Evaluated articles

CTLA-4 antibody-drug conjugate reveals autologous destruction of B-lymphocytes associated with regulatory T cell impairment

1. Musleh M Muthana
2. Xuexiang Du
3. Mingyue Liu
4. Xu Wang
5. Wei Wu
6. Chunxia Ai
7. Lishan Su
8. Pan Zheng
9. Yang Liu

• Curated by eLife

  eLife assessment

  This valuable study presents presents solid evidence that an anti-CTLA-4 antibody drug conjugate transiently depletes circulating B cells in a mouse model, showing how dysregulation of the T cell immune system can impact B cell homeostasis. The work will be of broad interest to immunologists and medical biologists, but a major limitation is that the mechanism of B-cell reduction remains unclear, as evidence of killing of B-cells by T-cells is not presented.

Reviewed by eLife

Identification of CD133+ intercellsomes in intercellular communication to offset intracellular signal deficit

1. Kota Kaneko
2. Yan Liang
3. Qing Liu
4. Shuo Zhang
5. Alexander Scheiter
6. Dan Song
7. Gen-Sheng Feng

• Curated by eLife

  eLife assessment

  This important study was designed to examine the bypass of Ras/Erk signaling defects that enable limited regeneration in a mouse model of hepatic regeneration. This hepatocyte proliferation is associated with the expression by groups of cells of mRNA-loaded CD133+ intracellular vesicles that mediate an intercellular signaling pathway that supports proliferation. These are new observations, supported by convincing data, that have broad significance to the fields of regeneration and cancer.

Reviewed by eLife

Within-host diversity improves phylogenetic and transmission reconstruction of SARS-CoV-2 outbreaks

1. Arturo Torres Ortiz
2. Michelle Kendall
3. Nathaniel Storey
4. James Hatcher
5. Helen Dunn
6. Sunando Roy
7. Rachel Williams
8. Charlotte Williams
9. Richard A Goldstein
10. Xavier Didelot
11. Kathryn Harris
12. Judith Breuer
13. Louis Grandjean

• Curated by eLife

  eLife assessment

  This valuable study presents a novel and theoretically interesting model to account for viral diversity within hosts in evolutionary and genomic analyses of pathogens. The simulation results presented are solid, although there are some aspects of the methodology that require further investigation in order to establish their validity. The application to SARS-CoV-2 shows promise, but would benefit from further evaluation.

Reviewed by eLife

Engineering of the endogenous HBD promoter increases HbA2

1. Mandy Y Boontanrart
2. Elia Mächler
3. Simone Ponta
4. Jan C Nelis
5. Viviana G Preiano
6. Jacob E Corn

• Curated by eLife

  eLife assessment

  This study presents the important finding that gene editing could be used to activate delta-globin expression to treat disorders of red blood cell synthesis. The evidence supporting the claims of the authors is solid, particularly in the immortalized cell lines, although inclusion of a larger number of donor patient samples may have strengthened the conclusions that were able to be drawn from the primary cell experiments. The data show this approach to have promise and identify avenues of effort that could be pursued to advance it to a clinical strategy for hemoglobinopathy treatment.

Reviewed by eLife

Early-life experience reorganizes neuromodulatory regulation of stage-specific behavioral responses and individuality dimensions during development

1. Reemy Ali Nasser
2. Yuval Harel
3. Shay Stern

• Curated by eLife

  eLife assessment

  Early life stress can have profound effects on animal behavior, including potential influences on individuality. In this valuable work, the authors use a rich new dataset to solidly demonstrate that the behavioral consequences of early life stress in C. elegans can be buffered by neuromodulators previously implicated in patterns of individuality. While much remains to be learned about the mechanisms by which stress might influence individuality, these studies provide an important entry point that will be of interest to neurobiologists studying interactions between behavior, neuromodulation, stress, and individuality.

