The cellular basis of compensatory muscle growth in the teleost Odontesthes bonariensis

This study evaluates white muscle growth and in vivo cell proliferation during a fasting and refeeding trial, using pejerrey Odontesthes bonariensis as animal model, in order to better understand the cellular basis governing catch-up growth. Experiments consisted in two groups of fish, a control one continuously fed ad libitum, and a group fasted for 2 weeks and then fed for another 2 weeks. We examined how the formation of new muscle fibers and their increase in size were related to muscle precursor cell (MPC) proliferation under both experimental conditions. During fasting, the number of 5-ethynyl-2'-deoxyuridinepositive (EdU+) cells decreased along with myogenic regulatory factors (MRF) mRNA levels related to myoblast proliferation and differentiation, and the muscle stem cell-markerPax7 mRNA level increased. Analysis of myomere cross-sectional area, distribution of muscle fiber sizes and number of fibers per myomere showed that muscle hypertrophy but not hyperplasia was inhibited during fasting. Both higher igf2 mRNA level and the persistence of cell proliferation could be supporting new myofibre formation. On the other hand, an exacerbated MPC proliferation occurred during catch-up growth, and this increase in cell number could be contributing to the growth of both pre-existing and newly form small fibers. The finding that some MPCs proliferate during fasting and that muscle growth mechanisms, hyperplasia and hypertrophy, are differentially regulated could help to explain why re-fed fish could growth at higher rates, and why they return to the lost growth trajectory.

Author Correction: Cellular basis of omentum activation and expansion revealed by single-cell RNA sequencing using a parabiosis model

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Tbx1, a gene encoded in 22q11.2 copy number variant, is a link between alterations in fimbria myelination and cognitive speed in mice

Copy number variants (CNVs) have provided a reliable entry point to identify the structural correlates of atypical cognitive development. Hemizygous deletion of human chromosome 22q11.2 is associated with impaired cognitive function; however, the mechanisms by which the CNVs contribute to cognitive deficits via diverse structural alterations in the brain remain unclear. This study aimed to determine the cellular basis of the link between alterations in brain structure and cognitive functions in mice with a heterozygous deletion of Tbx1, one of the 22q11.2-encoded genes. Ex vivo whole-brain diffusion-tensor imaging (DTI)–magnetic resonance imaging (MRI) in Tbx1 heterozygous mice indicated that the fimbria was the only region with significant myelin alteration. Electron microscopic and histological analyses showed that Tbx1 heterozygous mice exhibited an apparent absence of large myelinated axons and thicker myelin in medium axons in the fimbria, resulting in an overall decrease in myelin. The fimbria of Tbx1 heterozygous mice showed reduced mRNA levels of Ng2, a gene required to produce oligodendrocyte precursor cells. Moreover, postnatal progenitor cells derived from the subventricular zone, a source of oligodendrocytes in the fimbria, produced fewer oligodendrocytes in vitro. Behavioral analyses of these mice showed selectively slower acquisition of spatial memory and cognitive flexibility with no effects on their accuracy or sensory or motor capacities. Our findings provide a genetic and cellular basis for the compromised cognitive speed in patients with 22q11.2 hemizygous deletion.

Fellow As Clinical Teacher, Benign Hematology Curriculum Improves Learning and Reaction to Academic Medicine

Introduction: The expansion of medical schools, faculty attrition, and trainees' disinterest in academia, all highlight the need to encourage the next generation of academic physicians. The published literature indicates that early academic career awareness and involvement in scholarship activities can positively influence trainees' interest in academia. Teaching experience has been shown to positively influence interest in an academic career, trainees who can engage in educational activities, and who transform their work into educational scholarship are more likely than their counterparts to pursue the medical educator academic track. We hypothesized that heightening diverse trainees' awareness of opportunities to engage in various educational roles through the fellow as clinical teacher (FACT) may help them consider future academic positions as well as improve their medical knowledge. Method: We implemented a hematology FACT program that utilized an hour didactics session that is held every month focused on benign hematology curriculum. We aimed to help fellows to 1) develop as teachers, 2) improve knowledge in benign hematology, and 3) increase their career interest in educators' academic track. After implementing the program, post-intervention surveys focusing on evaluating their reaction to the program, whether participation in the program increased their interest in academic medicine, and whether attending the program benefitted their knowledge and advanced their learning. Focusing on level 1 and 2 on the Kirkpatrick four-level educational model. Results: The FACT program included nine participants, all participants served as trainees and educators in the program. Participants were asked to indicate the most challenging topics in the benign hematology field to guide building the content of the curriculum. The cellular basis of hematopoiesis was noted as the most challenging for six participants. Majority of participants reported having struggles evaluating hemoglobinopathy disorders, hematologic women's health issues, bleeding disorders, and transfusion medicine challenges. Those subjects concluded majority of the curriculum content. Post-intervention surveys were sent out to all participants after eighteen months of implementing the program, asking their feedback about the program, their reaction about the program and knowledge benefit, nine surveys were collected. The implemented program helped improving participants' level of knowledge for hemophilia and other bleeding disorders such as Von Willebrand Disease, in most participants (7 of 9). Also, five participants reported a benefit in regards to cellular basis of hematopoiesis and hemoglobinopathy disorders. The majority of participants (7 of 9) found that the course material was very useful and they rated the lectures to be very good to excellent. And all participants agreed on the discussed topics to be appropriate for their level of training, moreover, it improved the overall understanding and level of interest in benign hematology. All participants noted the impact of the program on augmenting their teaching skills and interest in exploring the academic medicine track. The drawback of the program reported by participants (3 of 9) was experiencing a communication barrier and feeling restricted communicating their questions, opinions, and concerns to their co-fellow educators. Discussion: Implementing the fellow as clinical teacher program has been a strategy that is used to increase trainees' interest in academic careers and educators' tracks, although its barriers and impact on fellow's education is not clear. In this review, we aimed at evaluating the program from trainees' perspectives. The program was beneficial to all trainees, all served as educators at a certain time, it was appropriate for their level of training, it improved the overall knowledge for benign hematology topics, and it positively impacted their teaching skills and interest in academic medicine. With a longer follow-up time, it would be beneficial to evaluate the program's impact on the fellows' commitment towards academic medicine. Conclusion: Fellow as clinical teacher program could be a tool to increase hematology fellows' interest in academic educators' track, increase level of knowledge and confidence managing different challenging topics, without affecting the quality of medical education. Disclosures Ellis: Rafael Pharmaceuticals: Consultancy.

Mosaic and non-mosaic pcdh19 mutation leads to neuronal hyperexcitability in zebrafish

Epilepsy is one of the most common neurological disorders. The X-linked gene PCDH19 is associated with sporadic and familial epilepsy in humans, typically with early-onset clustering seizures and intellectual disability in females but not in so-called carrier males, suggesting that mosaic PCDH19 expression is required to produce epilepsy. To characterize the role of loss of PCDH19 function in epilepsy, we generated zebrafish with truncating pcdh19 variants. We observed hyperexcitability phenotypes in both mosaic and non-mosaic pcdh19+/- and -/- mutant larvae, indicating that Pcdh19 cellular mosaicism is not required for network hyperexcitability in zebrafish. Further, zebrafish with non-mosaic pcdh19 mutation display reduced numbers of inhibitory interneurons and transcriptional down-regulation of key inhibitory synapse components, suggesting a potential cellular basis for the observed hyperexcitability. Our findings in both mosaic and non-mosaic pcdh19 mutant zebrafish challenge the prevailing theory that mosaicism governs all PCDH19-related phenotypes and point to interneuron-mediated mechanisms underlying these phenotypes.