High performance transparent polymeric materials are of great interests in many fields including automotive and electronics. Conventional transparent plastics like polycarbonate (PC) and poly(methyl methacrylate) (PMMA) possess relatively unsatisfactory mechanical performance, while high performance polymeric systems like solid-state drawn high-density polyethylene (HDPE) typically have an opaque appearance, limiting applications where both mechanical and optical properties are required. In this study, we successfully combined high transparency and high strength in HDPE films by carefully controlling processing parameters
Animal development requires coordination among cyclic processes, sequential cell fate specifications, and once-a-lifetime morphogenic events, but the underlying timing mechanisms are not well understood. Caenorhabditis elegans undergoes four molts at regular 8 to 10 hour intervals. The pace of the cycle is governed by PERIOD/lin-42 and other as-yet unknown factors. Cessation of the cycle in young adults is controlled by the let-7 family of microRNAs and downstream transcription factors in the heterochronic pathway. Here, we characterize a negative feedback loop between NHR-23, the worm homolog of mammalian retinoid-related orphan receptors (RORs), and the let-7 family of microRNAs that regulates both the frequency and finite number of molts. The molting cycle is decelerated in nhr-23 knockdowns and accelerated in let-7(−) mutants, but timed similarly in let-7(−) nhr-23(−) double mutants and wild-type animals. NHR-23 binds response elements (ROREs) in the let-7 promoter and activates transcription. In turn, let-7 dampens nhr-23 expression across development via a complementary let-7-binding site (LCS) in the nhr-23 3′ UTR. The molecular interactions between NHR-23 and let-7 hold true for other let-7 family microRNAs. Either derepression of nhr-23 transcripts by LCS deletion or high gene dosage of nhr-23 leads to protracted behavioral quiescence and extra molts in adults. NHR-23 and let-7 also coregulate scores of genes required for execution of the molts, including lin-42. In addition, ROREs and LCSs isolated from mammalian ROR and let-7 genes function in C. elegans, suggesting conservation of this feedback mechanism. We propose that this feedback loop unites the molting timer and the heterochronic gene regulatory network, possibly by functioning as a cycle counter.
Animal physiology and development both rely on biological clocks, but the extent to which feedback loops among core components of the circadian clock and conserved microRNAs operate within developmental timers is not well understood. Here, we show that a negative feedback loop between NHR-23/RORα and let-7 modulates the PER dependent rhythm of the C. elegans molting cycle. Related quiescent intervals are delayed and protracted in nhr-23 knockdowns, advanced and abbreviated in particular let-7 mutants, and yet scheduled more regularly in double mutants. NHR-23 binds upstream ROR Response Elements (REs) and activates transcription of primary let-7 when larvae are active, whereas let-7 targets an LCS in the 3′UTR and represses expression of nhr-23 transcripts when larvae are quiescent. Moreover, NHR-23 and let-7 have scores of shared targets that are cyclically expressed and mediate related transitions in cell and animal behavior. ROREs are also found upstream of vertebrate let-7 homologs, while LCSs are found in 3′UTRs of ROR transcripts. Conservation of this feedback loop has implications for human clocks and related malignancies and disorders of sleep and metabolism.
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