MAGI-1 PDZ2 Domain Blockade Averts Adenovirus Infection via Enhanced Proteolysis of the Apical Coxsackievirus and Adenovirus Receptor.

Adenoviruses (AdVs) are etiological agents of gastrointestinal, heart, eye, and respiratory tract infections that can be lethal for immunosuppressed people. Many AdVs use the coxsackievirus and adenovirus receptor (CAR) as a primary receptor. The CAR isoform resulting from alternative splicing that includes the eighth exon, CAREx8, localizes to the apical surface of polarized epithelial cells and is responsible for the initiation of AdV infection. We have shown that the membrane level of CAREx8 is tightly regulated by two MAGI-1 PDZ domains, PDZ2 and PDZ4, resulting in increased or decreased AdV transduction, respectively. We hypothesized that targeting the interactions between the MAGI-1 PDZ2 domain and CAREx8 would decrease the apical CAREx8 expression level and prevent AdV infection. Decoy peptides that target MAGI-1 PDZ2 were synthesized (TAT-E6 and TAT-NET1). PDZ2 binding peptides decreased CAREx8 expression and reduced AdV transduction. CAREx8 degradation was triggered by the activation of the regulated intramembrane proteolysis (RIP) pathway through a disintegrin and metalloproteinase (ADAM17) and γ-secretase. Further analysis revealed that ADAM17 interacts directly with the MAGI-1 PDZ3 domain, and blocking the PDZ2 domain enhanced the accessibility of ADAM17 to the substrate (CAREx8). Finally, we validated the efficacy of TAT-PDZ2 peptides in protecting the epithelia from AdV transduction in vivo using a novel transgenic animal model. Our data suggest that TAT-PDZ2 binding peptides are novel anti-AdV molecules that act by enhanced RIP of CAREx8 and decreased AdV entry. This strategy has additional translational potential for targeting other viral receptors that have PDZ binding domains, such as the angiotensin-converting enzyme 2 receptor. IMPORTANCE Adenovirus is a common threat in immunosuppressed populations and military recruits. There are no currently approved treatments/prophylactic agents that protect from most AdV infections. Here, we developed peptide-based small molecules that can suppress AdV infection of polarized epithelia by targeting the AdV receptor, coxsackievirus and adenovirus receptor (CAREx8). The newly discovered peptides target a specific PDZ domain of the CAREx8-interacting protein MAGI-1 and decrease AdV transduction in multiple polarized epithelial models. Peptide-induced CAREx8 degradation is triggered by extracellular domain (ECD) shedding through ADAM17 followed by γ-secretase-mediated nuclear translocation of the C-terminal domain. The enhanced shedding of the CAREx8 ECD further protected the epithelium from AdV infection. Taken together, these novel molecules protect the epithelium from AdV infection. This approach may be applicable to the development of novel antiviral molecules against other viruses that use a receptor with a PDZ binding domain.

The Effect of Model Fidelity on Learning Outcomes of a Simulation-Based Education Program for Central Venous Catheter Insertion.

INTRODUCTION: Simulation-based education for central venous catheter (CVC) insertion has been repeatedly documented to improve performance, but the impact of simulation model fidelity has not been described. The aim of this study was to examine the impact of the physical fidelity of the simulation model on learning outcomes for a simulation-based education program for CVC insertion. METHODS: Forty consecutive residents rotating through the medical intensive care unit of an academic medical center completed a simulation-based education program for CVC insertion. The curriculum was designed in accordance with the principles of deliberate practice and mastery learning. Each resident underwent baseline skills testing and was then randomized to training on a commercially available CVC model with high physical fidelity (High-Fi group) or a simply constructed model with low physical fidelity (Low-Fi group) in a noninferiority trial. Upon completion of their medical intensive care unit rotation 4 weeks later, residents returned for repeat skills testing on the high-fidelity model using a 26-item checklist. RESULTS: The mean (SD) posttraining score on the 26-item checklist for the Low-Fi group was 23.8 (2.2) (91.5%) and was not inferior to the mean (SD) score for the High-Fi group of 22.5 (2.6) (86.5%) (P < 0.0001). Residents in both groups judged the training program to be highly useful despite perceiving a lesser degree of physical realism in the low-fidelity model compared with the high-fidelity model (P = 0.05). CONCLUSIONS: Simulation-based education using equipment with low physical fidelity can achieve learning outcomes comparable with those with high-fidelity equipment, as long as other aspects of fidelity are maintained and robust educational principles are applied during the design of the curriculum.

Diagnosis and treatment of pulmonary arterial hypertension.

The diagnosis of pulmonary hypertension requires a high index of suspicion and careful attention to assessing the severity and classification of disease. Proper evaluation and understanding of determinants of severity in pulmonary arterial hypertension are necessary to guide appropriate therapy. This article discusses the diagnosis and treatment of this complex and multifactorial disease.

Chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) should be differentiated from other etiologies of pulmonary hypertension since surgical intervention may be potentially curative. The presentation of this illness is nonspecific and may mimic other cardiopulmonary disease states. Without treatment, progressive pulmonary hypertension, right heart failure, and death will ensue. Echocardiography, lung ventilation-perfusion scan, right heart catheterization, and angiography are required for proper diagnosis and preoperative assessment. Definitive treatment requires surgical resection of thromboembolic material. The role of medical therapy remains to be defined.