Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), are present in most gliomas and secondary glioblastomas, but are rare in other neoplasms. IDH1/2 mutations are heterozygous, and affect a single arginine residue. Recently, IDH1 mutations were identified in 8% of acute myelogenous leukemia (AML) patients. A glioma study revealed that IDH1 mutations cause a gain-of-function, resulting in the production and accumulation of 2-hydroxyglutarate (2-HG). Genotyping of 145 AML biopsies identified 11 IDH1 R132 mutant samples. Liquid chromatography-mass spectrometry metabolite screening revealed increased 2-HG levels in IDH1 R132 mutant cells and sera, and uncovered two IDH2 R172K mutations. IDH1/2 mutations were associated with normal karyotypes. Recombinant IDH1 R132C and IDH2 R172K proteins catalyze the novel nicotinamide adenine dinucleotide phosphate (NADPH)–dependent reduction of α-ketoglutarate (α-KG) to 2-HG. The IDH1 R132C mutation commonly found in AML reduces the affinity for isocitrate, and increases the affinity for NADPH and α-KG. This prevents the oxidative decarboxylation of isocitrate to α-KG, and facilitates the conversion of α-KG to 2-HG. IDH1/2 mutations confer an enzymatic gain of function that dramatically increases 2-HG in AML. This provides an explanation for the heterozygous acquisition of these mutations during tumorigenesis. 2-HG is a tractable metabolic biomarker of mutant IDH1/2 enzyme activity

Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. PKM2 interaction with phosphotyrosine-containing proteins inhibits enzyme activity and increases availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small molecule PKM2 activators inhibit growth of xenograft tumors. Structural studies reveal that small molecule activators bind PKM2 at the subunit interaction interface, a site distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small molecule activation of PKM2 can interfere with anabolic metabolism

Experimental investigation of AC two-channel gliding arcs discharge plasma driven kerosene cracking

To improve the ignition and combustion performance of aviation kerosene, two-channel gliding arcs plasma was adopted to crack kerosene into active components, such as gaseous light hydrocarbons and H2. The influence of carrier gas flow rate on discharge characteristics and cracking effects were investigated. Experimental results indicate that, compared to single channel discharge, the power of two-channel gliding arcs discharge is greater while the arcs cover twice as much area as that of single channel discharge. The cracking rate of two-channel discharge plasma is greater than that of single channel discharge while it shows an upward trend with greater carrier gas flow rate. Among the main components of cracking gas, the molar percentage of hydrogen is the highest and exceeds 50%. Greater carrier gas flow rate would result in lower molar percentage of hydrogen. Interestingly, the ethyl group prefers to form C2H2 as the carrier gas flow rate increases in the two-channel gliding arcs discharge while the molar percentage of C2H2 and C2H4 changes inconspicuously in the single channel discharge

Time-Varying Wear Calculation Method for Fractal Rough Surfaces of Friction Pairs

For the wear problem of the real rough surface during sliding friction, based on fractal theory and Hertz contact theory, a 3-D fractal rough surface with random characteristics is constructed, and the relationship between the wear deformation depth of the rough peak and its real contact area during the wear process is derived. Furthermore, considering the peak wear and pit scratch phenomena of rough surfaces in different contact states, the time-varying wear calculation model of the worn surface and the compensation wear calculation model of the unworn surface are established, respectively, and the relationship between the instantaneous wear amount and the dynamic change in the rough surface topography is comprehensively characterized. Combined with image digitization technology, the 3-D rough surface is converted into a 2-D discrete plane with 3-D information. According to the dynamic real-time update of the graph data, the iterative calculation of the wear cycle is completed, the time-varying wear calculation method for fractal rough surfaces of friction pairs is proposed, and the dynamic change in the wear amount and surface topography of the rough surface is simulated. The simulation results are experimentally verified and the influence of friction parameters on the surface topography is analyzed. The results show that after the wear simulation, the profile height of the rough surface is reduced, and the average wear depth is 0.02 mm. Increases in rotational speeds and external loads can exacerbate surface wear, surface topography tends to be flattened, and surface carrying capacity increases. This provides theoretical guidance for the development and manufacture of friction pairs

The Characteristics of Gliding Arc Plasma and Its Activating Effect for Ramjet Combustion