Reviewed by eLife

Mec1-independent activation of the Rad53 checkpoint kinase revealed by quantitative analysis of protein localization dynamics

1. Brandon Ho
2. Ethan J Sanford
3. Raphael Loll-Krippleber
4. Nikko P Torres
5. Marcus B Smolka
6. Grant W Brown

• Curated by eLife

  eLife Assessment:

  In addition to identifying several components regulated by checkpoint kinases, the authors identify a novel non-canonical activation mode for the central checkpoint kinase Rad53, a phosphorylation event that does not depend on Mec1 and instead depends on proteins involved in retrograde signaling through Rtg3. The study thus reveals unanticipated complexities in the DNA replication stress response. Overall, the work is well done and the data support the main conclusions.

Reviewed by eLife

Response outcome gates the effect of spontaneous cortical state fluctuations on perceptual decisions

1. Davide Reato
2. Raphael Steinfeld
3. André Tacão-Monteiro
4. Alfonso Renart

• Curated by eLife

  eLife assessment

  Reao et al. investigate a question that has long puzzled neuroscientists: what features of ongoing brain activity predict trial-to-trial variability in responding to the same sensory stimuli? The data demonstrate that the outcome of the previous trial, specifically a miss, allows these associations to be seen - while a correct response appears less likely to do so. and this is a valuable advance in our understanding of the relationship between brain state, behavioral state, and performance. Technically, the study is solid, ie, the methods, data and analyses broadly support the claims, with some weaknesses remaining.

Reviewed by eLife

A billion years arms-race between viruses, virophages, and eukaryotes

1. Jose Gabriel Nino Barreat
2. Aris Katzourakis

• Curated by eLife

  eLife assessment

  The important study by Barreat and Katzourakis examines the evolutionary history of eukaryotic viruses (and related mobile elements) in the Bamfordvirae kingdom, and evaluates potential alternative scenarios regarding the origin of different lineages in this highly diverse kingdom. Through convincing phylogenetic analyses, the authors propose a new evolutionary model for the origin of this kingdom where their last common ancestor is inferred to have been an exogenous, non-virophage DNA virus with a small genome. This work advances our understanding of the deep evolutionary history of viruses, the interaction between viruses and the first eukaryotes, and the diversification of viral lineages.

Reviewed by eLife

ZMYM2 controls human transposable element transcription through distinct co-regulatory complexes

1. Danielle J Owen
2. Elisa Aguilar-Martinez
3. Zongling Ji
4. Yaoyong Li
5. Andrew D Sharrocks

Reviewed by eLife

Structural and mechanistic insights into ribosomal ITS2 RNA processing by nuclease-kinase machinery

1. Jiyun Chen
2. Hong Chen
3. Shanshan Li
4. Xiaofeng Lin
5. Rong Hu
6. Kaiming Zhang
7. Liang Liu

• Curated by eLife

  eLife assessment

  This study represents a valuable mechanistic contribution towards understanding how ribosomal RNA is processed during ribosome biogenesis. The biochemical evidence supporting the major conclusions is convincing. This work will be of interest to cell biologists and biochemists working on ribosome biogenesis.

Reviewed by eLife

Structural insight into guanylyl cyclase receptor hijacking of the kinase–Hsp90 regulatory mechanism

1. Nathanael A Caveney
2. Naotaka Tsutsumi
3. K Christopher Garcia

• Curated by eLife

  eLife assessment

  In this important study, the human membrane receptor guanyl cyclase GC-C was expressed in hamster cells, co-purified in complex with endogenous HSP90 and CDC37 proteins, and the structure of the complex was determined by cryo-EM. The study shows that the pseudo-kinase domain of GC-C associates with CDC37 and HSP90, similarly to how the bona fide protein kinases CDK4, CRAF and BRAF have been shown to interact. The methodology used is state of the art and the evidence presented is compelling.

Reviewed by eLife

Tetraose steroidal glycoalkaloids from potato provide resistance against Alternaria solani and Colorado potato beetle

1. Pieter J Wolters
2. Doret Wouters
3. Yury M Tikunov
4. Shimlal Ayilalath
5. Linda P Kodde
6. Miriam F Strijker
7. Lotte Caarls
8. Richard GF Visser
9. Vivianne GAA Vleeshouwers

• Curated by eLife

  eLife assessment

  This valuable study links natural variation in steroidal glycoalkaloid production to disease and insect resistance in potato species. The study design is straightforward and thorough, and the evidence supporting the main conclusions is solid. The work will be of interest to plant biologists and breeders.

