Evaluated articles

eLife assessment

This valuable paper examines the Bithorax complex in several butterfly species, in which the complex is contiguous and not split, as it is in the well-studied fruit fly Drosophila. Based on genetic screens and genetic manipulations of a boundary element involved in segment-specific regulation of Ubx, the authors provide solid evidence for their conclusions, which could be further strengthened by additional data and analyses. The data presented are relevant for those interested in the evolution and function of Hox genes and of gene regulation in general.

eLife assessment

This paper investigates the potential role of extracellular vesicles in providing extracellular matrix signals for migration of vascular smooth muscle cells. The findings could be useful for researchers interested in cell migration, but the evidence supporting the conclusions is presently incomplete.

eLife assessment

This study employs multiscale simulations to show that PIP2 lipids bind to the DIV S4-S5 linker within the inactivated state of a voltage-gated sodium channel, affecting the coupling of voltage sensors to the ion-conducting pore. The authors report the valuable finding that PIP2 prolongs inactivation by binding to the same site that binds the C-terminal tail during recovery from inactivation, suggesting binding to gating charges in the resting state that may impede activation. The coarse-grained and atomistic molecular dynamics simulations are solid, supporting the claims, although they do lack validation through experiment or simulation, such as studies of linker mutants to confirm PIP2 binding sites, a resting state Nav1.4 model to confirm voltage sensor binding, as well as tests using flexible linkers to probe interactions with PIP2 without backbone restraints.

eLife assessment

This research is a potentially important contribution to the field of protein biosynthesis pathways and their link to aging, especially regarding the thorough analysis of variation in measures expected to correlate with elongation rate in old and new daughter cells derived from old and new mother cells. However, the imaging results, analysis, and methodologies are incomplete, as in its current form several key questions remain unanswered.

eLife assessment

This study presents a valuable new approach for efficient computation of statistics on correlations between genetic variants (linkage disequilibrium, or LD), which the authors apply to quantify the extent of LD across chromosomes. The method appears solid, although the presentation of equations needs clarification and improvement. The authors document that cross-chromosome LD can be substantial, which has implications for geneticists who are interested in population structure and its impact on genetic association studies.

eLife assessment

In this important study, the authors apply a residue-resolution protein coarse-grained model to investigate the differences in molecule dimensions and phase behaviour of three HP1 paralogs, HP1 paralog mixtures, and HP1/DNA mixtures. The simulations are well designed to investigate the impact of HP1 sequence on its phase behaviour. Solid evidence reveals that electrostatic interactions are a key determinant of HP1 paralog phase behaviour, thereby advancing our understanding of the molecular mechanisms driving the phase separation behaviour of HP1 paralogs.

eLife assessment

P-glycoprotein (Pgp) is a major ABC-transporter that couples ATP hydrolysis with the export of xenobiotics and drugs, influencing their pharmacokinetics. The authors provide convincing cryo-EM Pgp structures of drug complexes in previously unforeseen outward-facing conformations. These structures reveal important mechanistic insights that could be of broader impact, but because these transient-like states were captured by cysteine cross-linking the substrate to Pgp, support for the conclusions is incomplete, and further validation is required.

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This important study will provide evidence about a novel screen-triage-treat strategy for cervical cancer prevention. The strategy would contribute to improving access to cervical cancer prevention to vulnerable women with low access to health care, and, therefore, at the highest risk of cervical cancer. However, the current protocol description is currently incomplete and missing key information for clarity and reproducibility.

eLife assessment

This important study advances our understanding of the biological significance of the DNA sequence adjacent to telomeres. The data presented convincingly demonstrates that subtelomeric repeats are non-essential and have a minimal, if any, role in maintaining telomere integrity of budding yeast. The work will be of interest to telomere community specifically and the genome integrity community more broadly.

eLife assessment

This study provides valuable findings showing the production of IL-22 from intestinal ILC3 during intermittent fasting promotes beigeing of white adipose tissue. However, the study is incomplete because of the lack of mechanistic insight. In particular, the authors should clearly show the mechanism by which IL-22-derived from ILC3 directly induces beigeing.

