Ogt Deficiency Induces Abnormal Cerebellar Function and Behavioral Deficits of Adult Mice through Modulating RhoA/ROCK Signaling.

Previous studies have shown the essential roles of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in neuronal development, function and neurologic diseases. However, the function of Ogt and O-GlcNAcylation in the adult cerebellum has not been well elucidated. Here, we have found that cerebellum has the highest level of O-GlcNAcylation relative to cortex and hippocampus of adult male mice. Specific deletion of Ogt in granule neuron precursors (GNPs) induces abnormal morphology and decreased size of the cerebellum in adult male Ogt deficient [conditional knock-out (cKO)] mice. Adult male cKO mice show the reduced density and aberrant distribution of cerebellar granule cells (CGCs), the disrupted arrangement of Bergman glia (BG) and Purkinje cells. In addition, adult male cKO mice exhibit aberrant synaptic connection, impaired motor coordination, and learning and memory abilities. Mechanistically, we have identified G-protein subunit α12 (Gα12) is modified by Ogt-mediated O-GlcNAcylation. O-GlcNAcylation of Gα12 facilitates its binding to Rho guanine nucleotide exchange factor 12 (Arhgef12) and consequently activates RhoA/ROCK signaling. RhoA/ROCK pathway activator LPA can rescue the developmental deficits of Ogt deficient CGCs. Therefore, our study has revealed the critical function and related mechanisms of Ogt and O-GlcNAcylation in the cerebellum of adult male mice.SIGNIFICANCE STATEMENT Cerebellar function are regulated by diverse mechanisms. To unveil novel mechanisms is critical for understanding the cerebellar function and the clinical therapy of cerebellum-related diseases. In the present study, we have shown that O-GlcNAc transferase gene (Ogt) deletion induces abnormal cerebellar morphology, synaptic connection, and behavioral deficits of adult male mice. Mechanistically, Ogt catalyzes O-GlcNAcylation of Gα12, which promotes the binding to Arhgef12, and regulates RhoA/ROCK signaling pathway. Our study has uncovered the important roles of Ogt and O-GlcNAcylation in regulating cerebellar function and cerebellum-related behavior. Our results suggest that Ogt and O-GlcNAcylation could be potential targets for some cerebellum-related diseases.

Clinical manifestations in a Chinese girl with heterozygous de novo NAA10 variant c. 247C > T, p. (Arg83Cys): a case report.

The NAA10 gene encodes the catalytic subunit of the N-terminal acetyltransferase protein complex A (NatA), which is supposed to acetylate approximately 40% of the human proteins. After the advent of next-generation sequencing, more variants in the NAA10 gene and Ogden syndrome (OMIM# 300855) have been reported. Individuals with NAA10-related syndrome have a wide spectrum of clinical manifestations and the genotype-phenotype correlation is still far from being confirmed. Here, we report a three years old Chinese girl carrying a heterozygous de novo NAA10 [NM_003491: c. 247C > T, p. (Arg83Cys)] variant (dbSNP# rs387906701) (ClinVar# 208664) (OMIM# 300013.0010). The proband not only has some mild and common clinical manifestations, including dysmorphic features, developmental delay, obstructive hypertrophic cardiomyopathy, and arrhythmia, but also shows some rare clinical features such as exophthalmos, blue sclera, cutaneous capillary malformations, and adenoid hypertrophy. Our attempt is to expand the clinical phenotype associated with NAA10-related syndrome and explore genotype-phenotype correlation with such syndrome.

Association between postoperative hypoalbuminemia and postoperative pulmonary imaging abnormalities patients undergoing craniotomy for brain tumors: a retrospective cohort study.

