Cell Biology

eLife assessment

This manuscript describes valuable new findings on the impact of chromatin context on the outcomes of microhomology-mediated end joining of DNA double-strand breaks (DSBs), specifically a preference for DSB-proximal microhomologies in repair within a heterochromatic compared to a euchromatic locus. The authors develop the Drosophila spermatogonia as a model for repair at induced DSBs in a mitotically-active tissue and leverage this system to provide convincing evidence that the local environment impacts the preference for repair mechanism and outcome. The work could be strengthened by the use of additional euchromatin insertion(s) to robustly validate the findings.

eLife assessment

This is a theoretical analysis that gives compelling evidence that length control of bundles of actin filaments undergoing assembly and disassembly emerges even in the absence of a length control mechanism at the individual filament level. Furthermore, the length distribution should exhibit a variance that grows quadratically with the average bundle length. The experimental data are compatible with these fundamental theoretical findings, but further investigations are necessary to make the work conclusive concerning the validity of the inferences for filamentous actin structures in cells.

eLife assessment

The work by Hornberger and team presents a novel workflow for the visualisation of myofibrils with high resolution and contrast that will be highly valued by the scientific community. The methods include solid validation of both sample preparation and analysis, and have been used to make the fundamental discovery of myofibrillogenesis as the mechanism of mechanical loading-induced growth. Whether this mechanism is present in other settings of muscle growth (i.e., non-loading), other striated tissue (e.g myocardium), or is sex-dependent, will require future experiments.

eLife assessment

This important study combines experiments with optogenetic actuation and theory to understand how signalling proteins control the switch between cell protrusion and retraction, two processes in single-cell migration. The authors examine the role of a guanine exchange factor (GEF) on the downstream effectors RhoA and Cdc42, which trigger retraction and protrusion, respectively. The experimental and theoretical evidence provides a convincing explanation for why and how a single signalling protein – here, a GEF of RhoA – can control both protrusion and retraction.

eLife assessment

This study presents a valuable finding on the cell composition in mouse spleen depleted for the CD47 receptor and its signaling ligand Thrombospondin in hematopoietic differentiation. The supporting evidence is convincing with analytical improvements on the individual contributions of the signaling components and with functional studies. This work has implications for the role of CD47/Thsp in extramedullary erythropoiesis in mouse spleen and will be of interest to researchers in cell signaling, transfusion medicine, and cell therapy.

eLife assessment

This important study sheds light on the role of sphingolipids on the maturation of Parkinson's disease-associated Synphilin-1 inclusion bodies (SY1 IBs) on the mitochondrial surface in a yeast model using Synthetic Genetic Array (SGA) and state-of-the-art imaging techniques. The authors provide solid evidence that downregulating the sphingolipid biosynthesis pathway leads to defective maturation and enhanced toxicity of SY1 IBs in both yeast and mammalian cells. However, these data neither explain the role of mitochondrial surface sphingolipids in SY1 IB maturation (the cellular site of maturation of smaller toxic aggregates to bigger less toxic IBs), nor the requirement of mitochondrial activity in IB maturation.

eLife assessment

This valuable work deals with mathematical modeling of centrosome maturation, building on the insight that autocatalytic assembly of the centrosome leads to size inequality. To remedy this, the authors propose a catalytic growth model with a shared enzyme pool that is able to reproduce various experimental results such as centrosome size scaling with cell size and centrosome growth curves in C. elegans. While finding the work of interest, the strength of the evidence presented in favor of the model is incomplete.

eLife assessment

This important study defined the physiological function of a conserved meiosis factor during murine spermatogenesis. The genetic and cellular biological evidence supporting the conclusion is convincing. This work will be of broad interest to cell biologists, geneticists, and reproductive biologists.

eLife assessment

This study in budding yeast (S. cerevisiae) presents important findings demonstrating that the exonuclease Xrn1 regulates autophagy in response to methionine deprivation through effects on TORC1. There is solid evidence that the impact of Xrn1 on TORC1 is contingent on its catalytic activity rather than the degradation of any specific category of mRNAs. A major strength is the novel mechanism, in which Xrn1 modulates the nucleotide-binding state of the Gtr1/2 complex.

eLife assessment

This fundamental study employs a combination of cryo-electron microscopy, molecular dynamics, and mass spectrometry to elucidate the role of α-tubulin acetylation at the lumenal lysine 40 residue (αK40) within the cilium. Compelling evidence shows αK40 acetylation to impact the structure and stability of doublet microtubules in cilia by affecting the lateral rotational angle. The work will be of relevance to those interested in cytoskeleton and structural biology.

