Circadian regulation of macromolecular complex turnover and proteome renewal.

Although costly to maintain, protein homeostasis is indispensable for normal cellular function and long-term health. In mammalian cells and tissues, daily variation in global protein synthesis has been observed, but its utility and consequences for proteome integrity are not fully understood. Using several different pulse-labelling strategies, here we gain direct insight into the relationship between protein synthesis and abundance proteome-wide. We show that protein degradation varies in-phase with protein synthesis, facilitating rhythms in turnover rather than abundance. This results in daily consolidation of proteome renewal whilst minimising changes in composition. Coupled rhythms in synthesis and turnover are especially salient to the assembly of macromolecular protein complexes, particularly the ribosome, the most abundant species of complex in the cell. Daily turnover and proteasomal degradation rhythms render cells and mice more sensitive to proteotoxic stress at specific times of day, potentially contributing to daily rhythms in the efficacy of proteasomal inhibitors against cancer. Our findings suggest that circadian rhythms function to minimise the bioenergetic cost of protein homeostasis through temporal consolidation of protein turnover.

An Anatomical Guide to the Terminal Facial Artery: Lumen Diameter and Associated Anatomy Relevant to Dermatologic Procedures.

BACKGROUND: Dermal filler injection in the vicinity of the terminal facial artery (FA) can lead to vascular compromise with devastating consequences, including tissue necrosis, blindness, and stroke. OBJECTIVE: The purpose of this study was to examine lumen diameter and other anatomical features of the terminal FA relevant to dermal filler injection. MATERIALS AND METHODS: Eighteen embalmed adult cadavers were dissected along the distribution of the terminal FA. Gross and microscopic measurements were taken at predetermined points in its course. RESULTS: Mean lumen diameter was largest at the midpoint between the oral commissure and the lateral supra-alar crease (0.81 ± 0.36 mm; point P1) and smallest at the midpoint between the lateral supra-alar crease and the medial canthus (0.43 ± 0.23 mm; point P3). Mean cutaneous depth was deepest at the lateral supra-alar crease (5.06 ± 1.84 mm; point P2) and most superficial at the midpoint between the lateral supra-alar crease and the medial canthus (3.13 ± 2.07 mm; point P3). CONCLUSION: The large-caliber lumen diameter of the terminal FA creates the potential for intra-arterial injection with commonly used filler needles and blunt-tipped cannulas at all points in its course in the nasolabial fold and midface.

Lumen Diameter and Associated Anatomy of the Superior Labial Artery With a Clinical Application to Dermal Filler Injection.

BACKGROUND: Vascular compromise and subsequent tissue necrosis is a rare but disfiguring complication of dermal filler injection that frequently occurs in regions of the lip and nasolabial fold supplied by the superior labial artery (SLA). OBJECTIVE: The purpose of this study was to examine lumen diameter and other anatomical features of the SLA relevant to dermal filler injection in the clinical setting. MATERIALS AND METHODS: Eighteen adult cadavers were dissected. Detailed measurements of the SLA were taken at predetermined points along its course. RESULTS: Lumen diameter of the SLA was largest at the labial commissure (0.85 ± 0.34 mm; Point P1) and smallest at the midline (0.56 ± 0.21 mm; Point P4). The deepest mean cutaneous depth of the SLA was at its branch point from the facial artery (5.49 ± 1.95 mm; SLA branch point), whereas the most superficial mean cutaneous depth was at the midpoint between the labial commissure and peak of Cupid's bow (4.29 ± 1.54 mm; Point P2). CONCLUSION: The variable, superficial course of the SLA and its large caliber place it at significant risk for intra-arterial injection with dermal filler at all points along its course.

p130Cas substrate domain signaling promotes migration, invasion, and survival of estrogen receptor-negative breast cancer cells.

Elevated Src tyrosine kinase activity is commonly observed in breast cancer and likely contributes to neoplasia and malignancy. p130Cas ("Crk-associated substrate") is a major Src substrate found at the sites where integrins mediate cell adhesion to the extracellular matrix. Src phosphorylates multiple tyrosines in the p130Cas "substrate domain" (SD) and this signaling event has been implicated in the promotion of cell motility, primarily from studies on fibroblasts. In breast cancer, studies on p130Cas have focused on its role in conferring antiestrogen resistance to cells that express the estrogen receptor (ER+). However, little is known regarding the role of p130Cas in the more aggressive estrogen receptor negative (ER-) breast cancers for which there is a need for development of effective targeted therapies. We found high levels of p130Cas SD tyrosine phosphorylation to be a common characteristic of ER- breast cancer cell lines, with particularly high levels observed for the BT-549 cell line. Using RNA interference to knock down p130Cas expression in BT-549 cells, combined with rescue by WT p130Cas versus a signaling-deficient control, we provide evidence that p130Cas SD tyrosine phosphorylation is an important signaling event in the migration, invasion, proliferation, and survival of this ER-breast cancer cell line.