Reversible modulation of circadian time with chronophotopharmacology.

The circadian clock controls daily rhythms of physiological processes. The presence of the clock mechanism throughout the body is hampering its local regulation by small molecules. A photoresponsive clock modulator would enable precise and reversible regulation of circadian rhythms using light as a bio-orthogonal external stimulus. Here we show, through judicious molecular design and state-of-the-art photopharmacological tools, the development of a visible light-responsive inhibitor of casein kinase I (CKI) that controls the period and phase of cellular and tissue circadian rhythms in a reversible manner. The dark isomer of photoswitchable inhibitor 9 exhibits almost identical affinity towards the CKIα and CKIδ isoforms, while upon irradiation it becomes more selective towards CKIδ, revealing the higher importance of CKIδ in the period regulation. Our studies enable long-term regulation of CKI activity in cells for multiple days and show the reversible modulation of circadian rhythms with a several hour period and phase change through chronophotopharmacology.

[Thalamus and Attention].

Attention is the process by which information and selection occurs, the thalamus plays an important role in the selective attention of visual and auditory information. Selective attention is a conscious effort; however, it occurs subconsciously, as well. The lateral geniculate body (LGB) filters visual information before it reaches the cortex (bottom-up attention). The thalamic reticular nucleus (TRN) provides a strong inhibitory input to both the LGB and pulvinar. This regulation involves focusing a spotlight on important information, as well as inhibiting unnecessary background information. Behavioral contexts more strongly modulate activity of the TRN and pulvinar influencing feedforward and feedback information transmission between the frontal, temporal, parietal and occipital cortical areas (top-down attention). The medial geniculate body (MGB) filters auditory information the TRN inhibits the MGB. Attentional modulation occurring in the auditory pathway among the cochlea, cochlear nucleus, superior olivary complex, and inferior colliculus is more important than that of the MGB and TRN. We also discuss the attentional consequence of thalamic hemorrhage.

Effects of biotin deficiency on embryonic development in mice.

OBJECTIVE: The purpose of this investigation was to determine the effects of biotin deficiency on maternal metabolism and embryonic development in pregnant mouse dams. METHODS: The pregnant mice were randomly assigned to one of three dietary groups and given a biotin-deficient diet, biotin-supplemented diet, or biotin-control diet during gestation. On days of gestation (dgs) 0, 4, 8, 12, and 16, organic acids including 3-hydroxyisovaleric acid in urine were discovered by high-performance liquid chromatography, and the biotin level in the serum and urine was determined by a bioassay. On dg 18, fetuses were examined for morphologic development. RESULTS: In the biotin-deficient group, biotin excretion in urine decreased on dg 4 and was subsequently below the lower limit, whereas the urinary concentration of 3-hydroxyisovaleric acid increased after dg 12. In contrast, the biotin concentration in urine significantly increased on dgs 4, 8 and 12 in the biotin-supplemented group, but decreased on dg 16 in the biotin-supplemented and biotin-control groups. The urinary excretion of pyruvic acid in the biotin-deficient group was significantly higher than that in the biotin-supplemented group throughout the entire gestation. These concentrations in urine significantly increased on dg 16 compared with dg 0. The inhibition of embryonic development and external malformations such as cleft palate (100%), micrognathia (100%), and micromelia (91.4%) were also detected in biotin-deficient fetuses. CONCLUSION: These findings indicated that, as the requirement of biotin increases during gestation and/or embryonic development, a large amount of biotin is necessary for maintaining normal reproductive performance during the late stage of gestation.