Evaluated articles

A mechanistic theory of planning in prefrontal cortex

1. Kristopher T Jensen
2. Peter Doohan
3. Mathias Sablé-Meyer
4. Sandra Reinert
5. Alon Baram
6. Thomas Akam
7. Timothy EJ Behrens

• Curated by eLife

  eLife Assessment

  This important study advances our understanding of the neural substrate of planning trajectories towards a goal by using recurrent neural networks. The manuscript provides solid evidence for most of the claims, but it remains unclear whether the dynamics do indeed bear the defining characteristics of attractors, and the interpretation and scope of some claims may need to be reassessed in light of prior work. The work will be of broad interest to theoretical and systems neuroscientists and to cognitive scientists.

Reviewed by eLife

The CLAMP GA-binding transcription factor regulates heat stress-induced transcriptional repression

1. Joseph Aguilera
2. Jingyue Duan
3. Kaitlyn Cortez
4. Rachel S Lee
5. Angelica Aragon
6. Mukulika Ray
7. Erica Larschan

• Curated by eLife

  eLife Assessment

  This important study presents evidence that the Chromatin-linked adaptor for MSL complex proteins (CLAMP) GA-binding transcription factor (TF) regulates ~75% of HS-induced repression in Drosophila and suggests that CLAMP is the first known transcription factor to induce heat-stress-mediated repression of gene expression. While mechanistic details remain to be sorted out, this manuscript provides convincing evidence that novel pathways involving the CLAMP transcription factor repress gene expression during heat shock stress.

Reviewed by eLife

Human CD1c-autoreactive T cells recognise Mycobacterium tuberculosis–infected antigen-presenting cells and display cytotoxic effector programmes

1. Matthew Milton
2. Sahar H Farag
3. Diana Garay-Baquero
4. Jennie Gullick
5. Daniel Burns
6. Rita Szoke-Kovacs
7. Patrick Trimby-Smith
8. Alex Look
9. Richard Stopforth
10. Marco Lepore
11. David K Cole
12. Laura Denney
13. Andrew White
14. Sally Sharpe
15. Alasdair Leslie
16. Andres Vallejo
17. Liku Tezera
18. Paul Elkington
19. Salah Mansour

• Curated by eLife

  eLife Assessment

  The study investigates how CD1c-restricted T cells respond to Mtb-infected APCs, leading to increased cytokine production and cytotoxic activity that may help control Mtb infection. While the work is important and will interest researchers in the field, the supporting evidence is incomplete and could be strengthened by additional experiments. Experiments would: (i) evaluate THP1-CD1c cells to determine whether MHC surface expression is reduced or entirely abolished, (ii) enhance confidence in the purity of the CD1c-specific T cell population isolated from blood, and (iii) suggest what additional signal THP1-CD1c cells treated with Mtb express that is absent from the untreated cells.

Reviewed by eLife

Evaluating the applicability of replication success metrics in animal-to-human translation: A simulation study

1. Carolyne Jie Huang
2. Samuel Pawel
3. Kimberley Elaine Wever
4. Benjamin Victor Ineichen
5. Rachel Heyard

• Curated by eLife

  eLife Assessment

  This is a detailed and well-designed simulation study of the utility of replication metrics in animal-to-human study translations in bridging the gap between laboratory discoveries and health practice, a critical consideration in turning laboratory scientific research findings into tangible, real-world applications, to directly help human health. The study approaches are solid, and the findings are important, as they offer insights into clinical research translations to advance health decision-making. There is some potential for the strength and applicability of the presented evidence to be improved upon revision.

Reviewed by eLife

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 Caenorhabditis 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 having a genome-wide atlas of protein expression and localization. In this paper, the authors develop a rational strategy for at-scale tagging of all protein coding genes with fluorescent markers, providing solid evidence that it would be a feasible foundation for a community-based, genome-wide effort. This work should serve as an important springboard for discussions about how to achieve this worthy and impactful goal.

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

  In this important study, the authors present an interesting platform for digital twin construction of iPSC-CMs using an AI-based approach. The concept is timely and could have meaningful impact as the field continues to explore integration of computational and experimental models. The evidence is convincing overall, although additional attention to framing and calibration of claims would enhance clarity and better reflect the current level of validation.

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 J 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 work is a compelling example of the potential of this approach. The authors generate protein chimeras to provide convincing evidence that their identified nanobodies target the coiled-coil region of the SMC subunit, demonstrating that this region is critical for SMC function in vivo. Overall, the work is significant for the fields of genome organisation, 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