The vascular permeability of the endothelium is finely controlled by vascular endothelial (VE)-cadherinmediated endothelial cell-cell junctions. In the majority of normal adult tissues, endothelial cells in blood vessels maintain vascular permeability at a relatively low level, while in response to inflammation, they limit vascular barrier function to induce plasma leakage and extravasation of immune cells as a defense mechanism. Thus, the dynamic but also simultaneously tight regulation of vascular permeability by endothelial cells is responsible for maintaining homeostasis and, as such, impairments of its underlying mechanisms result in hyperpermeability, leading to the development and progression of various diseases including coronavirus disease 2019 (COVID-19), a newly emerging infectious disease. Recently, increasing numbers of studies have been unveiling the important role of Rap1, a small guanosine 5′-triphosphatase (GTPase) belonging to the Ras superfamily, in the regulation of vascular permeability. Rap1 enhances VE-cadherin-mediated endothelial cell-cell junctions to potentiate vascular barrier functions via dynamic reorganization of the actin cytoskeleton. Importantly, Rap1 signaling activation reportedly improves vascular barrier function in animal models of various diseases associated with vascular hyperpermeability, suggesting that Rap1 might be an ideal target for drugs intended to prevent vascular barrier dysfunction. Here, we describe recent progress in understanding the mechanisms by which Rap1 potentiates VE-cadherin-mediated endothelial cell-cell adhesions and vascular barrier function. We also discuss how alterations in Rap1 signaling are related to vascular barrier dysfunction in diseases such as acute pulmonary injury and malignancies. In addition, we examine the possibility of Rap1 signaling as a target of drugs for treating diseases associated with vascular hyperpermeability.
: Accumulating evidence supports the "glucagonocentric hypothesis", in which antecedent α-cell failure and inhibition of glucagon secretion are responsible for diabetes progression. Protein kinase C (PKC) is involved in glucagon secretion from α-cells, although which PKC isozyme is involved and the mechanism underlying this PKC-regulated glucagon secretion remains unknown. Here, the involvement of PKCδ in the onset and progression of diabetes was elucidated. Immunofluorescence studies revealed that PKCδ was expressed and activated in α-cells of STZ-induced diabetic model mice. Phorbol 12-myristate 13-acetate (PMA) stimulation significantly augmented glucagon secretion from isolated islets. Pre-treatment with quercetin and rottlerin, PKCδ signaling inhibitors, significantly suppressed the PMA-induced elevation of glucagon secretion. While Go6976, a Ca 2+ -dependent PKC selective inhibitor did not suppress glucagon secretion. Quercetin suppressed PMA-induced phosphorylation of Tyr 311 of PKCδ in isolated islets. However, quercetin itself had no effect on either glucagon secretion or glucagon mRNA expression. Our data suggest that PKCδ signaling inhibitors suppressed glucagon secretion. Elucidation of detailed signaling pathways causing PKCδ activation in the onset and progression of diabetes followed by the augmentation of glucagon secretion could lead to the identification of novel therapeutic target molecules and the development of novel therapeutic drugs for diabetes.
Schwannoma is a benign neurogenic tumor arising from the sheath of peripheral nerves. It occurs very rarely in the mesentery, where it is difficult to diagnose. Herein we describe a case in which contrast-enhanced CT and gadolinium-DTPA-enhanced MR showed a locally enhanced well-defined tumor with a cystic component just anterior to the duodenum. These findings corresponded well to the resected specimen.
Summary Lateral plate mesoderm (LPM) cells differentiate into various cell types including endothelial and hematopoietic cells. In zebrafish embryos, LPM cells migrate toward the midline along the ventral surfaces of somites during which their cell fate specification depends upon efficient integrin-mediated cell adhesion and migration. Herein, we present a protocol for analysis of integrin-mediated cell adhesion of LPM cells isolated from zebrafish embryos. This allows the study of the molecular mechanisms underlying integrin activation required for LPM cell fate specification. For complete details on the use and execution of this protocol, please refer to Rho et al. (2019) .
Direct MR arthrography enabled accurate diagnosis of PSMs and could replace diagnostic arthroscopy.
Spinal lesions in upper and sublaxilar cervical vertebrae were studied radiologically in 263 patients (25 men and 238 women) with rheumatoid arthritis (RA). Their average age was 58.9 years, and their disease duration was ranged from 6 months to 24 years (mean 13 years). Functional lateral views of the cervical spine were made. Atlantaxial subluxation (AAS) and vertical subluxation (VS) were evaluated as upper cervical lesions. Subaxilar subluxation (SAS) and endplate erosion were evaluated as subaxilar cervical lesions. One hundred and seventy-eight (67.7%) of the patients had a cervical lesion. Upper and subaxilar cervical abnormalities were recognized in 136 (51.7%) and 113 (43.0%) patients, respectively. There was no linkage between upper and subaxilar cervical lesions. While the prevalence of these lesions increased with time, the frequency was found to be over 50% within only 5 years from onset in patients with mutilating deformity. This prevalence tended to be associated with disease activity.
Surgery is one of the most prevalent methods of control- ling and eradicating tumor growth in the human body, with a projection of 45 million surgical procedures per year by 2030 [1]. In brain tumor resection surgeries, pre- operative images used for the detection and localization of the cancer regions become less reliable throughout surgery when used intraoperatively due to the brain moving during the procedure, referred to as brain shift. To solve the brain shift problem, intraoperative MRI (iMRI) has been used, but it is costly, time intensive, and only available at the most advanced care facilities [2]. Intraoperative fluorescence-guided methods, both exoge- nous (introducing foreign fluorophore molecules into the body) and endogenous (utilizing innate fluorophores within the body), have been investigated as an alternative to iMRI to circumvent the brain shift problem. This paper introduces the proposed design, shown in Fig. 1(a), of an endoscopic tool for intraoperative brain tumor detection incorporating a laser-based endogenous fluorescence method previously explored by [3], called TumorID, depicted in Fig. 1(b). The device has also been deployed on ex-vivo pituitary adenoma tissue by [4] for intraoperative pituitary adenoma identification and subtype classification. This study explores whether a non-perpendicular angle of incidence (AoI) will sig- nificantly affect the emitted spectral data. With a better understanding of the relationship between AoI and col- lected spectra, the results can help shed light on the potential steering modality ( optical [5] or fiber [6]) and end-effector movement profile for the proposed optics- based endoscopic tool.
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