DBS and Autonomy: Clarifying the Role of Theoretical Neuroethics.

Gilbert, Viaña, and Ineichen call for further empirical work on the effects of deep brain stimulation (DBS) on personality, identity, agency, authenticity, autonomy and self (PIAAAS) (Gilbert et al. 2018a). In particular, they emphasize the need for more sophisticated instruments measuring potential changes in PIAAAS.

Journey in reverse: TTP from bedside to blood bank to bench.

Thrombotic thrombocytopenic purpura (TTP) is the most extensive and dangerous intravascular platelet clumping disorder. For more than a half-century after its initial recognition, mortality was near 100% and the etiology totally obscure. Then, in the late 1970s to early 1980s, empiric, but successful, therapy by a few clinician/blood bank partnerships was followed by sudden laboratory insight into pathophysiology.

Pathological shear stress directly regulates platelet alphaIIbbeta3 signaling.

Integrin mechanotransduction is a ubiquitous biological process. Mechanical forces are transduced transmembranously by an integrin's ligand-bound extracellular domain through its beta-subunit's cytoplasmic domain connected to the cytoskeleton. This often culminates in the activation of tyrosine kinases directing cell responses.

Filamin A binding stabilizes nascent glycoprotein Ibalpha trafficking and thereby enhances its surface expression.

The glycoprotein (Gp) Ib-IX-V complex is essential for platelet-mediated hemostasis and thrombosis. The cytoplasmic domain of its largest polypeptide subunit GpIbalpha possesses a binding region for filamin A, which links GpIb-IX-V to the platelet cytoskeleton. There is evidence that filamin A binding to GpIbalpha directs the surface expression of GpIb-IX.

Role of the Pyk2-MAP kinase-cPLA2 signaling pathway in shear-dependent platelet aggregation.

Mechanisms of shear-induced platelet aggregation are not established. Data that ristocetin-induced von Willebrand factor (VWF) binding to glycoprotein (Gp) Ibalpha activates proline-rich tyrosine kinase 2 (Pyk2) and extracellular-regulated kinase (ERK) has led to speculation that these events are coupled and that a MAP kinase may activate cytosolic phospholipase A2 (cPLA2)-mediated arachidonic acid (AA) release. To test this hypothesis and clarify the role of AA metabolism in shear-induced VWF-dependent platelet aggregation, we examined Pyk2, ERK1/2, and p38 phosphorylation, and arachidonic acid release and metabolism in platelets subjected to pathological shear stress in vitro.

Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome.

Objective: To evaluate the usefulness and feasibility of measuring plasma von Willebrand factor (vWF)-cleaving metalloprotease activity (ADAMTS 13) in the differential diagnosis of thrombotic thrombocytopenic purpura (TTP), the hemolytic uremic syndrome, and other thrombotic microangiopathies.

Data Sources: Articles published in the medical literature.

Data Extraction And Synthesis: In TTP, a multimeric form of vWF that is larger than that ordinarily found in the plasma may cause systemic platelet aggregation under the high-shear conditions of the microcirculation.

Pathological shear stress stimulates the tyrosine phosphorylation of alpha-actinin associated with the glycoprotein Ib-IX complex.

Shear-induced platelet responses are triggered by VWF binding to the platelet GpIb-IX complex, and there is evidence that this ligand-receptor coupling stimulates transmembranous signaling through the cytoplasmic tail of glycoprotein (Gp) Ib alpha. To investigate the mechanism by which signaling is effected, new molecular interactions involving GpIb-IX that develop in response to pathological shearing stress were examined in intact human platelets. Exposure to shear, but not alpha-thrombin, results in the co-immunoprecipitation of the actin cross-linking protein alpha-actinin with the GpIb-IX complex.

Cytoplasmic domains of GpIbalpha and GpIbbeta regulate 14-3-3zeta binding to GpIb/IX/V.

Shear stress causes the platelet glycoprotein (Gp) Ib/IX/V to bind to von Willebrand factor, resulting in platelet adhesion. GpIb/IX/V also functions to stimulate transmembranous signaling, leading to platelet activation and the expression of a ligand-receptive GpIIb-IIIa complex. The highly conserved cytoplasmic domain of GpIbalpha binds directly to a dimeric 14-3-3 adapter protein zeta isoform.

The glycoprotein Ib/IX complex regulates cell proliferation.

The glycoprotein (Gp) Ib/IX complex contains three transmembranous leucine-rich repeat polypeptides (GpIbalpha, GpIbbeta, and GpIX) that form the platelet von Willebrand factor (vWF) receptor. GpIb/IX functions to effect platelet adhesion, activation, and aggregation under conditions of high shear stress. GpIb/IX is expressed late in the ontogeny of megakaryocytes, the precursor cell that releases platelets when it reaches its terminal stage of differentiation.