Cell Biology

eLife assessment

The manuscript describes important findings regarding the significance of CHD2 in ovarian folliculogenesis. Overall, the results lead to convincing conclusions, with minimal concerns raised by the reviewers. Both the results and conclusions are well discussed. This work will be of interest to ovarian biologists and physicians working on female fertility.

eLife assessment

This important study provides solid evidence for a non-genomic action of progesterone in Xenopus oocyte activation. The findings demonstrate that two non-genomic progesterone receptors, ABHD2 and mPRb, function as a novel progesterone-stimulated phospholipase A2. However, the findings are reliant on high concentrations of inhibitor drugs, and mechanistic details about the molecular interaction and respective functions of ABHD2 and mPRb are incomplete. The findings will be of broad interest to reproductive endocrinologists and physiologists.

eLife assessment

This important study advances our understanding of sperm motility regulation during fertilization by uncovering the midpiece/mitochondria contraction associated with motility cessation and structural changes in the midpiece actin network as its mode of action by using various advanced microscopic techniques. The evidence supporting the association is solid, but the evidence to support the causality of contraction and motility cessation is incomplete and would benefit from time-resolved imaging monitoring contraction, motility, and cell viability simultaneously. With the causality part strengthened, the work will be significant and of broad interest to cell biologists working on the cytoskeleton, mitochondria, cell fusion, and fertilization.

eLife assessment

This important work substantially advances our understanding of osteoblast migration to the sites of bone formation and regeneration. The evidence supporting the conclusion is compelling, with rigorous in vitro assays for cellular and biochemical aspects and with appropriate in vivo models. The work will be of broad interest to developmental biologists and bone biologists.

eLife assessment

This study represents a useful description of a third interaction site between melanophilin and myosin-5a which has a role in regulating the distribution of pigment granules in melanocytes. While much of the data forms a solid case for this interaction, the inclusion of key controls for the cellular studies and measurement of interaction affinities would have been helpful.

eLife assessment

This manuscript presents a useful presentation of a new method for assessing the adhesion strength of axons with the use of a laser-induced shock wave. However, the strength of the evidence is incomplete as critical controls for calibration and time course are lacking.

eLife assessment

This manuscript offers valuable information on the effect of two small molecule combinations (2C), CHIR99021 and A-485, during the reprogramming of mature cardiomyocytes into regenerative cardiac cells. This manuscript is incomplete, as the mechanistic insights derived from transcriptomic and genomic datasets are without experimental validation. This manuscript also needs additional experimental support to confirm the regenerative potential of 2C and improvements in the data analysis and presentation. Overall, this interesting work provides insights into the development of therapeutic targets for cardiac regeneration in infarcted hearts.

eLife assessment

This useful study, which systematically addresses off-target effects of a commonly used chemotherapy drug on bone and bone marrow cells and which therefore is of potential interest to a broad readership, presents evidence that reducing systemic inflammation induced by doxorubicin limits bone loss to some extent. The demonstration of the effect of systemic inflammation on bone loss is convincing. Building on prior work, this study sets the scene for additional genetic and pharmacologic experiments as well as future analyses of the bone phenotypes, which should speak to the mechanisms involved in doxorubicin-induced bone loss – which are not addressed in the current study – and which may substantiate the clinical relevance of targeting inflammation in order to limit the negative impact of chemotherapies on bone quality.

eLife assessment

This important study characterizes various cell populations and describes a developmental trajectory using snRNAseq data, highlighting the cell state transitions including periosteal stem cells during bone repair. However, there was a general consensus that the evidence provided is currently incomplete, necessitating the additional data and a more thorough verification of the conclusions. Despite this, the work provides a helpful resource that will be of broad interest to the bone community.

eLife assessment

This is a useful study that shows changes in the chromatin landscape of GABAergic neurons in induced pluripotent stem cells (iPSCs) derived from both Dravet Syndrome (DS) patients and healthy donors. The strength of the evidence is currently incomplete because the authors compared iPSCs from different individuals, rather than isogenic controls, and they did not examine the expression of the gene and encoded protein (SCN1A or Nav1.1) that are thought to be responsible for the majority of DS cases in these iPSCs. The work would be of interest to scientists who study development, developmental disorders, and epigenetic contributions to disease.

