PLK4 was identified as a promising therapeutic target through a systematic approach that combined RNAi screening with gene expression analysis in human breast cancers and cell lines. A drug discovery program culminated in CFI-400945, a potent and selective PLK4 inhibitor. Cancer cells treated with CFI-400945 exhibit effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication, mitotic defects, and cell death. Oral administration of CFI-400945 to mice bearing human cancer xenografts results in the significant inhibition of tumor growth at doses that are well tolerated. Increased antitumor activity in vivo was observed in PTEN-deficient compared to PTEN wild-type cancer xenografts. Our findings provide a rationale for the clinical evaluation of CFI-400945 in patients with solid tumors, in particular those deficient in PTEN.

Down Syndrome cell adhesion molecule(Dscam) genes encode neuronal cell recognition proteins of the immunoglobulin superfamily1,2. In Drosophila, Dscam1 generates 19,008 different ecto-domains by alternative splicing of three exon clusters, each encoding half or a complete variable immunoglobulin domain3. Identical isoforms bind to each other, but rarely to isoforms differing at any one of the variable immunoglobulin domains4,5. Binding between isoforms on opposing membranes promotes repulsion6. Isoform diversity provides the molecular basis for neurite self-avoidance6–11. Self-avoidance refers to the tendency of branches from the same neuron (self-branches) to selectively avoid one another12. To ensure that repulsion is restricted to self-branches, different neurons express different sets of isoforms in a biased stochastic fashion7,13. Genetic studies demonstrated that Dscam1 diversity has a profound role in wiring the fly brain11. Here we show how many isoforms are required to provide an identification system that prevents non-self branches from inappropriately recognizing each other. Using homologous recombination, we generated mutant animals encoding 12, 24, 576 and 1,152 potential isoforms. Mutant animals with deletions encoding 4,752 and 14,256 isoforms14 were also analysed. Branching phenotypes were assessed in three classes of neurons. Branching patterns improved as the potential number of isoforms increased, and this was independent of the identity of the isoforms. Although branching defects in animals with 1,152 potential isoforms remained substantial, animals with 4,752 isoforms were indistinguishable from wild-type controls. Mathematical modelling studies were consistent with the experimental results that thousands of isoforms are necessary to ensure acquisition of unique Dscam1 identities in many neurons. We conclude that thousands of isoforms are essential to provide neurons with a robust discrimination mechanism to distinguish between self and non-self during self-avoidance.

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MiR‐140 is a microRNA specially involved in chondrogenesis and osteoarthritis pathogenesis. However, its transcriptional regulation and target genes in cartilage development are not fully understood. Here we detected that miR‐140 was uniquely expressed in chondrocyte and suppressed by Wnt/β‐catenin signalling. The miR‐140 primary transcript was an intron‐retained RNA co‐expressed with Wwp2‐C isoform, which was directly induced by Sox9 through binding to the intron 10 of Wwp2 gene. Knockdown of miR‐140 in limb bud micromass cultures resulted in arrest of chondrogenic proliferation. Sp1, the activator of the cell cycle regulator p15INK4b, was identified as a target of miR‐140 in maintaining the chondrocyte proliferation. Collectively, our findings expand our understanding of the transcriptional regulation and the chondrogenic role of miR‐140 in chondrogenesis.

A composite scaffold was fabricated with a method involving both electrospinning and 3D printing to give microscale pores and good mechanical properties. Biocompatibility and cell infiltration on the scaffold was evaluated by an in vitro study.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children and adults. While ADHD patients often display circadian abnormalities, the underlying mechanisms are unclear. Here we found that the zebrafish mutant for the circadian gene period1b (per1b) displays hyperactive, impulsive-like, and attention deficit-like behaviors and low levels of dopamine, reminiscent of human ADHD patients. We found that the circadian clock directly regulates dopamine-related genes monoamine oxidase and dopamine ␤ hydroxylase, and acts via genes important for the development or maintenance of dopaminergic neurons to regulate their number and organization in the ventral diencephalic posterior tuberculum. We then found that Per1 knock-out mice also display ADHD-like symptoms and reduced levels of dopamine, thereby showing highly conserved roles of the circadian clock in ADHD. Our studies demonstrate that disruption of a circadian clock gene elicits ADHD-like syndrome. The circadian model for attention deficiency and hyperactive behavior sheds light on ADHD pathogenesis and opens avenues for exploring novel targets for diagnosis and therapy for this common psychiatric disorder.

Background: Oxidative damage in the central nervous system is increasingly recognized as an important pathological process in many diseases. Previously, our laboratory found that oxidative damage to lipids and proteins was increased in postmortem brain tissue from patients with bipolar disorder and schizophrenia. In the current study, we analyzed oxidative damage to nucleic acids in the CA1, CA3 and dentate gyrus regions of postmortem hippocampus tissue from patients with bipolar disorder, schizophrenia and major depression. Methods: We examined oxidative damage to nucleic acids by performing immunohistochemistry with a monoclonal antibody that recognizes both 8-hydroxy-guanosine in RNA and 8-hydroxy-2'-deoxyguanosine in DNA. Results: We found that the amount of oxidative damage to nucleic acids was elevated in the CA1, CA3 and dentate gyrus regions of the hippocampus among patients with bipolar disorder, schizophrenia and major depressive disorder. This damage was predominantly in the cytoplasm, suggesting that the damage was primarily to RNA. Compared with oxidative damage in control samples, the magnitude of damage was high in patients with schizophrenia, modest in patients with bipolar disorder and lower in patients with major depression. Limitations: The interpretation of our results is limited by a number of factors, including the retrospective review of patient history, the relatively small sample size and the inclusion of patients who had substance abuse and were undergoing various drug treatments at the time of death. Conclusion: Our results suggest that oxidative damage to RNA, rather than to DNA, occurs in vulnerable neurons of the brain in patients with major mental illness and may contribute to the pathology of these disorders. The magnitude of RNA oxidative damage may be associated with the severity of mental illness.

Transferring the solution-state chemistry of organic-based molecular switches (OMS) into the solid state usually faces several fatal problems, such as spatial confinement or inefficient conversion. As a result, their switching behavior usually cannot be maintained. Herein, we report a redoxswitchable metal−organic framework (MOF) that can undergo a reversible single-crystal-to-single-crystal (SCSC) transformation through a hydroquinone/quinone redox reaction. The redox-triggered transformation is quantitatively reversible while maintaining the crystallinity of the MOF scaffold. In addition, the transformation occurs gradually in the MOF backbone and from the outsurface of MOF to the inside. This study represents a general strategy to enable efficient conversion of the functionality of an OMS from solution into solid state, by incorporation of OMS into the framework of MOF. Furthermore, the material exhibits interesting changes in spectroscopic properties through reversible SCSC transformation and, thus, may be a starting point for the use of such materials in memory storage or redox-based electronic devices.