Reviewed by eLife

Differential translation of mRNA isoforms underlies oncogenic activation of cell cycle kinase Aurora A

1. Roberta Cacioppo
2. Hesna Begum Akman
3. Taner Tuncer
4. Ayse Elif Erson-Bensan
5. Catherine Lindon

• Curated by eLife

  eLife assessment

  In this important study, the authors provide compelling evidence that the interplay between alternative polyadenylation (APA) of mRNA encoding Aurora Kinase A (AURKA) and hsa-let-7a miRNA governs AURKA protein levels. The authors show that short 3'UTR isoform of mRNA encoding AURKA is efficiently translated throughout the cell cycle, while the long 3'UTR isoform is suppressed by hsa-let-7a miRNA in a cell cycle-dependent manner. These findings delineate post-transcriptional mechanisms regulating AURKA expression that may be implicated in increase in AURKA protein that is frequently observed across a variety of cancers.

Reviewed by eLife

Steroidogenesis and androgen/estrogen signaling pathways are altered in in vitro matured testicular tissues of prepubertal mice

1. Laura Moutard
2. Caroline Goudin
3. Catherine Jaeger
4. Céline Duparc
5. Estelle Louiset
6. Tony Pereira
7. François Fraissinet
8. Marion Delessard
9. Justine Saulnier
10. Aurélie Rives-Feraille
11. Christelle Delalande
12. Hervé Lefebvre
13. Nathalie Rives
14. Ludovic Dumont
15. Christine Rondanino

• Curated by eLife

  eLife assessment

  This study reports useful information on the limits of the organotypic culture of neonatal mouse testes, which has been regarded as an experimental strategy that can be extended to humans in the clinical setting for the conservation and subsequent re-use of testicular tissue. The evidence that the culture of testicular fragments of 6.5-day-old mouse testes does not allow optimal differentiation of steroidogenic cells is compelling and should enable further optimizations in the future.

Reviewed by eLife

Evolution of an extreme hemoglobin phenotype contributed to the sub-Arctic specialization of extinct Steller’s sea cows

1. Anthony V Signore
2. Phillip R Morrison
3. Colin J Brauner
4. Angela Fago
5. Roy E Weber
6. Kevin L Campbell

• Curated by eLife

  eLife assessment

  This important study functionally characterizes hemoglobin from Steller's sea cow, a cold-water adapted sirenian that went extinct ~250 years ago. Using ancestral sequence reconstruction, site-directed mutagenesis and biochemical assays to compare Steller's hemoglobin to those from (sub)tropical extant sea cows (all of which are proficient divers despite lacking massive muscle oxygen storage), the authors build a solid case for the molecular basis of cold adaptation, centered around an increased solubility and higher oxygen carrying capacity. Remarkably, a single amino acid replacement would explain most of the distinctive functional features of this hemoglobin, which include a hitherto unknown resistance to DPG. Overall, this work will be of interest to evolutionary biologists, physiologists, and biochemists, as well as an enjoyable and informative read for the general public.

Reviewed by eLife

Profiling the bloodstream form and procyclic form Trypanosoma brucei cell cycle using single-cell transcriptomics

1. Emma M Briggs
2. Catarina A Marques
3. Guy R Oldrieve
4. Jihua Hu
5. Thomas D Otto
6. Keith R Matthews

• Curated by eLife

  eLife assessment

  This important study identifies more than 1500 genes that are differentially transcribed over the cell cycle of the single-celled eukaryotic pathogen, Trypanosoma brucei. Analysis of the two major developmental stages of these pathogens suggests that a core set of genes are similarly regulated in both stages, while many cell cycle-related changes in gene expression were unique to one stage. Intriguingly, the levels of far fewer proteins are differentially regulated over the trypanosome cell cycle, indicating that protein levels are primarily regulated by post-transcriptional processes. The study represents a significant technical advance in analyzing gene expression at the single-cell level in unfractionated trypanosome cultures.