eLife assessment

This work presents an important technological advance, in the form of a high throughput platform for Single Particle Tracking allowing us to measure millions of cells and thousands of compounds per day. Analysis of the diffusional behaviour of fluorescently-tagged targets permits the identification of, and differentiation between, small molecules that bind directly or affect the target indirectly. The evidence provided is compelling, although some methodological information is undisclosed.

eLife assessment

Varadharajan et al. explore the mechanistic basis of MBOAT7 SNP association with steatotic liver disease and link its function in LPI acylation to altered lipidomics of endosomal/lysosomal system and impaired TFEB mediated lysosomal biogenesis. The findings are important with theoretical and practical implications in MAFLD, alcohol-induced hepatic steatosis, and lysosomal diseases. The strength of evidence is convincing using methodology in line with current state-of-the-art.

eLife assessment

In this valuable manuscript, Yao et al. describe new methods for assessing the intracellular itinerary of Botulinum neurotoxin A (BoNT/A), a potent toxin used in clinical and cosmetic applications. The current manuscript challenges previously held views on how the catalytic portion of the toxin makes its way from the endocytic compartment to the cytosol, to meet its substrates. The approach taken is deemed innovative and the experiments are carefully performed, however, they are somewhat incomplete with respect to the drawn conclusions, as it is possible that the scope of their findings could be restricted to the specific neuron model and molecular tools that were used. This paper could be of interest to both cell biologists and physicians.

eLife assessment

BMP signaling plays a vital role in skeletal tissues, and the importance of its role in microtia prevention is novel and promising. This important study sheds light on the role of BMP signaling in preventing microtia in the ear, with solid data broadly supporting the claims of the authors.

eLife assessment

This useful work describes a novel microscopy-based method to correlate the degree of pigmentation with the gene expression profile of human-induced pluripotent stem cell-derived Retinal Pigmented Epithelial (iPSC-RPE) cells at the single cell level. The presented evidence is solid in showing that there is heterogeneous gene expression in iPSC-derived RPE cells, and there is no significant correlation with the pigmentation. By analyzing the expression of some genes related to function, lysosomal- and complement-related pathways were partially enriched in darker cells. This methodology can be used by other researchers interested in analyzing gene expression related to microscopic images.

eLife assessment

This valuable manuscript demonstrates that the glycosyltransferase UGGT slows the degradation of endoplasmic reticulum (ER)-associated degradation substrates through a mechanism involving re-glucosylation of asparagine-linked glycans following release from the calnexin/calreticulin lectins. The evidence supporting this conclusion is solid using genetically-deficient cell models and biochemical methods to monitor the degradation of trafficking-incompetent ER-associated degradation substrates, although the manuscript could be improved through additional studies directed towards defining potential functional differences between UGGT1 and UGGT2 and additional insights into the impact of UGGT on the nature of substrate glycosylation within the ER. This work will be of specific interest to those interested in mechanistic aspects of ER protein quality control and protein secretion.

eLife assessment

This study presents a valuable finding on how the GAP DLC1, a deactivator of the small GTPase RhoA, regulates RhoA activity globally as well as at Focal Adhesions. Using a new acute optogenetic system coupled to a RhoA activity biosensor, the authors present solid evidence that DLC1 amplifies local Rho activity at Focal Adhesions. Nevertheless, the proposed mechanism could be further supported by a deeper analysis of the data.

eLife assessment

This important study identifies the mitotic localization mechanism for Aurora B and INCENP (parts of the chromosomal passenger complex, CPC) in Trypanosoma brucei. The mechanism differs from that in the more commonly studied opisthokonts and is supported by compelling RNAi and imaging experiments, targeted mutations, immunoprecipitations with crosslinking/mass spec, and AlphaFold interaction predictions. The findings will be of interest to cell biologists working on cell division, parasitologists, and those interested in the evolution of mitotic mechanisms.

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.