SUMMARY Wnt signaling plays critical roles in development of various organs and pathogenesis of many diseases, and augmented Wnt signaling has recently been implicated in mammalian aging and aging-related phenotypes. We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. C1q activates canonical Wnt signaling by binding to Frizzled receptors and subsequently inducing C1s-dependent cleavage of the ectodomain of Wnt coreceptor low-density lipoprotein receptor-related protein 6. Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption. Our findings therefore suggest the unexpected role of complement C1q in Wnt signal transduction and modulation of mammalian aging.

(104)-oriented Bi4Ti3O12, La-substituted Bi4Ti3O12[(Bi3.44La0.56)Ti3O12] and Nd-substituted Bi4Ti3O12[(Bi3.54Nd0.46)Ti3O12] films were epitaxially grown on (111)SrRuO3//(111)SrTiO3 substrates at 700 °C by metalorganic chemical vapor deposition. All deposited films showed strong (104) orientations. The values of the remanent polarization (Pr) and coercive field (Ec) of the (104)-oriented epitaxial (Bi3.54Nd0.46)Ti3O12 thin film were 25 μC/cm2 and 135 kV/cm, respectively. This Pr value was larger than that of the (104)-oriented (Bi3.44La0.56)Ti3O12 film: Pr and Ec values of the (Bi3.44La0.56)Ti3O12 were 17 μC/cm2 and 145 kV/cm, respectively. These good ferroelectric properties of (Bi3.54Nd0.46)Ti3O12 films can be explained by a large tilting of TiO6 octahedra induced by the substitution of Nd3+, the ionic radius of which is smaller than that of La3+. Moreover, this Pr value is almost equal to that of commercially used lead zirconate titanate (PZT) films for nonvolatile ferroelectric random access memory (FeRAM) applications. These (104)-oriented epitaxial (Bi3.54Nd0.46)Ti3O12 thin films also showed a fatigue-free character. As a result, lead-free Nd-substituted Bi4Ti3O12 films with good ferroelectric properties comparable with those of PZT films are useful candidates for FeRAM applications.

The DNA damage response (DDR) plays a pivotal role in maintaining genome integrity. DNA damage and DDR activation are observed in the failing heart, however, the type of DNA damage and its role in the pathogenesis of heart failure remain elusive. Here we show the critical role of DNA single-strand break (SSB) in the pathogenesis of pressure overload-induced heart failure. Accumulation of unrepaired SSB is observed in cardiomyocytes of the failing heart. Unrepaired SSB activates DDR and increases the expression of inflammatory cytokines through NF-κB signalling. Pressure overload-induced heart failure is more severe in the mice lacking XRCC1, an essential protein for SSB repair, which is rescued by blocking DDR activation through genetic deletion of ATM, suggesting the causative role of SSB accumulation and DDR activation in the pathogenesis of heart failure. Prevention of SSB accumulation or persistent DDR activation may become a new therapeutic strategy against heart failure.

Hypertension induces structural remodelling of arteries, which leads to arteriosclerosis and end-organ damage. Hyperplasia of vascular smooth muscle cells (VSMCs) and infiltration of immune cells are the hallmark of hypertensive arterial remodelling. However, the precise molecular mechanisms of arterial remodelling remain elusive. We have recently reported that complement C1q activates β-catenin signalling independent of Wnts. Here, we show a critical role of complement C1-induced activation of β-catenin signalling in hypertensive arterial remodelling. Activation of β-catenin and proliferation of VSMCs were observed after blood-pressure elevation, which were prevented by genetic and chemical inhibition of β-catenin signalling. Macrophage depletion and C1qa gene deletion attenuated the hypertension-induced β-catenin signalling, proliferation of VSMCs and pathological arterial remodelling. Our findings unveil the link between complement C1 and arterial remodelling and suggest that C1-induced activation of β-catenin signalling becomes a novel therapeutic target to prevent arteriosclerosis in patients with hypertension.

The site engineering approach based on site-selective substitutions was utilized to improve the ferroelectric properties in Bi4Ti3O12 thin film. Thin films of (Bi4−xNdx)(Ti3−yVy)O12 with both A- and B-sites substitutions were deposited on (111)Pt/Ti/SiO2/Si substrates at 600 °C by metalorganic chemical vapor deposition. Although the films substituted for the A site by Nd, (Bi4−xNdx)Ti3O12, showed no significant improvement in ferroelectricity, additional substitution for the B site by V contributed to a large ferroelectricity. Superior properties compared to (Bi4−xLax)(Ti3−yVy)O12 were confirmed for (Bi4−xNdx)(Ti3−yVy)O12 films. We also showed orientation control using Ru-based substrates. (104)-preferred orientation was obtained on (111)Pt/Ti/SiO2/Si substrates, while (110) and (111) orientations with an advantage for large polarization were stabilized on (001)Ru/SiO2/Si substrates and actually a larger ferroelectricity was obtained; the remanent polarization (2Pr) and coercive field (2Ec) of the (Bi3.35Nd0.65)(Ti2.87V0.13)O12 film were 34 μC/cm2 and 290 kV/cm, respectively. No fatigue phenomenon was also observed for the (Bi3.35Nd0.65)(Ti2.87V0.13)O12 film up to 109 switching cycles.