PRC1 Stabilizes Cardiac Contraction by Regulating Cardiac Sarcomere Assembly and Cardiac Conduction System Construction.

Cardiac development is a complex process that is strictly controlled by various factors, including PcG protein complexes. Several studies have reported the critical role of PRC2 in cardiogenesis. However, little is known about the regulation mechanism of PRC1 in embryonic heart development. To gain more insight into the mechanistic role of PRC1 in cardiogenesis, we generated a PRC1 loss-of-function zebrafish line by using the CRISPR/Cas9 system targeting rnf2, a gene encoding the core subunit shared by all PRC1 subfamilies. Our results revealed that Rnf2 is not involved in cardiomyocyte differentiation and heart tube formation, but that it is crucial to maintaining regular cardiac contraction. Further analysis suggested that Rnf2 loss-of-function disrupted cardiac sarcomere assembly through the ectopic activation of non-cardiac sarcomere genes in the developing heart. Meanwhile, Rnf2 deficiency disrupts the construction of the atrioventricular canal and the sinoatrial node by modulating the expression of bmp4 and other atrioventricular canal marker genes, leading to an impaired cardiac conduction system. The disorganized cardiac sarcomere and defective cardiac conduction system together contribute to defective cardiac contraction. Our results emphasize the critical role of PRC1 in the cardiac development.

TransVG++: End-to-End Visual Grounding With Language Conditioned Vision Transformer.

In this work, we explore neat yet effective Transformer-based frameworks for visual grounding. The previous methods generally address the core problem of visual grounding, i.e., multi-modal fusion and reasoning, with manually-designed mechanisms. Such heuristic designs are not only complicated but also make models easily overfit specific data distributions. To avoid this, we first propose TransVG, which establishes multi-modal correspondences by Transformers and localizes referred regions by directly regressing box coordinates. We empirically show that complicated fusion modules can be replaced by a simple stack of Transformer encoder layers with higher performance. However, the core fusion Transformer in TransVG is stand-alone against uni-modal encoders, and thus should be trained from scratch on limited visual grounding data, which makes it hard to be optimized and leads to sub-optimal performance. To this end, we further introduce TransVG++ to make two-fold improvements. For one thing, we upgrade our framework to a purely Transformer-based one by leveraging Vision Transformer (ViT) for vision feature encoding. For another, we devise Language Conditioned Vision Transformer that removes external fusion modules and reuses the uni-modal ViT for vision-language fusion at the intermediate layers. We conduct extensive experiments on five prevalent datasets, and report a series of state-of-the-art records.

Associations Among Self-rated Oral Health, Subjective Oral Conditions, Oral Health Behaviours, and Oral Healthrelated Quality of Life (OHRQoL).

PURPOSE: To evaluate the relationship between self-rated oral health, subjective oral conditions, oral health behaviours, and oral health-related quality of life (OHRQoL) in Chinese college students. MATERIALS AND METHODS: An online cross-sectional survey was conducted, inviting college students from eastern China to participate. A total of 1708 participants were included. A structural equation model was constructed to explain and assess the associations among self-rated oral health, subjective oral conditions, oral health behaviours, and OHRQoL. RESULTS: Self-rated oral health had a direct positive effect on subjective oral conditions and OHRQoL. Oral health behaviours had direct negative impacts on subjective oral conditions and OHRQoL as well as on tooth condition perception and oral health interventions. Subjective oral conditions had a direct positive effect on OHRQoL. There was a positive correlation between oral health behaviours and self-rated oral health. In addition, subjective oral conditions partially mediated both the effect of oral health behaviours on OHRQoL and the effect of self-rated oral health on OHRQoL. CONCLUSION: There were influential associations between self-rated oral health, subjective oral conditions, oral health behaviours, and OHRQoL among college students in eastern China. Making the most of their association can be a guide to radically improving the oral health of college students.

Generation and characterization of cardiac valve endothelial-like cells from human pluripotent stem cells.

The cardiac valvular endothelial cells (VECs) are an ideal cell source that could be used for making the valve organoids. However, few studies have been focused on the derivation of this important cell type. Here we describe a two-step chemically defined xeno-free method for generating VEC-like cells from human pluripotent stem cells (hPSCs). HPSCs were specified to KDR+/ISL1+ multipotent cardiac progenitors (CPCs), followed by differentiation into valve endothelial-like cells (VELs) via an intermediate endocardial cushion cell (ECC) type. Mechanistically, administration of TGFb1 and BMP4 may specify VEC fate by activating the NOTCH/WNT signaling pathways and previously unidentified targets such as ATF3 and KLF family of transcription factors. When seeded onto the surface of the de-cellularized porcine aortic valve (DCV) matrix scaffolds, hPSC-derived VELs exhibit superior proliferative and clonogenic potential than the primary VECs and human aortic endothelial cells (HAEC). Our results show that hPSC-derived valvular cells could be efficiently generated from hPSCs, which might be used as seed cells for construction of valve organoids or next generation tissue engineered heart valves.

Mga Modulates Bmpr1a Activity by Antagonizing Bs69 in Zebrafish.

MAX giant associated protein (MGA) is a dual transcriptional factor containing both T-box and bHLHzip DNA binding domains. In vitro studies have shown that MGA functions as a transcriptional repressor or activator to regulate transcription of promotors containing either E-box or T-box binding sites. BS69 (ZMYND11), a multidomain-containing (i.e., PHD, BROMO, PWWP, and MYND) protein, has been shown to selectively recognizes histone variant H3.3 lysine 36 trimethylation (H3.3K36me3), modulates RNA Polymerase II elongation, and functions as RNA splicing regulator. Mutations in MGA or BS69 have been linked to multiple cancers or neural developmental disorders. Here, by TALEN and CRISPR/Cas9-mediated loss of gene function assays, we show that zebrafish Mga and Bs69 are required to maintain proper Bmp signaling during early embryogenesis. We found that Mga protein localized in the cytoplasm modulates Bmpr1a activity by physical association with Zmynd11/Bs69. The Mynd domain of Bs69 specifically binds the kinase domain of Bmpr1a and interferes with its phosphorylation and activation of Smad1/5/8. Mga acts to antagonize Bs69 and facilitate the Bmp signaling pathway by disrupting the Bs69-Bmpr1a association. Functionally, Bmp signaling under control of Mga and Bs69 is required for properly specifying the ventral tailfin cell fate.