Accumulation of sphingolipids, especially sphingosines, in the lysosomes is attributed to the pathogenesis of several lysosomal storage diseases. In search for a lysosomal protein that mediates the release of sphingosines, we identified SPNS1 which shares the highest homology to SPNS2, a sphingosine-1-phosphate (S1P) transporter. We generated knockout cells and mice for Spns1 and employed lipidomics and metabolomics to identify SPNS1 ligands. We found that knockouts of Spns1 resulted in the accumulation of sphingolipids, including sphingosines in embryonic brains and cell lines. These results suggest that deficiency of SPNS1 affects the clearance of sphingolipids in lysosomes. Biochemical assays demonstrated that sphingosines released from lysosomes required SPNS1. Furthermore, by performing a comprehensive analysis of metabolites from livers of postnatal Spns1 knockout mice (gSpns1-cKO), we detected a striking accumulation of lysoglycerophospholipids including LPC, LPE, LPG, and lysoplasmalogens. Interestingly, the release of these lysoglycerophospholipids also required SPNS1. Global knockout of Spns1 (gSpns1-KO) resulted in embryonic lethality between E12.5-E13.5 with developmental defects. Postnatal deletion of Spns1 in mice caused lipid accumulation in the lysosomes and pathological conditions reminiscent of lysosomal storage diseases. These results reveal a critical molecular role of SPNS1 as a transporter for lysosphingolipids and lysoglyerophospholipids from the lysosomes and link its physiological functions with lysosomal storage diseases.

This paper presents a synchronous proportional derivative (PD) control method using a time delay estimator (SPD-TDE) for a four-degree-of-freedom (DOF) parallel robot in practice. The proposed control is a method that is developed from a synchronous PD control method combined with a time delay estimator to guarantee the tracking objectives and synchronous requirements of the robot. Firstly, the synchronous PD control method is designed by defining cross-coupling errors. A cross-coupling error is determined by incorporating the tracking error and deviation of tracking error among two adjacent joints or synchronous errors. Then, the asynchronous problem between the kinematic chains is solved and guarantees that the goal of synchronicity is achieved. Consequently, to improve the tracking performance of the robot, a time delay estimator is used to estimate and eliminate the uncertainty components of the system, such as modeling errors and actuator faults. In addition, the Lyapunov theory is also used to demonstrate the stability and robustness of the proposed control method. Finally, a testbench 4-DOF parallel robot is built, and the controllers are embedded in the control board from MATLAB Simulink using the Waijung block set library to operate the robot preset trajectory tracking. The experimental results of the proposed control method for the 4-DOF parallel robot are compared with those obtained using other controllers to prove its effectiveness.