Reviewed by eLife

Molecular basis of ligand-dependent Nurr1-RXRα activation

1. Xiaoyu Yu
2. Jinsai Shang
3. Douglas J Kojetin

• Curated by eLife

  eLife assessment

  This is a fundamental study of the activation process of Nurr1, an orphan nuclear receptor that may be a significant target for the treatment of neurodegenerative disorders. Nurr1 functions as a monomer, but may also heterodimerize with RXR which represses Nurr1 transcriptional activation. The authors provide compelling evidence for Nurr1 activation through ligand-induced dissociation of an inactive Nurr1-RXRa heterodimer. These data will be important for biochemists and cell biologists working on regulatory / activation mechanisms of nuclear hormone receptors.

Reviewed by eLife

A critical region of A20 unveiled by missense TNFAIP3 variations that lead to autoinflammation

1. Elma El Khouri
2. Farah Diab
3. Camille Louvrier
4. Eman Assrawi
5. Aphrodite Daskalopoulou
6. Alexandre Nguyen
7. William Piterboth
8. Samuel Deshayes
9. Alexandra Desdoits
10. Bruno Copin
11. Florence Dastot Le Moal
12. Sonia Athina Karabina
13. Serge Amselem
14. Achille Aouba
15. Irina Giurgea

• Curated by eLife

  eLife assessment

  This manuscript is of big interest to physicians and geneticists who may struggle with interpreting the clinical significance of novel or rare missense variants in the TNFAIP3 gene in patients with systemic inflammatory diseases. There is also much debate about the potential mechanisms by which these missense mutations might be pathogenic. El Khour et al. addressed these questions by using a combination of in silico analysis and in vitro functional assays. However, their conclusions require additional experimental support and should be expanded to include other reported likely pathogenic missense variants.

Reviewed by eLife

Plasticity of gene expression in the nervous system by exposure to environmental odorants that inhibit HDACs

1. Sachiko Haga-Yamanaka
2. Rogelio Nunez-Flores
3. Christi A Scott
4. Sarah Perry
5. Stephanie Turner Chen
6. Crystal Pontrello
7. Meera G Nair
8. Anandasankar Ray

• Curated by eLife

  eLife assessment

  This interesting and important work shows that diacety, a volatile organic compound released by yeast in fermenting fruit, can act as a histone deacetylase (HDAC) inhibitor and trigger wide changes in gene expression, together with suppression neurotoxicity in a Drosophila model of Huntington's disease. While the effects on gene expression changes and degenerative phenotypes are convincingly shown, further studies are required to determine whether and how olfactory sensory neurons and odorant receptors mediate the effects of diacetyl described by the authors.

Reviewed by eLife

A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing

1. Raquel Granell
2. John A Curtin
3. Sadia Haider
4. Negusse Tadesse Kitaba
5. Sara A Mathie
6. Lisa G Gregory
7. Laura L Yates
8. Mauro Tutino
9. Jenny Hankinson
10. Mauro Perretti
11. Judith M Vonk
12. Hasan S Arshad
13. Paul Cullinan
14. Sara Fontanella
15. Graham C Roberts
16. Gerard H Koppelman
17. Angela Simpson
18. Steve W Turner
19. Clare S Murray
20. Clare M Lloyd
21. John W Holloway
22. Adnan Custovic
23. on behalf of UNICORN and Breathing Together investigators

• Curated by eLife

  eLife assessment

  Genome-wide association studies on asthma have been challenging due to innate heterogeneity and the syndromic nature of asthma, variable accuracy in phenotyping, and potential gene-environment interactions. Here, the authors identified genetic loci associated with subtypes of childhood wheezing in combined data of multiple birth cohorts, by coupling latent class analysis of clinical phenotypic data with GWAS discovery. A mechanistically plausible genetic locus close to annexin 1 (ANXA1) was associated exclusively with early-onset persistent wheeze and provides new translatable molecular insight into asthma pathogenesis.

Reviewed by eLife