Large-Vessel Vasculitis in Ophthalmology: Giant Cell Arteritis and Takayasu Arteritis.

ABSTRACT: Giant cell arteritis and Takayasu arteritis are large-vessel vasculitides that share multiple common features but also have significant differences in epidemiology, demographics, clinical presentation, evaluation, and treatment. Giant cell arteritis is more common in elderly patients of Caucasian descent versus Takayasu arteritis, which is more prevalent in younger patients of Asian descent. Although traditionally age has been the main criterion for differentiating the 2 etiologies, modifications in the diagnostic criteria have recognized the overlap between the 2 conditions. In this monograph, we review the diagnostic criteria for both conditions and describe the epidemiology, pathogenesis, histology, evaluation, and management for large-vessel vasculitis in ophthalmology. Additionally, we describe ocular imaging techniques that may be utilized by ophthalmologists to identify manifestations of large-vessel vasculiti- des in patients. Lastly, we compare and contrast the key clinical, laboratory, and pathologic features that might help ophthalmologists to differentiate the 2 entities.

Notch-induced endoplasmic reticulum-associated degradation governs mouse thymocyte ß-selection.

Signals from the pre-T cell receptor and Notch coordinately instruct ß-selection of CD4-CD8-double negative (DN) thymocytes to generate αß T cells in the thymus. However, how these signals ensure a high-fidelity proteome and safeguard the clonal diversification of the pre-selection TCR repertoire given the considerable translational activity imposed by ß-selection is largely unknown. Here, we identify the endoplasmic reticulum (ER)-associated degradation (ERAD) machinery as a critical proteostasis checkpoint during ß-selection. Expression of the SEL1L-HRD1 complex, the most conserved branch of ERAD, is directly regulated by the transcriptional activity of the Notch intracellular domain. Deletion of Sel1l impaired DN3 to DN4 thymocyte transition and severely impaired mouse αß T cell development. Mechanistically, Sel1l deficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. Accordingly, genetically inactivating PERK rescued T cell development from Sel1l-deficient thymocytes. In contrast, IRE1α/XBP1 pathway was induced as a compensatory adaptation to alleviate Sel1l-deficiency-induced ER stress. Dual loss of Sel1l and Xbp1 markedly exacerbated the thymic defect. Our study reveals a critical developmental signal controlled proteostasis mechanism that enforces T cell development to ensure a healthy adaptive immunity.

In vitro studies of deferasirox derivatives as potential organelle-targeting traceable anti-cancer therapeutics.

We report here strategic functionalization of the FDA approved chelator deferasirox (1) in an effort to produce organelle-targeting iron chelators with enhanced activity against A549 lung cancer cells. Derivative 8 was found to have improved antiproliferative activity relative to 1. Fluorescent cell imaging revealed that compound 8 preferentially localises within the lysosome.

An Expanded Porphycene with High NIR Absorptivity That Stabilizes Two Different Kinds of Metal Complexes.

A new expanded porphycene with 26 π-electrons has been prepared by the McMurry coupling of 1,4-bis(3,4-diethyl-2-pyrryl)benzene dialdehyde. Expansion of the porphycene framework provides a ligand capable of stabilizing a bis(rhodium) and a monoruthenium complex. These new porphycene derivatives absorb strongly in the NIR spectral region, with appreciable absorptivity up to 1300 nm. On the basis of their ground- and excited-state spectroscopic features and structural parameters, both the free-base system and the bis(rhodium) complex are considered to be Hückel-type aromatic systems. This conclusion is supported by DFT calculations.