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Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in working-age populations. Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase that demethylates RNAs involved in energy homeostasis, though its influence on DR is not well studied. Herein, we detected elevated FTO expression in vitreous fibrovascular membranes of patients with proliferative DR. FTO promoted cell cycle progression and tip cell formation of endothelial cells (ECs) to facilitate angiogenesis in vitro, in mice, and in zebrafish. FTO also regulated EC-pericyte crosstalk to trigger diabetic microvascular leakage, and mediated EC–microglia interactions to induce retinal inflammation and neurodegeneration in vivo and in vitro. Mechanistically, FTO affected EC features via modulating CDK2 mRNA stability in an m6A-YTHDF2-dependent manner. FTO up-regulation under diabetic conditions was driven by lactate-mediated histone lactylation. FB23-2, an inhibitor to FTO's m6A demethylase activity, suppressed angiogenic phenotypes in vitro. To allow for systemic administration, we developed a nanoplatform encapsulating FB23-2 and confirmed its targeting and therapeutic efficiency in mice. Collectively, our study demonstrates that FTO is important for EC function and retinal homeostasis in DR, and warrants further investigation as a therapeutic target for DR patients. Synopsis: The fat mass and obesity-associated (FTO) protein, an N6-methyladenosine (m6A) demethylase, influences endothelial cell (EC) function and retinal homeostasis in diabetic retinopathy (DR), thus providing a promising nanotherapeutic approach for DR. FTO expression is elevated in diabetic mice retinas and vitreous fibrovascular membranes of patients with proliferative DR. FTO triggers diabetes-induced microvascular dysfunction by facilitating neovascularization and regulating EC–pericyte/microglia crosstalk. FTO regulates CDK2 mRNA stability with the YTHDF2 reader in an m6A-dependent manner. Lactic acid regulates FTO expression via histone lactylation. FB23-2 suppresses demethylation activity of FTO to inhibit diabetes-induced EC phenotypes, showing therapeutic potential in DR in mice. The fat mass and obesity-associated (FTO) protein, an N6-methyladenosine (m6A) demethylase, influences endothelial cell (EC) function and retinal homeostasis in diabetic retinopathy (DR), thus providing a promising nanotherapeutic approach for DR. [ABSTRACT FROM AUTHOR]

Objective: Despite the increasing number of genes associated with Charcot–Marie‐Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal dominant mutations in aminoacyl‐tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding seryl‐tRNA synthetase 1 (SerRS) for 3 families affected with CMT. Methods: Whole‐exome sequencing was performed in 16 patients and 14 unaffected members of 3 unrelated families. The functional impact of the genetic variants identified was investigated using bioinformatic prediction tools and confirmed using cellular and biochemical assays. Results: Combined linkage analysis for the 3 families revealed significant linkage (Zmax LOD = 6.9) between the genomic co‐ordinates on chromosome 1: 108681600–110300504. Within the linkage region, heterozygous SerRS missense variants segregated with the clinical phenotype in the 3 families. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation. Interpretation: Our findings suggest the heterozygous SerRS variants identified represent a novel cause for autosomal dominant CMT. Mutant SerRS proteins are known to impact various molecular and cellular functions. Our findings provide significant advances on the current understanding of the molecular mechanisms associated with ARS‐related CMT. ANN NEUROL 2023;93:244–256 [ABSTRACT FROM AUTHOR]

