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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 forSpns1and employed lipidomics and metabolomics to identify SPNS1 ligands. We found that knockouts ofSpns1resulted 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 postnatalSpns1knockout 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 ofSpns1(gSpns1-KO) resulted in embryonic lethality between E12.5-E13.5 with developmental defects. Postnatal deletion ofSpns1in 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.SignificancePhospholipids, including glycerophospholipids and sphingolipids, are delivered to the lysosomes for recycling. The hydrolysis of these lipids by lysosomal enzymes generates the corresponding lysoglycerophospholipids, such as lysophosphatidylcholine and lysosphingolipids, such as sphingosine, which are believed to be exported out of the lysosomes for recycling in the cytoplasm. However, it is unknown how these lysophospholipids are released from the lysosomes. The current study utilized genetic knockout models in combination with mass spectrometry analysis of complex phospholipids and sphingolipids to characterize the roles of an orphan lysosomal transporter, namely SPNS1. These findings show that deficiency of SPNS1 results in the accumulation of lysophospholipids in cells and animal tissues and that the transporter is required to transport both lysoglycerophospholipids and lysosphingolipids out of the lysosomes. SPNS1 is critical for early development in mice. Ablation of SPNS1 at postnatal life causes pathological conditions reminiscent of lysosomal storage diseases in mice. These findings reveal the molecular functions of SPNS1 as a lysophospholipid transporter and provide a foundation for studying the transport of these lysolipids in lysosomal storage diseases.

β-cell dedifferentiation is important in the pathogenesis of type 2 diabetes, and the relationship between lysosome membrane proteins and pancreatic β-cell dedifferentiation is still unknown. Sidt2 is a lysosomal membrane protein identified in our previous study. After Sidt2 elimination, mice exhibited a diabetic phenotype. In the present study, we found that Sidt2 also can be considered a new insulin granule membrane protein. Sidt2 deficiency resulted in islet dysfunction and inhibited insulin secretion. The absence of Sidt2 also led to increased β cell dedifferentiation in mice. Further experiments showed that defects in insulin secretion caused dedifferentiation in the absence of Sid2. In summary, our study has found a new dedifferentiation regulatory mechanism mediated by a lysosomal membrane protein. This new secretory regulation pathway will enrich our understanding of the regulatory mechanisms involved in β cell dedifferentiation and provide new insights into the pathogenesis of diabetes.

HOCN and HNCO abundance ratio in molecular gas can tell us the information of their formation mechanism. We performed high-sensitivity mapping observations of HOCN, HNCO, and HNC18O lines around Sagittarius B2 (Sgr B2) with the IRAM 30 m telescope at the 3 mm wavelength. HNCO 404–303 and HOCN 404–303 are used to obtain the abundance ratio of HNCO to HOCN. The ratio of HNCO 404–303 to HNC18O 404–303 is used to calculate the optical depth of HNCO 404–303. The abundance ratio of HOCN and HNCO is observed to range from 0.4% to 0.7% toward most positions, which agrees well with the gas-grain model. However, the relative abundance of HOCN is observed to be enhanced toward the direction of Sgr B2 (S), with HOCN to HNCO abundance ratio of ∼0.9%. The reason for that still needs further investigation. Based on the intensity ratio of HNCO and HNC18O lines, we updated the isotopic ratio of 16O/18O to be 296 ± 54 in Sgr B2.

Diabetic retinopathy(DR)is the major microvascular disease in diabetic patients,and it is also one of the main blinding eye diseases in the current population.The typical pathological change of DR in the eyes is vascular endothelial growth factor(VEGF)-mediated neovascularization induced by retinal ischemic stimulation.Therefore,anti-VEGF drugs have gradually become one of the mainstream methods to treat DR and DR-induced diseases such as diabetic macular edema.Recent studies have proved that anti-VEGF drugs have certain effects on ocular blood vessels and blood flow in patients with DR,while the specific mechanism has not been fully elucidated.This article summarizes the research progress on the effects of intravitreal injection of anti-VEGF drugs on the ocular blood vessels and blood flow in patients with DR.

