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Thrombin is a central regulator of leukocyte recruitment and inflammation at sites of vascular injury, a function thought to involve primarily endothelial PAR cleavage. Here we demonstrate the existence of a distinct leukocyte-trafficking mechanism regulated by components of the haemostatic system, including platelet PAR4, GPIbα and fibrin. Utilizing a mouse endothelial injury model we show that thrombin cleavage of platelet PAR4 promotes leukocyte recruitment to sites of vascular injury. This process is negatively regulated by GPIbα, as seen in mice with abrogated thrombin-platelet GPIbα binding ( hGPIb α D277N ). In addition, we demonstrate that fibrin limits leukocyte trafficking by forming a physical barrier to intravascular leukocyte migration. These studies demonstrate a distinct ‘checkpoint’ mechanism of leukocyte trafficking involving balanced thrombin interactions with PAR4, GPIbα and fibrin. Dysregulation of this checkpoint mechanism is likely to contribute to the development of thromboinflammatory disorders. Thrombin is a key proinflammatory protease regulating leukocyte trafficking at sites of vascular injury. Here the authors show that balanced thrombin interactions with platelet proteins PAR4, GPIbα and fibrin plays a major role in regulating this process.

Neuronal intranuclear inclusion disease (NIID) is a clinically heterogeneous neurodegenerative condition characterized by pathological intranuclear eosinophilic inclusions. A CGG repeat expansion in NOTCH2NLC was recently identified to be associated with NIID in patients of Japanese descent. We screened pathologically confirmed European NIID, cases of neurodegenerative disease with intranuclear inclusions and applied in silico‐based screening using whole‐genome sequencing data from 20 536 participants in the 100 000 Genomes Project. We identified a single European case harbouring the pathogenic repeat expansion with a distinct haplotype structure. Thus, we propose new diagnostic criteria as European NIID represents a distinct disease entity from East Asian cases.

Abstract BACKGROUND Middle fossa (MF) encephaloceles are rare lesions resulting from herniation through defects in the tegmen tympani or mastoideum. Underlying etiologies and clinical presentations are variable. Surgical goals include fistula obliteration, resection of nonfunctioning parenchyma, and dehiscence repair. The middle cranial fossa approach (MCFA), transmastoid approach (TMA), and combined (MCFA + TMA) approaches have been described. The minimally invasive TMA provides excellent exposure of the pathology and allows for ample working room to repair the defect. OBJECTIVE To present short-term follow-up results in patients treated via the TM repair at our institution. METHODS A retrospective review of patients with symptomatic encephaloceles treated via the TMA by our multidisciplinary team. Patient demographics, clinical presentations, intraoperative findings, repair technique, and outcomes were highlighted. RESULTS A total of 16 encephaloceles in 13 patients were treated. Defect etiologies included spontaneous (50.0%), secondary to chronic infection (25.0%), or cholesteatoma (18.8%). Defects were most often within the tegmen mastoideum (68.8%). Average length of surgery was 3.3 h (95% CI: 2.86-3.67) and length of stay 3.9 d (95% CI: 3.09-4.79). On short-term follow-up (average 11.5 mo), no patients experienced postoperative cerebrospinal fluid leak or recurrence. The majority of patients (83.3%) experienced confirmed improvement or stabilization of hearing. CONCLUSION MF encephaloceles present with various clinical manifestations and result from multiple underlying etiologies. The TMA is an alternative to craniotomy and our short-term results suggest that this approach may be utilized effectively in appropriately selected cases.

This project describes strategies presented in the fiction of three American novelists which alter our relationship to the epistemological codes of modernity, standards in which we are implicated by a vast network of cultural assumptions and institutional apparatuses. Such confinement within an ethical hegemony—a system permitting only a limited range of acceptable conduct, contemplation, and resistance in both public and private spheres—restricts the bounds not only of what can be practiced but also of what can be safely thought. This system I identify as the epistemology of modernity and, ushered in by the advent of modernization, capitalist relations, and the contemporary continuation of enlightenment reason against which any form of expression must situate itself either in opposition or corroboration. Because divergence is permitted to a certain degree, the possibility of epistemological shifting cannot be achieved by outward participation in such a system and thus must be perceptual: achieved through mentality and self-awareness. The strategies involve a shift in epistemological and thus ethical relations to modernity. Briefly, for Nabokov, it is the ridding of focus on the self; for Pynchon, comprehending the influences of totality; and for Morrison, the depiction of the always-othered non-self rather than one reduced to normative social assumptions and interpretive practices. More specifically, each author offers a particular set of insights on which to build. The project at which most of Nabokov’s (1899–1977) written work is aimed involves the generation, almost separate from the fabric of reality, of a purely aesthetic world. While much of his project is (at worst) doomed to fail or (at best) susceptible to the inevitably invasive material of the real, it remains useful in seeing what potential arises when an imaginative mind consciously attempts to work outside of and resist established systems. Pynchon (b. 1937), on the other hand, is far more rooted in the project of describing the systemic effects of a totalizing modernity. His daunting narratives (often labeled encyclopedic) depict the overwhelming saturation of apparatuses under which individuals find themselves situated and interpolated. What Pynchon’s work portrays is the oppressive and interconnected systems conducting the flow of control in modern life and, most important for this project, the realization of this as a social technology along with the means by which, once understood as such, to subversively navigate it. Finally, Morrison (b. 1931) represents the most directly and aggressively destabilizing personality of this trio. Her novels adopt as a constituted whole an aesthetic form that seeks to confront and expose the hegemonic systems responsible for the perpetuation of ideologies that come to seem natural but which need not be. Rather than constructing an alternative world or showing the means by which one can navigate the current one, Morrison assails and deconstructions the assumptions that constitute modern reality. Together, these three novelists offer distinct possibilities for epistemological change that can be wrought, and my future work—proceeding this dissertation project—will turn to transforming the literary strategies uncovered here into an actionable praxis that reaches beyond the readership of the novel.