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Isocitrate dehydrogenase (IDH) mutations are common genetic alterations in myeloid disorders, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Epigenetic changes, including abnormal histone and DNA methylation, have been implicated in the pathogenic build-up of hematopoietic progenitors, but it is still unclear whether and how IDH mutations themselves affect hematopoiesis. Here, we show that IDH1-mutant mice develop myeloid dysplasia in that these animals exhibit anemia, ineffective erythropoiesis, and increased immature progenitors and erythroblasts. In erythroid cells of these mice, D-2-hydroxyglutarate, an aberrant metabolite produced by the mutant IDH1 enzyme, inhibits oxoglutarate dehydrogenase activity and diminishes succinyl–coenzyme A (CoA) production. This succinyl-CoA deficiency attenuates heme biosynthesis in IDH1-mutant hematopoietic cells, thus blocking erythroid differentiation at the late erythroblast stage and the erythroid commitment of hematopoietic stem cells, while the exogenous succinyl-CoA or 5-ALA rescues erythropoiesis in IDH1-mutant erythroid cells. Heme deficiency also impairs heme oxygenase-1 expression, which reduces levels of important heme catabolites such as biliverdin and bilirubin. These deficits result in accumulation of excessive reactive oxygen species that induce the cell death of IDH1-mutant erythroid cells. Our results clearly show the essential role of IDH1 in normal erythropoiesis and describe how its mutation leads to myeloid disorders. These data thus have important implications for the devising of new treatments for IDH-mutant tumors.

With the deepening of technology, unmanned driving has developed rapidly, and road detection is one of the key points. At present, the recognition accuracy and reasoning speed of lane line detection technology are mature, but there is a problem that large computing resources are required for reasoning, and it is not easy to deploy to low-cost mobile devices. Therefore, this paper proposes to use the DeepLabV3+ network model of semantic segmentation to detect lane lines, train the model with its own data set, and then export it as a pb file, and then convert it to the intermediate representation IR file of OpenVINO through Intel’s Model Optimizer, using Intel’s CPU Perform model reasoning. The final result shows that there is no difference in the accuracy of reasoning with Intel CPU after optimization, and the reasoning time is greatly shortened. The cost can be greatly reduced while getting better recognition results.

Isocitrate dehydrogenase (IDH) mutation is the most important initiating event in gliomagenesis, and the increasing evidence shows that IDH mutation is associated with the metabolic reprogramming in the tumor. Dysregulated cholesterol metabolism is a hallmark of tumor cells, but the cholesterol homeostasis in IDH-mutated glioma is still unknown. In this study, we found that astrocyte-specific mutant IDH1(R132H) knockin reduced the cholesterol contents and damaged the structure of myelin in mouse brains. In U87 and U251 cells, the expression of mutant IDH1 consistently reduced the cholesterol levels. Furthermore, we found that IDH1 mutation enhanced the production of 24(S)-hydroxycholesterol (24-OHC), which is not only the metabolite of cholesterol elimination, but also functions as an endogenous ligand for the liver X receptors (LXRs). In IDH1-mutant glioma cells, the elevated 24-OHC activated LXRs, which consequently accelerated the low-density lipoprotein receptor (LDLR) degradation by upregulating the inducible degrader of the LDLR (IDOL). The reduced LDLR expressions in IDH1-mutant glioma cells abated the uptakes of low-density lipoprotein (LDL) to decrease the cholesterol influx. In addition, the activated LXRs also promoted the cholesterol efflux by elevating the ATP-binding cassette transporter A1 (ABCA1), ABCG1, and apolipoprotein E (ApoE) in both IDH1-mutant astrocytes and glioma cells. As a feedback, the reduced cholesterol levels stimulated the cholesterol biosynthesis, which made IDH1-mutated glioma cells more sensitive to atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase. The altered cholesterol homeostasis regulated by mutant IDH provides a pivotal therapeutical strategy for the IDH-mutated gliomas.

Isocitrate dehydrogenase (IDH) mutations occur frequently in lower-grade gliomas, which result in genome-wide epigenetic alterations. The wild-type IDH1 is reported to participate in lipid biosynthesis and amino acid metabolism, but its role in tumorigenesis is still unclear. In this study, the expressions of IDH1 and podoplanin (Pdpn) were determined in IDH-mutated and IDH-wild-type gliomas, and their relationships in glioma were further analyzed. In addition, the regulation of wild-type IDH1 and mutant IDH1 on Pdpn expression was investigated by luciferase assays and promoter methylation analysis. Our study showed that Pdpn was almost undetectable in IDH-mutated glioma but strongly expressed in higher-grade IDH-wild-type glioma. Pdpn overexpression promoted the migration of glioma cells but had little effect on cell growth. Moreover, Pdpn expression was positively correlated with the increased wild-type IDH1 levels in IDH-wild-type glioma. Consistently, the wild-type IDH1 greatly promoted the transcription and expression of Pdpn, but the mutant IDH1 and D-2-hydroxyglutarate significantly suppressed Pdpn expression in glioma cells. Besides, our results revealed that the methylation of CpG islands in the Pdpn promoter was opposingly regulated by wild-type and mutant IDH1 in glioma. Collectively, our results indicated that wild-type and mutant IDH1 opposingly controlled the Pdpn expression in glioma by regulating its promoter methylation, which provides a basis for understanding the relationship between wild-type and mutant IDH1 in epigenetic regulation and tumorigenesis.