We report a survey of excited-state hydroxyl (ex-OH) masers at the 4.7 and 6.0 GHz transitions toward a sample consisting of 3348 massive star-forming region candidates selected from the all-sky Wide-field Infrared Survey Explorer point-source catalog. The survey was conducted with the Shanghai Tianma Radio Telescope. In total, 6, 9, and 30 sources were detected with the ex-OH masers at the 4766, 6031, and 6035 MHz transitions, respectively. Among them, one 4766 MHz, one 6031 MHz, and five 6035 MHz ex-OH maser sources are newly identified. A series of statistical analyses derived that the ex-OH masers were detected efficiently toward the subsamples associated with both the 6.7 GHz CH3OH maser and radio recombination lines (RRLs), whereas compared to the CH3OH masers, the ex-OH masers are more likely to be produced toward the sources with stronger 22 μm band emission. A significant luminosity correlation is found between the ex-OH masers and RRLs. In addition, we found that the magnetic field strength of most sources with the 6.7 GHz CH3OH maser was stronger relative to that of sources without the CH3OH maser. Combined with these, it demonstrates that the ex-OH maser is associated with more evolved star-forming regions, likely associated with thicker dust envelopes. Meanwhile, the ex-OH masers might be a potential tracer for measuring the Galactic magnetic field information on the large-scale views using their Zeeman pairs.

The technique of carbonated stabilization is an innovative method to improve the engineering performance of soft soils. However, the improvement in the engineering performance of stabilized soils with carbonized steel slag has not been studied. In addition, the effect of clay minerals on carbonation parameters and D-W cycle performance remains unknown. To this end, in this paper, three types of synthetic soils containing different clay minerals were prepared to be stabilized by carbonated steel slag. The strength performance and microstructural evolution of carbonated steel slag stabilized soils were investigated by drying-wetting (D-W) cycle tests, unconfined compression strength (UCS) tests, X-ray diffraction (XRD), thermogravimetry (TG), and scanning electron microscopy (SEM). The results showed that the compressive strength after and resistance to D-W cycles of carbonated steel slag stabilized soils were significantly improved due to carbonation treatment. The presence of clay minerals in stabilized soils led to the high values of optimum moisture content for carbonation (C-OMC). The C-OMC value of stabilized soils containing montmorillonite was higher than that of stabilized soils containing kaolinite. Montmorillonite had a higher negative effect on the D-W cycle performance of soils compared to kaolinite. This fact could be reflected by the fluctuation of UCS and mass change ratio (Rm). The main carbonation product by three types of carbonated steel slag stabilized soils was calcite, which remained stable after D-W cycles. After carbonation for 18 h, the generated calcite and carbonation degrees for three types of stabilized soils were obtained. In the microstructures of carbonated steel slag stabilized soils, the spindle-like clusters of the generated calcite appeared, which adhered to the surface of mineral particles. The aggregated degrees of the generated calcite in stabilized soils containing clay minerals tended to decrease after D-W cycles. In this work, a new type of carbonated steel slag stabilized soil was studied. The results indicated that the effect of clay minerals on the engineering characteristics of soil should be considered.

Peptide bonds, as the molecular bridges that connect amino acids, are crucial to the formation of proteins. Searches and studies of molecules with embedded peptide-like bonds are thus important for the understanding of protein formation in space. Here we report the first tentative detection of propionamide (C2H5CONH2), the largest peptide-like molecule detected in space toward Sagittarius B2(N1) at a position called N1E that is slightly offset from the continuum peak. A new laboratory measurements of the propionamide spectrum were carried out in the 9-461 GHz, which provide good opportunity to check directly for the transition frequencies of detected interstellar lines of propionamide. Our observing result indicates that propionamide emission comes from the warm, compact cores in Sagittarius B2, in which massive protostellars are forming. The column density of propionamide toward Sgr B2(N1E) was derived to be 1.5\times 10^{16} cm^-2, which is three fifths of that of acetamide, and one nineteenth of that of formamide. This detection suggests that large peptide-like molecules can form and survive during star-forming process and may form more complex molecules in the interstellar medium. The detection of propionamide bodes well for the presence of polypeptides, as well as other complex prebiotic molecules in the interstellar medium., 49 pages, 13 figures, accepted by ApJ