Background: The diagnostic criteria for Parkinson's disease (PD) remain complex, which is especially problematic for nonmovement disorder experts. A test is required to establish a diagnosis of PD with improved accuracy and reproducibility. Objective: The study aimed to investigate the sensitivity and specificity of tests using sniffer dogs to diagnose PD. Methods: A prospective, diagnostic case‐control study was conducted in four tertiary medical centers in China to evaluate the accuracy of sniffer dogs to distinguish between 109 clinically established medicated patients with PD, 654 subjects without PD, 37 drug‐naïve patients with PD, and 185 non‐PD controls. The primary outcomes were sensitivity and specificity of sniffer dog's identification. Results: In the study with patients who were medicated, when two or all three sniffer dogs yielded positive detection results in a sample tested, the index test sensitivity, specificity, and positive and negative likelihood ratios were 91% (95% CI: 84%–96%), 95% (95% CI: 93%–97%), and 19.16 (95% CI: 13.52–27.16) and 0.10 (95% CI: 0.05–0.17), respectively. The corresponding sensitivity, specificity, and positive and negative likelihood ratios in patients who were drug‐naïve were 89% (95% CI: 75%–96%), 86% (95% CI: 81%–91%), and 6.6 (95% CI: 4.51–9.66) and 0.13 (95% CI: 0.05–0.32), respectively. Conclusions: Tests using sniffer dogs may be a useful, noninvasive, fast, and cost‐effective method to identify patients with PD in community screening and health prevention checkups as well as in neurological practice. © 2022 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The study aimed at exploring how the presence of sodium chloride and freeze–thaw cycles influence the quality of frozen cooked noodles. The results showed that the multiple freeze–thaw cycles worsened both the textural characteristics and the post‐re‐heating overall sensory quality of frozen cooked noodles, but the addition of modified potato flour combined with sodium chloride in wheat flour alleviated this deterioration. In addition, the negative effects of freeze–thaw cycles on textural characteristics, cooking loss, and water absorption of frozen cooked noodles were reduced under the addition of 1.0%–1.5% sodium chloride, but then improved considerably with >1.5% sodium chloride addition. The results indicated that partial substitution of wheat flour by potato flour combined with the addition of a proper amount of sodium chloride could alleviate the damage caused by the generation of ice crystals during the freeze–thaw cycles and improve the quality properties of the frozen cooked noodles. Novelty impact statement: The present investigation revealed a significant effect of partial substitution of wheat flour with potato flour on qualities of frozen cooked noodles. Further, the addition of 1.0%–1.5% sodium chloride combined with potato flour presented a beneficial effect on the quality properties of the frozen cooked noodles. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the pro-apoptotic effects of polysaccharides derived from Lentinus edodes and further elucidated the mechanisms of this action. Our results demonstrated that marked morphological changes of apoptosis were observed after treatment of L. edodes polysaccharides [Lentinan (LTN)]. Moreover, LTN-induced cell apoptosis was characterized by a rapid stimulation of reactive oxygen species production, the loss of mitochondrial membrane potential and an increase in intracellular concentration of Ca(2+) . In addition, the results of the haematoxylin and eosin and TUNEL assay further confirmed that LTN-induced apoptosis in vivo. Furthermore, flow cytometry analysis showed that LTN could arrest the cell cycle at G2/M phase, and immunofluorescence showed LTN caused disruption of microtubule. These results suggest that disruption of cellular microtubule network, arrest of the cell cycle at G2/M phase and induction of apoptosis may be one of the possible mechanisms of anti-tumour effect of LTN. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the pro-apoptotic effects of polysaccharides derived from Lentinus edodes and further elucidated the mechanisms of this action. Our results demonstrated that marked morphological changes of apoptosis were observed after treatment of L. edodes polysaccharides [Lentinan (LTN)]. Moreover, LTN-induced cell apoptosis was characterized by a rapid stimulation of reactive oxygen species production, the loss of mitochondrial membrane potential and an increase in intracellular concentration of Ca2+. In addition, the results of the haematoxylin and eosin and TUNEL assay further confirmed that LTN-induced apoptosis in vivo. Furthermore, flow cytometry analysis showed that LTN could arrest the cell cycle at G2/M phase, and immunofluorescence showed LTN caused disruption of microtubule. These results suggest that disruption of cellular microtubule network, arrest of the cell cycle at G2/M phase and induction of apoptosis may be one of the possible mechanisms of anti-tumour effect of LTN. [ABSTRACT FROM AUTHOR]

Recently, extensive researches on estimating the value of e have been studied. In this paper, the structural characteristics of I. Schur type inequalities are exploited to generalize the corresponding inequalities by variable parameter techniques. Some novel upper and lower bounds for the I. Schur inequality have also been obtained and the upper bounds may be obtained with the help of Maple and automated proving package (Bottema). Numerical examples are employed to demonstrate the reliability of the approximation of these new upper and lower bounds, which improve some known results in the recent literature. [ABSTRACT FROM AUTHOR]

Metabasites within the Paleozoic volcanic-clastic sedimentary sequences in Hainan Island, South China, show large differences not only in the nature of protoliths, but also in zircon U-Pb sensitive high mass-resolution ion microprobe (SHRIMP) ages. The protoliths for the Tunchang area metabasites have intraoceanic arc geochemical affinities. In the east-central island gabbroic to diabasic rocks and pillow lavas are also present, while the Bangxi area metabasites with back-arc geochemical affinities in the northwest island consist of basaltic, gabbroic and/or picritic rocks. Three types of zircon domains/crystals in the Tunchang area metabasites are defined. Type 1 is comagmatic and yields concordant to approximately concordant 206 Pb/238 U ages ranging from 442.1 ± 13.7 Ma to 514.3 ± 30.2 Ma with a weighted U-Pb mean age of 445 ± 10 Ma. Type 2 is inherited and yields a weighted 207 Pb/206 Pb mean age of 2488.1 ± 8.3 Ma. Type 3 is magmatic with a 207 Pb/206 Pb age of ca 1450 Ma. Magmatic zircons in the Bangxi area metabasites yield a weighted U-Pb mean age of 269 ± 4 Ma. We suggest 450 Ma is the minimum age for crystallization of protoliths of the Tunchang area metabasites, because the age range of ca 440–514 Ma probably corresponds to both the time of igneous crystallization and the high-temperature overprint. The presence of abundant inherited zircons strongly favors derivation of these rocks from a NMORB-like mantle proximal to continental crust. A protolith age of ca 270 Ma for the Bangxi area metabasites probably records expansion of an epircontinental back-arc basin and subsequent generation of a small oceanic basin. The presence of ophiolitic rocks with an age of ca 450 Ma, not only in Hainan Island, but also in the Yangtze block, highlights the fact that the South China Caledonian Orogeny was not intracontinental in nature, but characterized by an ocean-related event. [ABSTRACT FROM AUTHOR]