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Introduction To ensure efficient heart contraction and proper blood circulation necessary for life, the cardiac conduction system (CCS) coordinates a fixed sequence of events. Electrical impulses are initiated in the [...], Comprehensive cis-regulatory landscapes are essential for accurate enhancer prediction and disease variant mapping. Although cis-regulatory element (CRE) resources exist for most tissues and organs, many rare--yet functionally important--cell types remain overlooked. Despite representing only a small fraction of the heart's cellular biomass, the cardiac conduction system (CCS) unfailingly coordinates every life-sustaining heartbeat. To globally profile the mouse CCS cis-regulatory landscape, we genetically tagged CCS component-specific nuclei for comprehensive assay for transposase-accessible chromatin-sequencing (ATAC-Seq) analysis. Thus, we established a global CCS-enriched CRE database, referred to as CCS- ATAC, as a key resource for studying CCS-wide and component-specific regulatory functions. Using transcription factor (TF) motifs to construct CCS component-specific gene regulatory networks (GRNs), we identified and independently confirmed several specific TF sub-networks. Highlighting the functional importance of CCS-ATAC, we also validated numerous CCS- enriched enhancer elements and suggested gene targets based on CCS single-cell RNA-Seq data. Furthermore, we leveraged CCS-ATAC to improve annotation of existing human variants related to cardiac rhythm and nominated a potential enhancer- target pair that was dysregulated by a specific SNP. Collectively, our results established a CCS-regulatory compendium, identified novel CCS enhancer elements, and illuminated potential functional associations between human genomic variants and CCS component-specific CREs.

A reason for online communities to confer recognition (e.g., badges) on members is to acknowledge and encourage contributions. Yet, it is unclear whether such recognition or lack of it changes members’ contribution behaviors over time. While anticipated recognition has been found to motivate members’ contributions, past findings are limited regarding members’ post-recognition behaviors. Especially, the impact of multiple recognitions over time remains unexplored. Also, the contribution behavior of deserving, yet unrecognized members lacks investigation, which can help uncover the negative side effects of recognition systems. Motivated by these gaps in understanding, we build on reinforcement theory to propose a positive role of first-time recognition as a social reinforcer of contribution behavior, while repeated recognition is hypothesized to suffer from reinforcer satiation. However, for deserving, yet unrecognized members we propose a decrease in contributions due to recognition inequity. Using quasi-experiments on 81,393 reviewers of one of the largest online business review sites, Yelp.com, we find empirical support for our hypotheses, with contribution effort and quantity as outcomes. Additional analysis with contribution quality as outcome shows differing relationships for repeatedly recognized versus deserving, unrecognized members. Other than its research contributions, this study provides practical insights for designing effective recognition systems for online communities. [ABSTRACT FROM AUTHOR]

CRISPR/Cas9-mediated genome editing holds clinical potential for treating genetic diseases, such as Duchenne muscular dystrophy (DMD), which is caused by mutations in the dystrophin gene.To correctDMDby skippingmutant dystrophin exons in postnatalmuscle tissue in vivo,we used adeno-associated virus-9 (AAV9) to deliver gene-editing components to postnatal mdx mice, a model of DMD. Different modes of AAV9 delivery were systematically tested, including intraperitoneal at postnatal day 1 (P1), intramuscular at P12, and retro-orbital at P18. Each of thesemethods restored dystrophin protein expression in cardiac and skeletal muscle to varying degrees, and expression increased from 3 to 12 weeks after injection. Postnatal gene editing also enhanced skeletal muscle function, as measured by grip strength tests 4 weeks after injection.This method provides a potentialmeans of correctingmutations responsible for DMD and other monogenic disorders after birth. [ABSTRACT FROM AUTHOR]