Search for: All records

Hypertrophic cardiomyopathy (HCM) is the most common heritable heart disease. Although the genetic cause of HCM has been linked to mutations in genes encoding sarcomeric proteins, the ability to predict clinical outcomes based on specific mutations in HCM patients is limited. Moreover, how mutations in different sarcomeric proteins can result in highly similar clinical phenotypes remains unknown. Posttranslational modifications (PTMs) and alternative splicing regulate the function of sarcomeric proteins; hence, it is critical to study HCM at the level of proteoforms to gain insights into the mechanisms underlying HCM. Herein, we employed high-resolution mass spectrometry–based top-down proteomics to comprehensively characterize sarcomeric proteoforms in septal myectomy tissues from HCM patients exhibiting severe outflow track obstruction ( n = 16) compared to nonfailing donor hearts ( n = 16). We observed a complex landscape of sarcomeric proteoforms arising from combinatorial PTMs, alternative splicing, and genetic variation in HCM. A coordinated decrease of phosphorylation in important myofilament and Z-disk proteins with a linear correlation suggests PTM cross-talk in the sarcomere and dysregulation of protein kinase A pathways in HCM. Strikingly, we discovered that the sarcomeric proteoform alterations in the myocardium of HCM patients undergoing septal myectomy were remarkably consistent, regardless of the underlying HCM-causing mutations. This study suggests that the manifestation of severe HCM coalesces at the proteoform level despite distinct genotype, which underscores the importance of molecular characterization of HCM phenotype and presents an opportunity to identify broad-spectrum treatments to mitigate the most severe manifestations of this genetically heterogenous disease. 

In May 2020, the New York City (NYC) Mayor’s Office of Climate Resiliency (MOCR) began convening bi-weekly discussions, called the Rapid Research and Assessment (RRA) Series, between City staff and external experts in science, policy, design, engineering, communications, and planning. The goal was to rapidly develop authoritative, actionable information to help integrate resiliency into the City’s COVID response efforts. The situation in NYC is not uncommon. Extreme events often require government officials, practitioners, and citizens to call upon multiple forms of scientific and technical assistance from rapid data collection to expert elicitation, each spanning more or less involved engagement. We compare the RRA to similar rapid assessment efforts and reflect on the nature of the RRA and similar efforts to exchange and co-produce knowledge. The RRA took up topics on social cohesion, risk communication, resilient and healthy buildings, and engagement, in many cases strengthening confidence in what was already known but also refining the existing knowledge in ways that can be helpful as the pandemic unfolds. Researchers also learned from each other ways to be supportive of the City of New York and MOCR in the future. The RRA network will continue to deepen, continue to co-produce actionable climate knowledge, and continue to value organizational sensemaking as a usable climate service, particularly in highly uncertain times. Given the complex, rare, and, in many cases, unfamiliar context of COVID-19, we argue that organizational sensemaking is a usable climate service.