Circadian rhythms are orchestrated by a master clock that emerges from a network of circadian pacemaker neurons. The master clock is synchronized to external light/dark cycles through photoentrainment, but the circuit mechanisms underlying visual photoentrainment remain largely unknown. Here, we report that Drosophila has eye-mediated photoentrainment via a parallel pacemaker neuron organization. Patch-clamp recordings of central circadian pacemaker neurons reveal that light excites most of them independently of one another. We also show that light-responding pacemaker neurons send their dendrites to a neuropil called accessary medulla (aMe), where they make monosynaptic connections with Hofbauer–Buchner eyelet photoreceptors and interneurons that transmit compound-eye signals. Laser ablation of aMe and eye removal both abolish light responses of circadian pacemaker neurons, revealing aMe as a hub to channel eye inputs to central circadian clock. Taken together, we demonstrate that the central clock receives eye inputs via hub-organized parallel circuits in Drosophila.
The Mre11–Rad50–Nbs1 (MRN) complex is well known for participating in DNA damage response pathways and mediating the ATM-dependent phosphorylation signaling cascade. Hypomorphic mutations in the human MRN complex have been identified in autosomal recessive genetic diseases, ataxia-telangiectasia–like disorder, and Nijmegen breakage syndrome. Here, we show that MRN forms a mitosis-specific complex with a protein, MMAP, which mediates a mitotic signaling cascade between PLK1 and KIF2A. We demonstrate that the assembly of this complex is crucial for normal spindle dynamics during mitosis. Thus, our study describes a signaling cascade in which PLK1-dependent phosphorylation promotes the assembly of the MRN–MMAP–PLK1–KIF2A complex, leading to mitotic spindle turnover and chromosome alignment.
Rapidly proliferating cancer cells have much higher demand for proteinogenic amino acids than normal cells. The use of amino acids in human proteomes is largely affected by their bioavailability, which is constrained by the biosynthetic energy cost in living organisms. Conceptually distinct from gene-based analyses, we introduce the energy cost per amino acid (ECPA) to quantitatively characterize the use of 20 amino acids during protein synthesis in human cells. By analyzing gene expression data from The Cancer Genome Atlas, we find that cancer cells evolve to utilize amino acids more economically by optimizing gene expression profile and ECPA shows robust prognostic power across many cancer types. We further validate this pattern in an experimental evolution of xenograft tumors. Our ECPA analysis reveals a common principle during cancer evolution.
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