
Calcineurin modulates the balance between progenitor proliferation and differentiation to facilitate beta cell regeneration.


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Stimulation of pancreatic beta cell regeneration could be a therapeutic lead to treat diabetes. Unlike humans, the zebrafish can efficiently regenerate beta cells, notably from ductal pancreatic progenitors. To gain insight into the molecular pathways involved in this process, we established the transcriptomic profile of the ductal cells after beta cell ablation in the adult zebrafish. These data highlighted the protein phosphatase calcineurin as a new potential modulator of beta cell regeneration. We showed that calcineurin overexpression abolished the regenerative response, leading to glycemia dysregulation. On the opposite, calcineurin inhibition increased ductal cell proliferation and subsequent beta cell regeneration. Interestingly, the enhanced proliferation of the progenitors was paradoxically coupled with their exhaustion. This suggests that the proliferating progenitors are next entering in differentiation. Calcineurin appears as a guardian which prevents an excessive progenitor proliferation to preserve the pool of progenitors. Altogether, our findings reveal calcineurin as a key player in the balance between proliferation and differentiation to enable a proper beta cell regeneration.

### Competing Interest Statement

The authors have declared no competing interest.

Negative cell cycle regulation by Calcineurin is necessary for proper beta cell regeneration in zebrafish

calcineurin-s-role-in-zebrafish-beta-cell-regeneration


Calcineurin's Role in Zebrafish Beta Cell Regeneration


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Cx41.8 mediates the correct temporal induction of HSPCs by regulating mitochondrial ROS production.


Haematopoietic stem and progenitor cells (HSPCs) derive from a subset of endothelial cells (ECs), known as haemogenic ECs by the process of endothelial-to-haematopoietic transition (EHT). Although many factors involved in EHT have been elucidated, we still have a poor understanding of the temporal regulation of this process. Mitochondrial-derived reactive oxygen species (ROS) have been shown to stabilise hypoxia-inducible factors 1/2α (Hif1/2α), allowing them to positively regulate EHT. Here, we show a developmental delay in EHT and HSPC induction in a gap junction mutant, connexin (cx)41 . 8 (orthologous to mammalian CX40 ), in zebrafish. In mammalian cells, CX40 has been shown to localise to the mitochondria. We demonstrate that Cx41.8 is important for the correct temporal generation of mitochondrial ROS, which stabilise the Hif pathway, allowing for the subsequent specification of the haemogenic endothelium. Taken together, our data indicate that Cx41.8 mediates the correct induction of HSPCs.

### Competing Interest Statement

The authors have declared no competing interest.

Connexin 41.8 mediates the correct temporal induction of haematopoietic stem and progenitor cells

connexin-41-8-role-in-haematopoietic-stem-cell-induction


Connexin 41.8 Role in Haematopoietic Stem Cell Induction



Evolutionary analysis of CaSR reveals critical residues for receptor activation and pathogenicity.


Calcium-sensing receptor evolution highlights hyper/hypocalcemia-causing mutations The Calcium Sensing Receptor (CaSR) is a key player in regulating calcium levels and has been linked to disorders like hypercalcemia and hypocalcemia. Despite advancements in understanding CaSR’s structure and functions, there are still gaps in our understanding of its specific residues and their differences from receptors within the same class. In this study, we used phylogeny-based techniques to identify functionally equivalent orthologs of CaSR, predict residue significance, and compute specificity-determining position (SDP) scores to understand its evolutionary basis. The analysis revealed exceptional conservation of the CaSR subfamily, with high SDP scores being critical in receptor activation and pathogenicity. To further enhance the findings, gradient-boosting trees were applied to differentiate between gain- and loss-of-function mutations responsible for hypocalcemia and hypercalcemia. Lastly, we investigated the importance of these mutations in the context of receptor activation dynamics. In summary, through comprehensive exploration of the evolutionary history of the CaSR subfamily, coupled with innovative phylogenetic methodologies, we identified activating and inactivating residues, providing valuable insights into the regulation of calcium homeostasis and its connections to associated disorders.

### Competing Interest Statement

The authors have declared no competing interest.

The open-source code is available at our GitHub repository: <https://github.com/CompGenomeLab/CaSR>

Evolutionary History of Calcium-Sensing Receptors Unveils Hyper/Hypocalcemia-Causing Mutations

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Evolutionary History of Calcium-sensing Receptors and Mutations



Endothelial cells migrate directionally driven by dual force-fields of shear stress and VEGFA gradients.


Emerging concepts of developmental vascular remodelling recently identified that selectively labelled sprouting tip cells and/or venous endothelial cells (ECs) accumulate in developing arteries, suggesting directional migration of specific ECs drives artery formation. However, a general population analysis and detailed quantitative investigation of migratory mechanisms is so far lacking. Here, we developed a universally applicable quantitative approach and a computational model allowing to track and simulate stochastically labelled EC populations irrespective of labelling density and origin. Dynamic mapping of EC distributions in a bespoke coordinate system revealed how ECs move during the most active remodelling phases in the mouse retina. Simulation and parameter sensitivity analysis illustrated that the population shift from veins to arteries cannot be explained by random walk, but best fits to a tuneable dual force-field between shear-force induced directionality against blood flow, and hypoxia mediated VEGFA-gradients. High migration rates require only weak flow-migration coupling, whereas low migration rates require strong coupling to the flow direction. Functional analysis identified Cdc42 as the critical mediator of overall population movement from veins to arteries, yet with surprising heterogeneity suggesting the existence of distinct cell populations. This new quantitative understanding will enable future tailored intervention and tuning of the remodelling process.

### Competing Interest Statement

The authors have declared no competing interest.

Reconstructing stochastic cell population trajectories reveals regulators and heterogeneity of endothelial flow-migration coupling driving vascular remodelling

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Understanding Endothelial Flow-Migration in Vascular Remodelling



TRIPLEX, a deep learning framework, integrates multi-resolution features to accurately predict spatial gene expression from Whole Slide Images (WSIs), outperforming current models in Mean Squared Error (MSE), Mean Absolute Error (MAE), and Pearson Correlation Coefficient (PCC).


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Accurate Spatial Gene Expression Prediction with Multi-resolution Features Integration



The author presents a deep learning method utilizing relational context information to enhance the extraction of protein-protein interactions from biomedical literature, outperforming prior models.


extracting-protein-protein-interactions-ppis-from-biomedical-literature-using-attention-based-relational-context-information


Extracting Protein-Protein Interactions (PPIs) from Biomedical Literature using Attention-based Relational Context Information



The author proposes a machine learning approach to predict cell identities during early C. elegans embryogenesis using spatial-temporal features, achieving over 91% accuracy.


Predicting-Cellular-Identities-in-C-elegans-Embryos-Using-Machine-Learning


Predicting Cellular Identities in C. elegans Embryos Using Machine Learning
