SARS-CoV-2 3CL (main protease) regulates caspase activation of gasdermin-D/E pores leading to secretion and extracellular activity of 3CL.

SARS-CoV-2 3C-like protease (3CL or M) cleaves the SARS-CoV-2 polyprotein and >300 intracellular host proteins to enhance viral replication. By lytic cell death following gasdermin (GSDM) pore formation in cell membranes, antiviral pyroptosis decreases 3CL expression and viral replication. Unexpectedly, 3CL and nucleocapsid proteins undergo unconventional secretion from infected cells via caspase-activated GSDMD/E pores in the absence of cell lysis.

Optimizing Osteotomy Geometries in Posterolateral Mandibulectomies.

Importance: Reconstructive stability after mandibulectomy with osseous autogenous transplant is influenced by masticatory forces and the resulting stress on the titanium plate.

Objective: To determine an optimal geometry of mandibular osteotomy that minimizes undesirable loading of the reconstruction plate.

Design, Setting, And Participants: In this combined in silico and in vitro basic science study, segmented computed tomography images of an adult male human mandible downloaded from the Visible Human Project were analyzed.

Assessing the Use of Patient-Reported Outcome Measures in the Routine Clinical Care of Chronic Rhinosinusitis Patients: A Canadian Perspective.

Importance: Chronic rhinosinusitis (CRS) is a common inflammatory disease of the paranasal sinuses with significant quality of life impairments. There is a need to implement outcome-based metrics to evaluate the outcomes of CRS treatment with endoscopic sinus surgery or biologics.

Objective: We aimed to understand Canadian otolaryngologists' opinions on patient-related outcome measures (PROM) for CRS and identify potential barriers to implementation.

Gelsolin controls the release of phosphatidylserine (PS)-positive microvesicles (MVs) from platelets.

Upon activation by vascular injury or extracellular agonists, platelets undergo rapid change shape, a process regulated by the actin cytoskeleton and accessory proteins. Platelet shape change is accompanied by the secretion of hemostatic factors and immunomodulatory cytokines from their intracellular granules, as well as the release of microvesicles (MVs) containing pro-inflammatory cytokines and procoagulant phosphatidylserine (PS). However, the role of actin dynamics in MV generation remains unclear.

Filamin A regulates platelet shape change and contractile force generation via phosphorylation of the myosin light chain.

Platelets are critical mediators of hemostasis and thrombosis. Platelets circulate as discs in their resting form but change shape rapidly upon activation by vascular damage and/or soluble agonists such as thrombin. Platelet shape change is driven by a dynamic remodeling of the actin cytoskeleton.

Spatiotemporal Nitric Oxide Modulation via Electrochemical Platform to Profile Tumor Cell Response.

Nitric oxide (NO) is a gaseous molecule intricately implicated in oncologic processes, encompassing the modulation of angiogenesis and instigating apoptosis. Investigation of the antitumor effects of NO is currently underway, necessitating a detailed understanding of its cellular-level reactions. Regulating the behavior of radical NO species has been a significant challenge, primarily due to its instability in aqueous environments by rapid O-induced degradation.

Surface topography modulates initial platelet adhesion to titanium substrata.

The clinical success of implanted biomaterials such as dental implants is largely determined by the molecular signaling that occurs at the tissue-implant interface. The modification of surface topography is a widely-employed strategy for optimizing tissue integration with dental implants. However, little is known regarding the direct, cellular-level effects of substratum topography on platelet signaling and adhesion, despite these cells being the first to encounter the implant surface during surgical placement.

Gelsolin regulates receptor-mediated and fluid-phase endocytosis in platelets.

Background: Endocytosis is the process by which platelets incorporate extracellular molecules into their secretory granules. Endocytosis is mediated by the actin cytoskeleton in nucleated cells; however, the endocytic mechanisms in platelets are undefined.

Objectives: To better understand platelet endocytosis, we studied gelsolin (Gsn), an actin-severing protein that promotes actin assembly.

Effects of crosstalk between steroid hormones mediated thyroid hormone in zebrafish exposed to 4-tert-octylphenol: Estrogenic and anti-androgenic effects.

Alkylphenols, such as nonylphenol and 4-tert-octylphenol (OP), are byproducts of the biodegradation of alkylphenol ethoxylates and present substantial ecological and health risks in aquatic environments and higher life forms. In this context, our study aimed to explore the effect of OP on reproductive endocrine function in both female and male zebrafish. Over a period of 21 days, the zebrafish were subjected to varying concentrations of OP (0, 0.

Reconstructive Techniques in Pediatric Congenital Microtia: A Systematic Review and Meta-analysis.

Autografts and allografts are commonly used in microtia reconstruction. We aimed to systematically review and compare these reconstructive materials in pediatric congenital microtia reconstruction. A systematic review of the literature was performed.

Thyroid-gonadal hormonal interplay in zebrafish exposed to sodium perchlorate: Implications for reproductive health.

Perchlorate, a widespread environmental contaminant originating from various industrial applications, agricultural practices, and natural sources, poses potential risks to ecosystems and human health. While previous studies have highlighted its influence on the thyroid endocrine system and its impact on gonadal maturation, reproduction, and sex hormone synthesis, the specific interplay between thyroid and steroid hormones, in this context, remains largely unexplored. Therefore, this study was undertaken to investigate the adverse effects and underlying mechanisms triggered by exposure to sodium perchlorate (SP) on reproductive endocrine activity in zebrafish.