NMDA receptors (NMDARs) are crucial for excitatory synaptic transmission and synaptic plasticity. The number and subunit composition of synaptic NMDARs are tightly controlled by neuronal activity and sensory experience, but the molecular mechanism mediating NMDAR trafficking remains poorly understood. Here, we report that RIM1, with a well-established role in presynaptic vesicle release, also localizes postsynaptically in the mouse hippocampus. Postsynaptic RIM1 in hippocampal CA1 region is required for basal NMDAR-, but not AMPA receptor (AMPAR)-, mediated synaptic responses, and contributes to synaptic plasticity and hippocampus-dependent memory. Moreover, RIM1 levels in hippocampal neurons influence both the constitutive and regulated NMDAR trafficking, without affecting constitutive AMPAR trafficking. We further demonstrate that RIM1 binds to Rab11 via its N terminus, and knockdown of RIM1 impairs membrane insertion of Rab11-positive recycling endosomes containing NMDARs. Together, these results identify a RIM1-dependent mechanism critical for modulating synaptic function by facilitating membrane delivery of recycling NMDARs., Rab3-interacting molecules (RIMs) are a key component of the presynaptic active zone that regulate neurotransmitter release. Here, the authors show that RIM1 also has postsynaptic function to organize NMDA receptors and synaptic response.

Background The homeostasis of lipid droplets (LDs) plays a crucial role in maintaining the physical metabolic processes in cells, and is regulated by many LD-associated proteins, including perilipin 5 (Plin5) in liver. As the putative sites of hepatitis C virus (HCV) virion assembly, LDs are vital to viral infection. In addition, the hepatic LD metabolism can be disturbed by non-structural HCV proteins, such as NS5A, but the details are still inexplicit. Methods HCV NS5A was overexpressed in the livers and hepatocytes of wild-type and Plin5-null mice. BODIPY 493/503 and oil red O staining were used to detect the lipid content in mouse livers and hepatocytes. The levels of lipids, lipid peroxidation and inflammation biomarkers were further determined. Immunofluorescence assay and co-immunoprecipitation assay were performed to investigate the relationship of Plin5 and NS5A. Results One week after adenovirus injection, livers expressing NS5A showed more inflammatory cell aggregation and more severe hepatic injuries in Plin5-null mice than in control mice, which was consistent with the increased serum levels of IL-2 and TNF-α (P

The failures of safety-critical software may result in the serious loss of property and life, thus software reliability has become very demanding. As an important quantitative approach for estimating and predicting software reliability, software reliability prediction technique is significantly useful for improving and ensuring software quality and testing efficiency. A novel software reliability prediction method based on general regression neural network (GRNN) is proposed, which makes it feasible that without constructing a statistical model like classic software reliability models and having difficulties of solving multivariate likelihood equations, this method can be used to predict software failures. It also incorporates test coverage which has increased prediction accuracy. By using probability plot technique and the least square fitting, the probability distribution functions of the original failure data can be determined. And large amount of data can be simulated to make the reliable prediction, which provides a way for solving the inaccuracy problem caused by small size sample of test failure data. A case study has also been done in a real failure data set. The results show that the proposed method can reflect the relationships among the time, test coverage and number of the faults. And it can improve the prediction accuracy.

Single mode fibers with an inner cladding of depressed index can be designed to have low absorption, scattering and splicing loss. Dual -shape core fibers with a depressed -index inner cladding maintain these desirable features and in addition can be insensitive with respect to macro- and microbending while allowing wider tolerances for critical design parameters. Triple -clad fibers can be produced economically with an inner claddingof only a few MCVD layers and a one -layer intermediate cladding of depressed index which prevents outercladding loss to add to the transmission loss and, despite a large mode size for low splicing loss, renders thisfiber insensitive with respect to micro- and macrobending.Such triple -clad fibers can also be designed to have zeroes of the dispersion coefficient at two or eventhree wavelengths. The core -index for these dispersion- flattened fibers is only 0.25% larger and the index of theintermediate cladding only 0.2% smaller than the index of the inner and outer cladding. The core radius needsto stay only within ±2.5% and the core index difference only within ±5% of the design values, for the dispersioncoefficient to deviate less than 3.5 ps /(nm km) from its flattened characteristic.