eLife assessment

This study makes a valuable contribution by characterizing the role of the exocyst in secretory granule exocytosis in the Drosophila larval salivary gland. The results lead to the novel interpretation that the exocyst participates not only in exocytosis, but also in earlier steps of secretory granule biogenesis and maturation. Although these ideas are potentially of interest to a wide range of membrane traffic researchers, the evidence is incomplete, and the authors are urged to consider the possibility that inactivation of an essential exocytosis component might have indirect effects on other parts of the secretory pathway.

eLife assessment

This fundamental study advances our understanding of the role of senescent osteoclasts (SnOCs) in the pathogenesis of spine instability. The authors provide compelling evidence for the SnOCs to induce sensory nerve innervation. Accordingly, reduction of SnOCs by the senolytic drug Navitoclax markedly reduces spinal pain sensitivity. This work will be of broad interest to regenerative biologists working on spinal pain.

eLife assessment

The authors performed a useful RNAi screen to identify epigenetic regulators involved in oxygen-glucose deprivation (OGD)-induced neuronal injury. PRMT5 was identified as a negative regulator of neuronal cell survival after OGD. Solid in vitro and in vivo data suggest that PRMT5 could be a novel therapeutic target for the treatment of ischemic stroke.

eLife assessment

This valuable prospective study develops a new tool to accelerate pharmacological studies by using neural networks to emulate the human ventricular cardiomyocyte action potential. The evidence supporting the conclusions is convincing, based on using a large and high-quality dataset to train the neural network emulator. There are nevertheless a few areas in which the article may be improved through validating the neural network emulators against extensive experimental data. In addition, the article may be improved through delineating the exact speed-up achieved and the scope for acceleration. The work will be of broad interest to scientists working in cardiac simulation and quantitative system pharmacology.

eLife assessment

This study presents a valuable dissection on how functional HSCs are expanded in PVA cultures. The functional and multi-omic analyses provided are convincing, although the additional data and their analysis provided during revision could have been included in the test to assist readers and to strengthen the published manuscript. Nevertheless, the present work will be of value for stem cell biologists interested in HSC regulation.

eLife assessment

The authors studied the mechanisms by which dead cells are removed from the wounded skin in a process called efferocytosis. By analyzing different cell populations in the skin, the authors find that proteins involved in mediating the cell death and marking the cells as undergoing this process are elevated during distinct times in the wound healing program. Interestingly, these same proteins are elevated even higher in diabetic wounds. Finally the authors demonstrate that blocking the process of efferocytosis alters the wound healing program, thus illustrating its importance in effective wound repair.

eLife assessment

The manuscript by Jingsong Zhou and colleagues uncovers why the extraocular muscles (EOMs) are preserved while other muscles undergo degenerative changes in amyotrophic lateral sclerosis (ALS). In this work, the authors have used a mouse model of familial ALS that carries a G93A mutation in the Sod1 gene to demonstrate that NaBu treatment partially restores the integrity of NMJ in the limb and diaphragm muscles of G93A mice. The findings of the study offer important information that EOMs are spared in ALS because they produce protective factors for the NMJ and, more specifically, factors secreted by EOM-derived satellite cells. While most of the experimental approaches are convincing, the use of sodium butyrate (NaBu) in this study needs further investigation, as NaBu might have a variety of biological effects. Overall, this work may help develop future therapeutic interventions for patients with ALS.

eLife assessment

In this study, the authors develop a strategy for fluorophore-tagging endogenous proteins in human induced pluripotent stem cells (iPSCs) using a split mNeonGreen approach, and they conclude that the system will be appropriate for performing live imaging studies of highly dynamic cellular processes such as cytokinesis in iPSCs. Experimentally, the methods are solid, and the data presented support the authors' conclusions. Overall, these methodologies should be useful to a wide audience of cell biologists who want to study protein localization and dynamics at endogenous levels in iPSCs.

eLife assessment

This is an important study for understanding the pathogenesis of ulcerative colitis. It convincingly demonstrates reduced levels of the vesicular trafficking protein Rab7 in ulcerative colitis and Crohn's disease, leading to altered levels of calcium-activated chloride channel regulator 1 (CLCA1) and subsequent mucin dysregulation, highlighting Rab7's significance in gut homeostasis maintenance. The manuscript advances the field as it provides insights into a novel regulatory pathway implicated in ulcerative colitis, potentially paving the way for the development of targeted therapeutic interventions.

eLife assessment

This study presents initial findings in the generation of 3D cell constructs from endometrial cell mixtures seeded in Matrigel scaffold and treated with hormones as a proof of concept. While the study findings are valuable, functional validation to demonstrate its robustness is lacking, and therefore the strength of evidence is incomplete. The term organoids might not be appropriate to describe this in vitro model.