Somatic mammalian cells possess well-established S-phase programs with specific regions of the genome replicated at precise times. The ATR–Chk1 pathway plays a central role in these programs, but the mechanism for how Chk1 regulates origin firing remains unknown. We demonstrate here the essential role of cyclin A2–Cdk1 in the regulation of late origin firing. Activity of cyclin A2–Cdk1 was hardly detected at the onset of S phase, but it was obvious at middle to late S phase under unperturbed condition. Chk1 depletion resulted in increased expression of Cdc25A, subsequent hyperactivation of cyclin A2–Cdk1, and abnormal replication at early S phase. Hence, the ectopic expression of cyclin A2–Cdk1AF (constitutively active mutant) fusion constructs resulted in abnormal origin firing, causing the premature appearance of DNA replication at late origins at early S phase. Intriguingly, inactivation of Cdk1 in temperature-sensitive Cdk1 mutant cell lines (FT210) resulted in a prolonged S phase and inefficient activation of late origin firing even at late S phase. Our results thus suggest that cyclin A2–Cdk1 is a key regulator of S-phase programs.

Physical, chemical, and biological properties of S-allylcysteine (SAC) were investigated. SAC showed stable properties under tested conditions, and its acute/subacute toxicity was very minor in mice and rats (LD(50) value >54.7 mM/kg po; >20 mM/kg ip). The pharmacokinetics of SAC was investigated after oral administration of garlic supplement containing SAC to human volunteers. SAC from garlic consumption was rapidly absorbed from the gastrointestinal tract, however, the half-life and excretion time were more than 10 h and 30 h, respectively.

NMDARs play a major role in patterning of topographic sensory maps in the brain. Genetic knock-out of the essential subunit of NMDARs in excitatory cortical neurons prevents whisker-specific neural pattern formation in the barrel cortex. To determine the role of NMDARs en route to the cortex, we generated sensory thalamus-specific NR1 (Grin1)-null mice (ThNR1KO). A multipronged approach, using histology, electrophysiology, optical imaging, and behavioral testing revealed that, in these mice, whisker patterns develop in the trigeminal brainstem but do not develop in the somatosensory thalamus. Subsequently, there is no barrel formation in the neocortex yet a partial afferent patterning develops. Whisker stimulation evokes weak cortical activity and presynaptic neurotransmitter release probability is also affected. We found several behavioral deficits in tasks, ranging from sensorimotor to social and cognitive. Collectively, these results show that thalamic NMDARs play a critical role in the patterning of the somatosensory thalamic and cortical maps and their impairment may lead to pronounced behavioral defects.