An SNX31 variant underlies dominant familial exudative vitreoretinopathy-like pathogenesis.

Familial exudative vitreoretinopathy (FEVR) is a complex hereditary eye disorder characterized by incomplete development of the retinal vasculature, which thereby affects retinal angiogenesis. But the genetic factors contributing to FEVR's development or pathogenesis remain elusive. In a Chinese family with FEVR with 19 members, by using whole-exome sequencing, we identified a candidate disease-causing DNA variant in sorting nexin 31 (SNX31) (c.963delG; p. Trp321Cys), which results in a frameshift mutation. We studied the biochemical mechanism of this mutation and determined that it is deficient in ß1-integrin binding and stability. The SNX31 c.963delG point mutation mouse model (SNX31m/m) was constructed with CRISPR/Cas9 technology. At 2-4 months of age, SNX31m/m mice showed fundus phenotypes similar to FEVR-like changes, including vascular leakage and retinal atrophy. Moreover, we found that VEGF and apoptotic pathways were involved in these ocular phenotypes. Hence, our study extended the FEVR mutation spectrum to include SNX31. These findings expanded our understanding of the molecular pathogenesis of FEVR and may facilitate the development of methods for the diagnosis and prevention of FEVR.

Novel risk-factor analysis and risk-evaluation model of falls in patients receiving maintenance hemodialysis.

This study investigated the prevalence of falls in maintenance hemodialysis (MHD) patients, and established a nomogram model for evaluating the fall risk of MHD patients. This study enrolled 303 MHD patients from the dialysis department of a tertiary hospital in July 2021. The general data of the participants, as well as the scores on the FRAIL scale, Sarcopenia Screening Questionnaire (SARC-F), Short Physical Performance Battery (SPPB) Scale, and of anxiety and depression, and the occurrence of falls were recorded. Using R language, data were assigned to the training set (n = 212) and test set (n = 91), and a logistic regression model was established. The regression model was verified by the receiver operating characteristic (ROC) curve, area under the curve (AUC), and the calibration curve. As a result, the prevalence of falls in MHD patients was 20.46%. Risk factors for falls in the optimal multivariate logistic regression model included hearing impairment, the depression score, and the SPPB score, of which a higher depression score (odds ratio (OR): 1.28, 95% confidence interval (CI): 1.09-1.49, p = 0.002) and SPPB ≤ 6 (ORvsSPPB9-12: 3.69, 95% CI: 1.04-13.14, p = 0.043) conferred independent risk for falls. AUC of the nomogram in the training was 0.773, which in the test group was 0.663. The calibration and standard curves were fitted closely, indicated that the evaluation ability of the model was good. Thus, a higher depression score and SPPB ≤ 6 are independent risk factors for falls in MHD patients, and the nomogram with good accuracy and discrimination that was established in this study has clinical application value.

O-GlcNAcylation of myosin phosphatase targeting subunit 1 (MYPT1) dictates timely disjunction of centrosomes.

The role of O-linked N-acetylglucosamine (O-GlcNAc) modification in the cell cycle has been enigmatic. Previously, both O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) disruptions have been shown to derail the mitotic centrosome numbers, suggesting that mitotic O-GlcNAc oscillation needs to be in concert with mitotic progression to account for centrosome integrity. Here, using both chemical approaches and biological assays with HeLa cells, we attempted to address the underlying molecular mechanism and observed that incubation of the cells with the OGA inhibitor Thiamet-G strikingly elevates centrosomal distances, suggestive of premature centrosome disjunction. These aberrations could be overcome by inhibiting Polo-like kinase 1 (PLK1), a mitotic master kinase. PLK1 inactivation is modulated by the myosin phosphatase targeting subunit 1 (MYPT1)-protein phosphatase 1cß (PP1cß) complex. Interestingly, MYPT1 has been shown to be abundantly O-GlcNAcylated, and the modified residues have been detected in a recent O-GlcNAc-profiling screen utilizing chemoenzymatic labeling and bioorthogonal conjugation. We demonstrate here that MYPT1 is O-GlcNAcylated at Thr-577, Ser-585, Ser-589, and Ser-601, which antagonizes CDK1-dependent phosphorylation at Ser-473 and attenuates the association between MYPT1 and PLK1, thereby promoting PLK1 activity. We conclude that under high O-GlcNAc levels, PLK1 is untimely activated, conducive to inopportune centrosome separation and disruption of the cell cycle. We propose that too much O-GlcNAc is equally deleterious as too little O-GlcNAc, and a fine balance between the OGT/OGA duo is indispensable for successful mitotic divisions.

O-GlcNAc: A Sweetheart of the Cell Cycle and DNA Damage Response.

The addition and removal of O-linked N-acetylglucosamine (O-GlcNAc) to and from the Ser and Thr residues of proteins is an emerging post-translational modification. Unlike phosphorylation, which requires a legion of kinases and phosphatases, O-GlcNAc is catalyzed by the sole enzyme in mammals, O-GlcNAc transferase (OGT), and reversed by the sole enzyme, O-GlcNAcase (OGA). With the advent of new technologies, identification of O-GlcNAcylated proteins, followed by pinpointing the modified residues and understanding the underlying molecular function of the modification has become the very heart of the O-GlcNAc biology. O-GlcNAc plays a multifaceted role during the unperturbed cell cycle, including regulating DNA replication, mitosis, and cytokinesis. When the cell cycle is challenged by DNA damage stresses, O-GlcNAc also protects genome integrity via modifying an array of histones, kinases as well as scaffold proteins. Here we will focus on both cell cycle progression and the DNA damage response, summarize what we have learned about the role of O-GlcNAc in these processes and envision a sweeter research future.

[Study on the Mechanism of Laser Paint Removal Based on Emission Spectrum and Composition Analysis].

The mechanism of laser paint removal is studied based on emission spectrum and composition analysis by using laser induced breakdown spectroscopy and X-ray energy spectrum technology. The electron density and electron temperature of the plasma was calculated with the LIBS spectrums with different laser parameters. The morphologies of ablated paint surface were analyzed with a scanning electron microscopy while the changes of paint composition before and after ablation were measured with an X-ray spectrometer. The results show that, the plasma electron density, temperature and ablation area gradually increase with the increasing of incident laser energy. The carbon (C) content in paint decreases from 78.25% to 67.07% after the laser irradiation, indicating the occurrence of the ablation in the process of laser paint removal. By comparing the content of titanium (Ti) elements, C element and aluminum (Al), we found that the paint ablation will be more severe at higher laser energy. This paper is important to in-depth study of laser paint removal mechanism.