eLife assessment:

This valuable study provides molecular-level insights into the functional mechanism of bacterial ice-nucleating proteins, detailing important electrostatic interactions in the domain architecture of multimeric assemblies. The evidence supporting the claims of the authors is solid, with results from protein engineering experiments, functional assays, and cryo-electron tomography, while the proposed structural model of protein self-assembly remains hypothetical. The work is of broad interest to researchers in the fields of protein structural biology, biochemistry, and biophysics, with implications in microbial ecology and atmospheric glaciation.

eLife assessment

Little is known about the role of the microbiome alterations in epithelial ovarian cancer. This important and rigorous study carefully examined the microbiome composition of 1001 samples from close to 200 ovarian cancer cases and controls, and presents compelling evidence that the fallopian tube microbiota are perturbed in ovarian cancer patients. These insights are expected to fuel further exploration into translational opportunities stemming from these findings.

eLife assessment

Despite the importance of T follicular helper cells (Tfh cells) in vaccine-induced humoral responses, it is still unclear which type of Tfh cells (Tfh1, Tfh2, and Tfh17) is critical for generating protective humoral immunity. By using the rhesus macaques model (most similar to human), the authors have addressed this potentially important question and obtained suggestive data that Tfh1 is critical. Although being suggestive, the evidence for the importance of Tfh1 is incomplete.

eLife assessment

Gain-of-function mutations and amplifications of PPM1D are found across several human cancers and are associated with advanced tumor stage, worse prognosis, and increased lymph node metastasis. Unfortunately, clinical translation has so far not been possible due to the lack of PPM1D inhibitors with favorable pharmacokinetic properties. This useful study leveraged CRISPR/Cas9 screening to identify that SOD1 inhibition is synthetic lethal with PPM1D mutation in leukemia, although the mechanistic analyses were incomplete.

eLife assessment

This important study in Drosophila identifies neuronal mechanisms influenced by altered activity during a critical period (CP) of larval locomotor circuit development. Increasing activity during the CP causes permanent network changes indicating that a setpoint of network excitability is determined during the CP. Most importantly, for excitability setpoint determination during the CP excitatory and inhibitory inputs are integrated such that the effect of CP hyperexcitation can be rescued by the stimulation of endogenous inhibitory inputs to the motoneurons. Solid experimental evidence supports their novel insight into how developing neural network excitability is tuned and how it can be entrained during the CP.

eLife assessment

Picard et al. propose a Facial Expression Pain Signature (FEPS) as a distinctive marker of pain processing in the brain. In this valuable study, they attempt to use functional magnetic resonance imaging (fMRI) data to predict facial expressions associated with painful heat stimulation. The crucial aspect of the claim is whether the proposed biomarker is distinctive, i.e., it is specific enough to distinguish facial expressions in response to pain from similar facial expressions of non-painful origin. The experimental setup does not control for that condition, so the evidence is incomplete to support their main claims.

eLife assessment

In this manuscript, Jain and colleagues explore whether increasing adult neurogenesis is protective against status epilepticus and the development of spontaneous recurrent seizures (chronic epilepsy) in a mouse pilocarpine model of temporal lobe epilepsy. This is an important work that provides solid data, contradicting previous studies on suppressing chronic seizures by reduced neurogenesis. To ensure the validity and robustness of the results, there is a need for additional controls and validations.

eLife assessment

Antibodies are some of the most important tools in biomedical research. However, their quality and specificity vary significantly. This fundamental study provides important guidelines for how the quality of an antibody should be assessed and recorded and provides compelling data on the selected antibodies. This paper will be of interest to researchers working in experimental cell biology.

eLife assessment

This study presents a valuable methodology with increased efficiency and precision of gene editing in human primary hematopoietic stem and progenitor cells. The evidence supporting the claims is solid, although a more extensive assessment of functional hematopoietic stem cell impacts and potential off-target effects would be helpful to further strengthen the conclusions. The work will be of interest to biologists studying hematopoietic stem and progenitor cells and gene targeting for potential clinical applications.