In order to improve the combustion performance of a ramjet under low temperature and pressure, a gliding arc plasma actuator was designed based on a typical evaporation flameholder. The discharge characteristics, as well as the activating effect of single-channel and three-channel gliding arc plasma under different carrier gas flow rates, were studied. Results show that with the increase in the carrier gas flow rate, the average duration of the gliding arc discharge becomes shorter, while the average power increases, and the specific input energy decreases. Compared with single-channel discharge, three-channel discharge has higher discharge power and energy injection rate, which makes a bigger actuated space. Through gliding arc plasma, the kerosene is cracked and H2, CH4, C2H2, C2H4, C3H6 and other small molecule components are produced. For three-channel gliding arc discharge, the effective cracking rate and the production rate of each component are higher than those of the single-channel discharge; both of them gradually increase with the increase in the carrier gas flow rate. The experiment results indicate that three-channel gliding arc plasma can effectively widen the ignition boundary and improve the combustion efficiency of ramjet combustion. The ignition pressure boundary is expanded from 60 kPa to 50 kPa under 390 K; the combustion efficiency is increased from 76% to 82%

The Characteristics of Gliding Arc Plasma and Its Activating Effect for Ramjet Combustion

In order to improve the combustion performance of a ramjet under low temperature and pressure, a gliding arc plasma actuator was designed based on a typical evaporation flameholder. The discharge characteristics, as well as the activating effect of single-channel and three-channel gliding arc plasma under different carrier gas flow rates, were studied. Results show that with the increase in the carrier gas flow rate, the average duration of the gliding arc discharge becomes shorter, while the average power increases, and the specific input energy decreases. Compared with single-channel discharge, three-channel discharge has higher discharge power and energy injection rate, which makes a bigger actuated space. Through gliding arc plasma, the kerosene is cracked and H2, CH4, C2H2, C2H4, C3H6 and other small molecule components are produced. For three-channel gliding arc discharge, the effective cracking rate and the production rate of each component are higher than those of the single-channel discharge; both of them gradually increase with the increase in the carrier gas flow rate. The experiment results indicate that three-channel gliding arc plasma can effectively widen the ignition boundary and improve the combustion efficiency of ramjet combustion. The ignition pressure boundary is expanded from 60 kPa to 50 kPa under 390 K; the combustion efficiency is increased from 76% to 82%

Prenatal diagnosis of mosaic chromosomal aneuploidy and uniparental disomy and clinical outcomes evaluation of four fetuses

Abstract Background Few co-occurrence cases of mosaic aneuploidy and uniparental disomy (UPD) chromosomes have been reported in prenatal periods. It is a big challenge for us to predict fetal clinical outcomes with these chromosome abnormalities because of their highly heterogeneous clinical manifestations and limited phenotype attainable by ultrasound. Methods Amniotic fluid samples were collected from four cases. Karyotype, chromosome microarray analysis, short tandem repeats, and whole exome sequencing were adopted to analyze fetal chromosomal aneuploidy, UPD, and gene variation. Meanwhile, CNVseq analysis proceeded for cultured and uncultured amniocytes in case 2 and case 4 and MS-MLPA for chr11 and chr15 in case 3. Results All four fetuses showed mosaic chromosomal aneuploidy and UPD simultaneously. The results were: Case 1: T2(7%) and UPD(2)mat(12%). Case 2: T15(60%) and UPD(15)mat(40%). Case 3: 45,X(13%) and genome-wide paternal UPD(20%). Case 4:  90% UPD(20)mat in uncultured amniocyte. By analyzing their formation mechanism of mosaic chromosomal aneuploidy and UPD, at least two adverse genetic events happened during their meiosis and mitosis. The fetus of case 1 presented a benign with a normal intrauterine phenotype, consistent with a low proportion of trisomy cells. However, the other three fetuses had adverse pregnancy outcomes, resulting from the UPD chromosomes with imprinted regions involved or a higher level of mosaic aneuploidy. Conclusion UPD is often present with mosaic aneuploidy. It is necessary to analyze them simultaneously using a whole battery of analyses for these cases when their chromosomes with imprinted regions are involved or known carriers of a recessive allele. Fetal clinical outcomes were related to the affected chromosomes aneuploidy and UPD, mosaic levels and tissues, methylation status, and homozygous variation of recessive genes on the UPD chromosome. Genetic counseling for pregnant women with such fetuses is crucial to make informed choices