The coordinate modulation of cadherin and integrin functions plays an essential role in fundamental physiological and pathological processes, including morphogenesis and cancer. However, the molecular mechanisms underlying the functional crosstalk between cadherins and integrins are still elusive. Here, we demonstrate that the small GTPase Rap1, a crucial regulator of the inside-out activation of integrins, is a target for E-cadherin-mediated outside-in signaling. In particular, we show that a strong activation of Rap1 occurs upon adherens junction disassembly that is triggered by E-cadherin internalization and trafficking along the endocytic pathway. By contrast, Rap1 activity is not influenced by integrin outside-in signaling. Furthermore, we demonstrate that the E-cadherin endocytosis-dependent activation of Rap1 is associated with and controlled by an increased Src kinase activity, and is paralleled by the colocalization of Rap1 and E-cadherin at the perinuclear Rab11-positive recycling endosome compartment, and the association of Rap1 with a subset of E-cadherin-catenin complexes that does not contain p120ctn. Conversely, Rap1 activity is suppressed by the formation of E-cadherin-dependent cell-cell junctions as well as by agents that inhibit either Src activity or E-cadherin internalization and intracellular trafficking. Finally, we demonstrate that the E-cadherin endocytosis-dependent activation of Rap1 is associated with and is required for the formation of integrin-based focal adhesions. Our findings provide the first evidence of an E-cadherin-modulated endosomal signaling pathway involving Rap1, and suggest that cadherins may have a novel modulatory role in integrin adhesive functions by fine-tuning Rap1 activation.

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Objective Accurate diagnostic testing to identify SARS–CoV-2 infection is critical. Although highly specific, SARS–CoV-2 reverse transcription polymerase chain reaction (RT-PCR), has shown, in clinical practice, to be affected by a non-insignificant proportion of false negative results. The study sought to explore whether the integration of lung ultrasound (LUS) with clinical evaluation is associated with increased sensitivity for the diagnosis of COVID-19 pneumonia, and therefore may facilitate the identification of false negative SARS-CoV-2 RT-PCR results. Methods This prospective cohort study enrolled consecutive adult patients with symptoms potentially related to SARS-CoV-2 infection admitted to the emergency department (ED) of an Italian academic hospital. Immediately after the initial assessment, a LUS evaluation was performed and the likelihood SARS-CoV-2 infection, based on both clinical and LUS findings (“integrated” assessment), was recorded. RT-PCR SARS-CoV-2 detection was subsequently performed. Results We enrolled 228 patients; 107 patients (46.9%) had SARS-CoV-2 infection. Sensitivity and negative predictive value of the clinical-LUS integrated assessment were higher than first RT-PCR [94.4% (95% CI 88.2-97.9), vs. 80.4% (95% CI 71.6-87.4); 95% (95% CI 89.5-98.2), vs. 85.2% (95% CI 78.3-90.6)]. Among the 142 patients who initially had negative RT-PCR, 21 resulted positive at a subsequent molecular test performed within 72 hours. All these false negative cases were correctly identified by the integrated assessment. Conclusion This study suggests that, in patients presenting to the ED with symptoms commonly associated with SARS-CoV-2 infection, the integration of LUS with clinical evaluation has high sensitivity and specificity for COVID-19 pneumonia and it may help to identify false negative results occurring with RT-PCR.

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Background: The aim of this study is to investigate the association between social relationships and Health Related Quality of Life (HRQL) among the elderly in Italy.