Development of compounds for targeted degradation of mammalian cryptochrome proteins.

The mammalian cryptochrome proteins (CRY1 and CRY2) are transcriptional repressors most notable for their role in circadian transcriptional feedback. Not all circadian rhythms depend on CRY proteins, however, and the CRY proteins are promiscuous interactors that also regulate many other processes. In cells with chronic CRY deficiency, protein homeostasis is highly perturbed, with a basal increase in cellular stress and activation of key inflammatory signalling pathways.

Chronic CRYPTOCHROME deficiency enhances cell-intrinsic antiviral defences.

The within-host environment changes over circadian time and influences the replication and severity of viruses. Genetic knockout of the circadian transcription factors CRYPTOCHROME 1 and CRYPTOCHROME 2 (/; CKO) leads to altered protein homeostasis and chronic activation of the integrated stress response (ISR). The adaptive ISR signalling pathways help restore cellular homeostasis by downregulating protein synthesis in response to endoplasmic reticulum overloading or viral infections.

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.

Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons.

Background: Inherited mutations in the LRRK2 protein are common causes of Parkinson's disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S. An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10.

Outcomes of Revisions for Failed Trapeziometacarpal Joint Arthritis Surgery.

Purpose: We compare outcomes of revision surgery for trapeziometacarpal (TM) arthritis with outcomes for both primary and revision surgery for TM arthritis reported in the literature. We hypothesized that patients undergoing revision surgery for TM arthritis would demonstrate pain and functional outcome scores that were worse than those of patients undergoing primary TM surgery.

Methods: A retrospective analysis of all patients undergoing revision TM surgery at a single institution from 1995 to 2015 was performed.