Granzyme B promotes matrix metalloproteinase-1 (MMP-1) release from gingival fibroblasts in a PAR1- and Erk1/2-dependent manner: A novel role in periodontal inflammation.

Objective: To gain insights into how proteases signal to connective tissues cells in the periodontium.

Background: The connective tissue degradation observed in periodontitis is largely due to matrix metalloproteinase (MMP) release by gingival fibroblasts. Granzyme B (GzmB) is a serine protease whose role in periodontitis is undefined.

Self-Aggregating Tau Fragments Recapitulate Pathologic Phenotypes and Neurotoxicity of Alzheimer's Disease in Mice.

In tauopathy conditions, such as Alzheimer's disease (AD), highly soluble and natively unfolded tau polymerizes into an insoluble filament; however, the mechanistic details of this process remain unclear. In the brains of AD patients, only a minor segment of tau forms β-helix-stacked protofilaments, while its flanking regions form disordered fuzzy coats. Here, it is demonstrated that the tau AD nucleation core (tau-AC) sufficiently induced self-aggregation and recruited full-length tau to filaments.

A novel association between platelet filamin A and soluble N-ethylmaleimide sensitive factor attachment proteins regulates granule secretion.

Background And Objective: The molecular mechanisms that underpin platelet granule secretion remain poorly defined. Filamin A (FLNA) is an actin-crosslinking and signaling scaffold protein whose role in granule exocytosis has not been explored despite evidence that gene mutations confer platelet defects in humans.

Methods And Results: Using platelets from platelet-specific conditional -knockout mice, we showed that the loss of FLNA confers a severe defect in alpha (α)- and dense (δ)-granule exocytosis, as measured based on the release of platelet factor 4 (aka CXCL4) and adenosine triphosphate (ATP), respectively.

Decoding the Roles of Amyloid-β (1-42)'s Key Oligomerization Domains toward Designing Epitope-Specific Aggregation Inhibitors.

Fibrillar amyloid aggregates are the pathological hallmarks of multiple neurodegenerative diseases. The amyloid-β (1-42) protein, in particular, is a major component of senile plaques in the brains of patients with Alzheimer's disease and a primary target for disease treatment. Determining the essential domains of amyloid-β (1-42) that facilitate its oligomerization is critical for the development of aggregation inhibitors as potential therapeutic agents.

Filamin A in platelets: Bridging the (signaling) gap between the plasma membrane and the actin cytoskeleton.

Platelets are anucleate cells that are essential for hemostasis and wound healing. Upon activation of the cell surface receptors by their corresponding extracellular ligands, platelets undergo rapid shape change driven by the actin cytoskeleton; this shape change reaction is modulated by a diverse array of actin-binding proteins. One actin-binding protein, filamin A (FLNA), cross-links and stabilizes subcortical actin filaments thus providing stability to the cell membrane.

Gelsolin Modulates Platelet Dense Granule Secretion and Hemostasis via the Actin Cytoskeleton.

Background And Objective:  The mechanisms underlying platelet granule release are not fully understood. The actin cytoskeleton serves as the platelet's structural framework that is remodeled upon platelet activation. Gelsolin is a calcium-dependent protein that severs and caps existing actin filaments although its role in modulating platelet granule exocytosis is unknown.

Platelet signaling at the nexus of innate immunity and rheumatoid arthritis.

Rheumatoid arthritis (RA) is a debilitating autoimmune disorder characterized by chronic inflammation of the synovial tissues and progressive destruction of bone and cartilage. The inflammatory response and subsequent tissue degradation are orchestrated by complex signaling networks between immune cells and their products in the blood, vascular endothelia and the connective tissue cells residing in the joints. Platelets are recognized as immune-competent cells with an important role in chronic inflammatory diseases such as RA.

Apoptosis in platelets is independent of the actin cytoskeleton.

Homeostasis between platelet production and clearance is essential for human health. A critical facet of the balance that facilitates platelet clearance from the circulation is apoptosis (programmed cell death). The precise cellular mechanisms that underpin platelet apoptosis are not defined.

Platelet factor 4 (CXCL4/PF4) upregulates matrix metalloproteinase-2 (MMP-2) in gingival fibroblasts.

Periodontitis is a chronic inflammatory disease characterized by the release of matrix metalloproteinases (MMPs) from resident connective tissue cells in tooth-supporting tissues (periodontium). Platelet activation, and the attendant release of pro-inflammatory chemokines such as platelet factor 4 (CXCL4/PF4), are associated with periodontitis although the associated biochemical pathways remain undefined. Here we report that recombinant PF4 is internalized by cultured human gingival fibroblasts (hGFs), resulting in significant (p < 0.

Filamin A regulates caspase-3 cleavage in platelets in a protein kinase C (PKC)-dependent manner.

Apoptosis is a critical process for the maintenance of cell populations, and involves mitochondrial depolarization, the sequential cleavage of caspase-9 and -3, followed by the externalization of phosphatidylserine (PS) on the plasma membrane. The actin cytoskeleton and its accessory proteins are known regulators of apoptotic signaling in nucleated cells but their roles in platelet apoptosis are undefined. Filamin A (FLNA) is a ubiquitously expressed actin-crosslinking protein that also serves as an intracellular signaling scaffold.