Hypoalbuminemia is associated with poor outcome in patients undergoing surgery intervention. The main aim for this study was to investigate the incidence and the risk factors of postoperative hypoalbuminemia and assessed the impact of postoperative hypoalbuminemia on complications in patients undergoing brain tumor surgery. This retrospective study included 372 consecutive patients who underwent brain tumors surgery from January 2017 to December 2019. The patients were divided into hypoalbuminemia (< 35 g/L) and non-hypoalbuminemia group (≥ 35 g/L) based on postoperative albumin levels. Logistic regression analyses were used to determine risk factors. Of the total 372 patients, 333 (89.5%) developed hypoalbuminemia after surgery. Hypoalbuminemia was associated with operation time (OR 1.011, P < 0.001), preoperative albumin (OR 0.864, P = 0.015) and peroperative globulin (OR 1.192, P = 0.004). Postoperative pulmonary imaging abnormalities had a higher incidence in patients with than without hypoalbuminemia (41.1% vs 23.1%, P = 0.029). The independent predictors of postoperative pulmonary imaging abnormalities were age (OR 1.053, P < 0.001), operation time (OR 1.003, P = 0.013) and lower postoperative albumin (OR 0.946, P = 0.018). Pulmonary imaging abnormalities [OR 19.862 (95% CI 2.546-154.936, P = 0.004)] was a novel independent predictors of postoperative pneumonia. Postoperative hypoalbuminemia has a higher incidence with the increase of operation time, and may be associated with postoperative complications in patients undergoing brain tumor surgery.

Biomimetic Nanoscale Erythrocyte Delivery System for Enhancing Chemotherapy via Overcoming Biological Barriers.

Overcoming multiple biological barriers, including circulation time in vivo, tumor vascular endothelium, reticuloendothelial system (RES), extracellular matrix (ECM), etc., is the key to improve the therapeutic efficacy of drug delivery systems in treating tumors. Inspired by the ability of natural erythrocytes to cross multiple barriers, in this study, a biomimetic delivery system named NE@DOX-Ang2 was developed for enhancing the chemotherapy of breast cancer, which employed nano-erythrocyte (NE) encapsulating doxorubicin (DOX) and surface modification with a targeted angiopep-2 peptide (Ang2). NE@DOX-Ang2 enhanced the capacity to cross biological barriers in a three-dimensional (3D) tumor spheroid model and in vivo in mice. Compared with a conventional drug delivery system of liposomes, the half-life of NE@DOX-Ang2 increased approximately 2.5 times. Moreover, NE@DOX-Ang2 exhibited excellent tumor-targeting ability and antitumor effects in vitro and in vivo. Briefly, the prepared nano-erythrocyte drug carrier has features of favorable biocompatibility and low immunogenicity and the advantage of prolonging the half-life of drugs, which may provide a novel perspective for development of clinically available nanomedicines.

Regulatory roles and mechanisms of alternative RNA splicing in adipogenesis and human metabolic health.

Alternative splicing (AS) regulates gene expression patterns at the post-transcriptional level and generates a striking expansion of coding capacities of genomes and cellular protein diversity. RNA splicing could undergo modulation and close interaction with genetic and epigenetic machinery. Notably, during the adipogenesis processes of white, brown and beige adipocytes, AS tightly interplays with the differentiation gene program networks. Here, we integrate the available findings on specific splicing events and distinct functions of different splicing regulators as examples to highlight the directive biological contribution of AS mechanism in adipogenesis and adipocyte biology. Furthermore, accumulating evidence has suggested that mutations and/or altered expression in splicing regulators and aberrant splicing alterations in the obesity-associated genes are often linked to humans' diet-induced obesity and metabolic dysregulation phenotypes. Therefore, significant attempts have been finally made to overview novel detailed discussion on the prospects of splicing machinery with obesity and metabolic disorders to supply featured potential management mechanisms in clinical applicability for obesity treatment strategies.

White matter repair and treatment strategy after intracerebral hemorrhage.

The predilection site of intracerebral hemorrhage (ICH) is in the basal ganglia, which is rich in white matter (WM) fiber bundles, such as cerebrospinal tract in the internal capsule. ICH induced damage to this area can easily lead to severe neurological dysfunction and affects the prognosis and quality of life of patients. At present, the pathophysiological mechanisms of white matter injury (WMI) after ICH have attracted researchers' attention, but studies on the repair and recovery mechanisms and therapy strategies remain rare. In this review, we mainly summarized the WM recovery and treatment strategies after ICH by updating the WMI-related content by reviewing the latest researches and proposing the bottleneck of the current research.