  In this study, the authors investigated how inference about the current task context, by weighting evidence based on surprise and uncertainty in the environment, is encoded in the cortex. Using MEG imaging and an impressive amount of analytic work based on normative decision modeling, they provided solid evidence for the involvement of the visual and parietal cortex. These results are a valuable complement to and extension of a previous study using fMRI measurements, by identifying the candidate regions that are of importance for the inference process, not just for encoding the end product.

Reviewed by eLife

Blood-derived dietary protein promotes sleep in the mosquito Aedes aegypti

1. Jiwei Zhang
2. Hitoshi Tsujimoto
3. Samaneh Biglari
4. Zach N Adelman
5. Alex C Keene

• Curated by eLife

  eLife Assessment

  This important study links blood-derived dietary content to sustained increases in sleep in the mosquito Aedes aegypti. Using multiple independent approaches, the authors provide convincing evidence for blood-induced changes in sleep. These findings have broad implications for understanding how specialized diets regulate sleep across species and for mosquito vector biology.

Reviewed by eLife

Early Sleep-Dependent Sensory Gating in the Olfactory System

1. Diego Serantes
2. Diego Gallo
3. Anttonella García
4. Joaquín González
5. Mateo Mendoza
6. Patricia Lagos
7. Pablo Torterolo
8. Matías Cavelli

• Curated by eLife

  eLife Assessment

  This study presents a well-executed investigation into how the olfactory system disconnects from the environment during sleep and anesthesia, identifying a potential gating mechanism at the earliest synaptic stages of the olfactory bulb. The findings are important, as they challenge current theories by demonstrating that sensory gating occurs in non-thalamic pathways even under controlled airflow conditions. The strength of evidence is solid, supported by rigorous multimodal recordings, although the reliance on anesthetic models to draw conclusions about natural sleep is a limitation that requires further contextualization.

Reviewed by eLife

Polo-like kinase phosphorylation of the orphan kinesin KIN-G negatively regulates centrin arm biogenesis in Trypanosoma brucei

1. Yasuhiro Kurasawa
2. Qing Zhou
3. Kyu Joon Lee
4. Huiqing Hu
5. Ziyin Li

• Curated by eLife

  eLife Assessment

  This important study provides new insight into the regulation of cell organization and division in Trypanosoma brucei through the control of a kinesin motor protein by a polo-like kinase. The authors present solid evidence from rigorous biochemical and imaging analyses showing that phosphorylation modulates kinesin function and cellular organization. However, direct in vivo evidence that PLK phosphorylates kinesin-G is lacking.

Reviewed by eLife

The targeted cytosolic degradation of class I histone deacetylases is essential for efficient alphaherpesvirus replication

1. Sheng-Li Ming
2. Meng-Hua Du
3. Jia-Ming Yang
4. Ya-Di Guo
5. Jia-Jia Pan
6. Wei-Fei Lu
7. Jiang Wang
8. Lei Zeng
9. Bei-Bei Chu

• Curated by eLife

  eLife Assessment

  In this study, the authors describe the degradation of HDACs in late HSV-1 infection and attempt to link this phenomenon to HDAC export to the cytoplasm and to DNA damage response. However, the evidence is incomplete, as many of the experiments are lacking in rigor. As a result, mechanistic links to the proposed model are weak.

Reviewed by eLife

Large scale prospective evaluation of co-folding across 557 Mac1-ligand complexes and three virtual screens

1. Jongbin Kim
2. Galen J Correy
3. Brendan W Hall
4. Moira M Rachman
5. Olivier Mailhot
6. Takaya Togo
7. Ryan L Gonciarz
8. Priyadarshini Jaishankar
9. R Jeffrey Neitz
10. Eric R Hantz
11. Yagmur U Doruk
12. Maisie GV Stevens
13. Morgan E Diolaiti
14. Rashad Reid
15. Saumya Gopalkrishnan
16. Nevan J Krogan
17. Adam R Renslo
18. Alan Ashworth
19. Brian K Shoichet
20. James S Fraser

• Curated by eLife

  eLife Assessment

  This study addresses an important gap in drug discovery by delivering a rigorous, large-scale evaluation of widely used co-folding methods for predicting ligand-bound protein complexes and virtual screening. A key strength is the comprehensive benchmarking framework, which leverages structures and chemical compounds that were absent from the AI models training set, thereby providing particularly compelling and unbiased evidence of co-folding performance. The findings clearly delineate the complementary roles of deep learning-based co-folding and physics-based docking, offering practical guidance for their rational integration into drug discovery workflows. Although the conclusions are convincing, improvements in the test cases, presentation, and usability can further strengthen the overall impact.

Reviewed by eLife, PREreview