ABSTRACT
BACKGROUND: Untreated surgical conditions account for one-third of the total global burden of disease, and a lack of trained providers is a significant contributor to the paucity of surgical care in low- and middle-income countries (LMICs). Wearable technology with real-time tele-proctoring has been demonstrated in high-resource settings to be an innovative method of advancing surgical education and connecting providers, but application to LMICs has not been well-described. METHODS: Google Glass with live-stream capability was utilized to facilitate tele-proctoring between a surgeon in Mozambique and a reconstructive surgeon in the United States over a 6-month period. At the completion of the pilot period, a survey was administered regarding the acceptability of the image quality as well as the overall educational benefit of the technology in different surgical contexts. RESULTS: Twelve surgical procedures were remotely proctored using the technology. No complications were experienced in any patients. Both participants reported moderate visual impairment due to image distortion and light over-exposure. Video-stream latency and connection disruption were also cited as limitations. Overall, both participants reported that the technology was highly useful as training tool in both the intraoperative and perioperative setting. CONCLUSIONS: Our experience in Mozambique demonstrates the feasibility of wearable technology to enhance the reach and availability of specialty surgical training in LMICs. Despite shortcomings in the technology and logistical challenges inherent to international collaborations, this educational model holds promise for connecting surgeons across the globe and introducing expanded access to education and mentorship in areas with limited opportunities for surgical trainees.
ABSTRACT
The molecular circadian clock in mammals is generated from transcriptional activation by the bHLH-PAS transcription factor CLOCK-BMAL1 and subsequent repression by PERIOD and CRYPTOCHROME (CRY). The mechanism by which CRYs repress CLOCK-BMAL1 to close the negative feedback loop and generate 24-h timing is not known. Here we show that, in mouse fibroblasts, CRY1 competes for binding with coactivators to the intrinsically unstructured C-terminal transactivation domain (TAD) of BMAL1 to establish a functional switch between activation and repression of CLOCK-BMAL1. TAD mutations that alter affinities for co-regulators affect the balance of repression and activation to consequently change the intrinsic circadian period or eliminate cycling altogether. Our results suggest that CRY1 fulfills its role as an essential circadian repressor by sequestering the TAD from coactivators, and they highlight regulation of the BMAL1 TAD as a critical mechanism for establishing circadian timing.
Subject(s)
ARNTL Transcription Factors/metabolism , Circadian Clocks , Cryptochromes/metabolism , Animals , Cells, Cultured , Fibroblasts/physiology , Humans , Mice , Mice, KnockoutABSTRACT
The circadian clock orchestrates global changes in transcriptional regulation on a daily basis via the bHLH-PAS transcription factor CLOCK:BMAL1. Pathways driven by other bHLH-PAS transcription factors have a homologous repressor that modulates activity on a tissue-specific basis, but none have been identified for CLOCK:BMAL1. We show here that the cancer/testis antigen PASD1 fulfills this role to suppress circadian rhythms. PASD1 is evolutionarily related to CLOCK and interacts with the CLOCK:BMAL1 complex to repress transcriptional activation. Expression of PASD1 is restricted to germline tissues in healthy individuals but can be induced in cells of somatic origin upon oncogenic transformation. Reducing PASD1 in human cancer cells significantly increases the amplitude of transcriptional oscillations to generate more robust circadian rhythms. Our results describe a function for a germline-specific protein in regulation of the circadian clock and provide a molecular link from oncogenic transformation to suppression of circadian rhythms.
