A392V and R945X mutations cause orofacial clefts via impairing PTCH1 function.

The Hedgehog (HH) signaling plays key roles in embryogenesis and organogenesis, and its dysfunction causes a variety of human birth defects. Orofacial cleft (OFC) is one of the most common congenital craniofacial defects, and its etiology is closely related to mutations in multiple components in the HH pathway, including the PTCH1 receptor. A quantity of PTCH1 variants have been associated with OFC, but the pathogenicity and underlying mechanism of these variants have not been functionally validated. In our previous studies, we identified two PTCH1 variants (A392V and R945X) in two families with hereditary OFC. Here we explore the functional consequences of these two variants. In zebrafish embryos, microinjection of wild type PTCH1 mRNA causes curved body axis and craniofacial anomalies. In contrast, microinjection of A392V and R945X PTCH1 mRNAs results in much milder phenotypes, suggesting these two variants are loss-of-function mutations. In mammalian cells, A392V and R945X mutations reverse the inhibitory effect of PTCH1 on HH signaling. Biochemically, the two mutants PTCH1 show lower expression levels and shortened half-life, indicting these mutations decrease the stability of PTCH1. A392V and R945X mutations also appear to cause PTCH1 to localize away from vesicles. Taken together, our findings indicate that A392V and R945X variants are loss-of-function mutations that disrupt the function of PTCH1 and thus cause dysregulation of HH signaling, leading to the pathogenesis of OFC.

Interference cancellation in MIMO NLOS optical-camera-communication-based intelligent transport systems.

The ever-increasing number of vehicles on a global level signifies the need for communications between vehicles and the surrounding environment. Visible light communications (VLC) is a viable complementary technology to congested radio-frequency-based wireless systems. In order to increase the reliability of the VLC link, two novel algorithms based on (i) channel inversion (CI) and (ii) frame subtraction and CI (FSCI) schemes are proposed to successfully extract the data in a non-line-of-sight multiple-input-multiple-output spatial-division multiplexing optical camera communications system. We have adopted differential modulation and frame subtraction schemes and proposed a unique packet structure to mark the packet and the position of the footprint of transmitters (Txs) in the image frame. We show that the FSCI scheme with much simpler receiver structures can offer almost the same bit error rate performance compared with the hybrid selection/equal gain combining (HS/EGC) technique at lower transmit power (illumination) levels of <13dBm for a single Tx and improved performance at higher illumination levels of >20dBm for multiple Txs. Compared with HS/EGC, CI schemes have a higher tolerance to the spacing between Txs, where the payload threshold level can be set to a fixed value of 0.5.