retina via the retinohypothalamic tract. The SCN maintains control across the body by synchronizing "slave oscillators", which exhibit their own near-24-hour rhythms and control circadian phenomena in local tissue. Through intercellular signalling mechanisms such as vasoactive intestinal peptide, the SCN signals other hypothalamic nuclei and the pineal gland to modulate body temperature and production of hormones such as cortisol and melatonin; these hormones enter the circulatory system, and induce clock-driven effects throughout the organism. It is not, however, clear precisely what signal (or signals) enacts principal entrainment to the many biochemical clocks contained in tissues throughout the body. See section "regulation of circadian oscillators" below for more details. Transcriptional and non-transcriptional control Evidence for a genetic basis of circadian rhythms in higher eukaryotes began with the discovery of the period (per) locus in Drosophila melanogaster from forward genetic screens completed by Ron Konopka and Seymour Benzer in 1971. Through the analysis of per circadian mutants and additional mutations on Drosophila clock genes, a model encompassing positive and negative autoregulatory feedback loops of transcription and translation has been proposed. Core circadian 'clock' genes are defined as genes whose protein products are necessary components for the generation and regulation of circadian rhythms. Similar models have been suggested in mammals and other organisms. Studies in cyanobacteria, however, changed our view of the clock mechanism, since it was found by Kondo and colleagues that these single-cell organisms could maintain accurate 24-hour timing in the absence of transcription, i.e. there was no requirement for a transcription-translation autoregulatory feedback loop for rhythms. Moreover, this clock was reconstructed in a test tube (i.e., in the absence of any cell components), proving that accurate 24-hour clocks can be formed without the need for genetic feedback circuits. However, this mechanism was only applicable to cyanobacteria and not generic. In 2011, a major breakthrough in understanding came from the Reddy laboratory at the University of Cambridge. This group discovered circadian rhythms in redox proteins (peroxiredoxins) in cells that lacked a nucleus – human red blood cells. In these cells, there was no transcription or genetic circuits, and therefore no feedback loop. Similar observations were made in a marine alga and subsequently in mouse red blood cells. More importantly, redox oscillations as demonstrated by peroxiredoxin rhythms have now been seen in multiple distant kingdoms of life (eukaryotes, bacteria and archaea), covering the evolutionary tree. Therefore, redox clocks look to be the