The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) poses a persistent threat to global public health. Although primarily a respiratory illness, extrapulmonary manifestations of COVID-19 include gastrointestinal, cardiovascular, renal and neurological diseases. Recent studies suggest that dysfunction of the endothelium during COVID-19 may exacerbate these deleterious events by inciting inflammatory and microvascular thrombotic processes. Although controversial, there is evidence that SARS-CoV-2 may infect endothelial cells by binding to the angiotensin-converting enzyme 2 (ACE2) cellular receptor using the viral Spike protein. In this review, we explore current insights into the relationship between SARS-CoV-2 infection, endothelial dysfunction due to ACE2 downregulation, and deleterious pulmonary and extra-pulmonary immunothrombotic complications in severe COVID-19. We also discuss preclinical and clinical development of therapeutic agents targeting SARS-CoV-2-mediated endothelial dysfunction. Finally, we present evidence of SARS-CoV-2 replication in primary human lung and cardiac microvascular endothelial cells. Accordingly, in striving to understand the parameters that lead to severe disease in COVID-19 patients, it is important to consider how direct infection of endothelial cells by SARS-CoV-2 may contribute to this process.

It has been suggested that gesture engrams, conceptual knowledge and/or the ability to infer function from structure can support object use. The present paper proposes an alternative view which is based upon the idea that object use requires solely the ability to reason about technical means provided by objects. Technical means are abstract principles which are not linked with any object representation (e.g., cutting involves the opposition between dense and permeable material). The technical reasoning model predicts that the inability to perform technical reasoning should impair performance in any situation requiring the use of objects (in a conventional way or not). Twenty left brain-damaged (LBD) patients, 11 right brain-damaged (RBD) patients and 41 healthy controls were examined on experimental tests assessing the conventional use of objects (e.g., screwing a screw with a screwdriver), conceptual knowledge about object function, pantomime of object use and recognition of object utilization gestures. We also designed the Unusual Use of Objects Test, which demands unusual applications of objects to achieve a purpose for which the usually applied object is not provided (e.g., screwing a screw with a knife). The key findings are that only LBD patients have more difficulties on the Unusual Use of Objects Test than controls or RBD patients, and that the severity of their impairment is correlated with that on conventional use of objects. Correlations with tests assessing conceptual knowledge as well as with tests of pantomime of object use and recognition of object utilization gestures were weaker. These results support the technical reasoning model and question the role of conceptual knowledge and gesture engrams in object use. Since the technical reasoning model also predicts two distinct technical disorders, the discussion focuses on the existence of these disorders in regard to individual performance profiles obtained in the Unusual Use of Objects Test.

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The activation of T cells requires the guanine nucleotide exchange factor VAV1. Using mice in which a tag for affinity purification was attached to endogenous VAV1 molecules, we analyzed by quantitative mass spectrometry the signaling complex that assembles around activated VAV1. Fifty VAV1-binding partners were identified, most of which had not been previously reported to participate in VAV1 signaling. Among these was CD226, a costimulatory molecule of immune cells. Engagement of CD226 induced the tyrosine phosphorylation of VAV1 and synergized with T cell receptor (TCR) signals to specifically enhance the production of interleukin-17 (IL-17) by primary human CD4 T cells. Moreover, co-engagement of the TCR and a risk variant of CD226 that is associated with autoimmunity (rs763361) further enhanced VAV1 activation and IL-17 production. Thus, our study reveals that a VAV1-based, synergistic cross-talk exists between the TCR and CD226 during both physiological and pathological T cell responses and provides a rational basis for targeting CD226 for the management of autoimmune diseases.