Meningovascular Syphilis: A Case of a Young Man Presenting With Acute Stroke and Pulmonary Emboli.

Syphilis is caused by the spirochete Treponema pallidum and classically progresses through a series of stages with increasing symptomatology if unrecognized and untreated. Importantly, central nervous system invasion can occur at any stage, which can lead to variable presentations of neurosyphilis. One such manifestation is meningovascular syphilis, which causes thrombosis of the cerebral vasculature, leading to stroke-like symptoms such as hemiplegia and aphasia. Young, healthy patients may present with these symptoms without any risk factors typically associated with the pathophysiology of cerebrovascular accidents. Further, patients living with HIV who present with stroke-like symptoms should have an even higher suspicion for neurosyphilis as a potential diagnosis. We present a case report of a 31-year-old male with sudden left-sided weakness and numbness who tested positive for both Treponema pallidum and human immunodeficiency virus (HIV).

Extracellular matrix regulates force transduction at VE-cadherin junctions.

Increased tension on VE-cadherin (VE-cad) complexes activates adaptive cell stiffening and local cytoskeletal reinforcement--two key signatures of intercellular mechanotransduction. Here we demonstrate that tugging on VE-cad receptors initiates a cascade that results in downstream integrin activation. The formation of new integrin adhesions potentiates vinculin and actin recruitment to mechanically reinforce stressed cadherin adhesions. This cascade differs from documented antagonistic effects of integrins on intercellular junctions. We identify focal adhesion kinase, Abl kinase, and RhoA GTPase as key components of the positive feedback loop. Results further show that a consequence of integrin involvement is the sensitization of intercellular force transduction to the extracellular matrix (ECM) not by regulating junctional tension but by altering signal cascades that reinforce cell-cell adhesions. On type 1 collagen or fibronectin substrates, integrin subtypes α2ß1 and α5ß1, respectively, differentially control actin remodeling at VE-cad adhesions. Specifically, ECM-dependent differences in VE-cad force transduction mirror differences in the rigidity sensing mechanisms of α2ß1 and α5ß1 integrins. The findings verify the role of integrins in VE-cad force transduction and uncover a previously unappreciated mechanism by which the ECM impacts the mechanical reinforcement of interendothelial junctions.

Mechanical disruption of E-cadherin complexes with epidermal growth factor receptor actuates growth factor-dependent signaling.

Increased intercellular tension is associated with enhanced cell proliferation and tissue growth. Here, we present evidence for a force-transduction mechanism that links mechanical perturbations of epithelial (E)-cadherin (CDH1) receptors to the force-dependent activation of epidermal growth factor receptor (EGFR, ERBB1)-a key regulator of cell proliferation. Here, coimmunoprecipitation studies first show that E-cadherin and EGFR form complexes at the plasma membrane that are disrupted by either epidermal growth factor (EGF) or increased tension on homophilic E-cadherin bonds. Although force on E-cadherin bonds disrupts the complex in the absence of EGF, soluble EGF is required to mechanically activate EGFR at cadherin adhesions. Fully quantified spectral imaging fluorescence resonance energy transfer further revealed that E-cadherin and EGFR directly associate to form a heterotrimeric complex of two cadherins and one EGFR protein. Together, these results support a model in which the tugging forces on homophilic E-cadherin bonds trigger force-activated signaling by releasing EGFR monomers to dimerize, bind EGF ligand, and signal. These findings reveal the initial steps in E-cadherin-mediated force transduction that directly link intercellular force fluctuations to the activation of growth regulatory signaling cascades.