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Clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR interference and programmable base editing have transformed the manipulation of eukaryotic genomes for potential therapeutic applications

Hypoxia, which occurs during tumor growth, triggers complex adaptive responses in which peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) plays a critical role in mitochondrial biogenesis and oxidative metabolism. However, how PGC-1α is regulated in response to oxygen availability remains unclear. We demonstrated that lysine demethylase 3A (KDM3A) binds to PGC-1α and demethylates monomethylated lysine (K) 224 of PGC-1α under normoxic conditions. Hypoxic stimulation inhibits KDM3A, which has a high KM of oxygen for its activity, and enhances PGC-1α K224 monomethylation. This modification decreases PGC-1α's activity required for NRF1- and NRF2-dependent transcriptional regulation of TFAM, TFB1M, and TFB2M, resulting in reduced mitochondrial biogenesis. Expression of PGC-1α K224R mutant significantly increases mitochondrial biogenesis, reactive oxygen species (ROS) production, and tumor cell apoptosis under hypoxia and inhibits brain tumor growth in mice. This study revealed that PGC-1α monomethylation, which is dependent on oxygen availability-regulated KDM3A, plays a critical role in the regulation of mitochondrial biogenesis.

During the operation of the High Temperature Gas-cooled Reactor (HTGR), the hot-spot temperature in the reactor core must be lower than the maximum permissible temperature of the fuel elements and the materials of construction, so that the reactor kept safe. However, no fixed temperature-measuring devices can be set in a pebble-bed core. A special spherical temperature-measuring device is adopted to make sure it brings as small impact to the reactor operation as possible. There are several metal wires with different melting points inside. The graphite thermometric balls will be put onto the top of HTR-10 reactor core, and they record and reflect the highest temperature in different positions in the core when flowing in the pebble bed. Before the reactor core temperature-measuring experiment of HTR-10, we must study the heat transfer characteristics of the graphite thermometric sphere to find out the relationship of the melting conditions and the temperature in the reactor core. A 3-D model of the graphite thermometric ball is established, and CFD method is adopted to research and figure out the thermal equilibrium time and temperature difference between the metal wires in the ball and the hot fluid outside the balls. Multiple situations are simulated, and the heat transfer process of the thermometric sphere is comprehensively studied. The heat convection is certified the most important aspect. Thermal equilibrium can be achieved within 19 minutes, far shorter than the period while the spheres flowing through the core. The simulation results can also applied to derive the thermal fluid temperature backward.

Sustainability 10(1), 235 (2018). doi:10.18154/RWTH-2018-222281 special issue: "Special Issue "Nuclear Waste Management and Sustainability of Nuclear Systems" / Guest Editor: Prof. Michael I. Ojovan, Department of Materials, Imperial College London, London; Mr. Zoran Drace, European Union Project for Chernobyl, Ukraine (Director) and International Project on Innovative Nuclear Reactors and Fuel Cycles (INPRO), IAEA (Former Head)", Published by MDPI, Basel

Mineral calcination worldwide accounts for some 5–10% of all anthropogenic carbon dioxide (CO2) emissions per year. Roughly half of the CO2 released results from burning fossil fuels for heat generation, while the other half is a product of the calcination reaction itself. Traditionally, the fuel combustion process and the calcination reaction take place together to enhance heat transfer. Systems have been proposed that separate fuel combustion and calcination to allow for the sequestration of pure CO2 from the calcination reaction for later storage/use and capture of the combustion gases. This work presents a new tube-in-tube helical system for the calcination of minerals that can use different heat transfer fluids (HTFs), employed or foreseen in concentrated solar power (CSP) plants. The system is labeled ‘flameless’ since the HTF can be heated by other means than burning fossil fuels. If CSP or high-temperature nuclear reactors are used, direct CO2 emissions can be divided in half. The technical feasibility of the system has been accessed with a brief parametric study here. The results suggest that the introduced system is technically feasible given the parameters (total heat transfer coefficients, mass- and volume flows, outer tube friction factors, and –Nusselt numbers) that are examined. Further experimental work will be required to better understand the performance of the tube-in-tube helical system for the flameless calcination of minerals.

Tumors override energy stress to grow. However, how nucleotide synthesis is regulated under energy stress is unclear. We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. Knock-in of nonphosphorylatable PRPS1/2 mutants, which have uninhibited activity, in brain tumor cells under energy stress exhausts cellular ATP and NADPH and increases reactive oxygen species levels, thereby promoting cell apoptosis. The expression of those mutants inhibits brain tumor formation and enhances the inhibitory effect of the glycolysis inhibitor 2-deoxy-d-glucose on tumor growth. Our findings highlight the significance of recalibrating tumor cell metabolism by fine-tuning nucleotide and NAD synthesis in tumor growth. Significance: Our findings elucidate an instrumental function of AMPK in direct regulation of nucleic acid and NAD synthesis in tumor cells in response to energy stress. AMPK phosphorylates PRPS1/2, converts PRPS1/2 hexamers to monomers, and inhibits PRPS1/2 activity and subsequent nucleotide and NAD synthesis to maintain tumor cell growth and survival. Cancer Discov; 8(1); 94–107. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1

Phosphofructokinase 1 (PFK1) plays a critical role in glycolysis; however, its role and regulation in tumorigenesis are not well understood. Here, we demonstrate that PFK1 platelet isoform (PFKP) is the predominant PFK1 isoform in human glioblastoma cells and its expression correlates with total PFK activity. We show that PFKP is overexpressed in human glioblastoma specimens due to an increased stability, which is induced by AKT activation resulting from phosphatase and tensin homologue (PTEN) loss and EGFR-dependent PI3K activation. AKT binds to and phosphorylates PFKP at S386, and this phosphorylation inhibits the binding of TRIM21 E3 ligase to PFKP and the subsequent TRIM21-mediated polyubiquitylation and degradation of PFKP. PFKP S386 phosphorylation increases PFKP expression and promotes aerobic glycolysis, cell proliferation, and brain tumor growth. In addition, S386 phosphorylation in human glioblastoma specimens positively correlates with PFKP expression, AKT S473 phosphorylation, and poor prognosis. These findings underscore the potential role and regulation of PFKP in human glioblastoma development., Phosphofructokinase 1 (PFK1) plays a critical role in glycolysis. Here the authors show that PFK1 platelet isoform is upregulated in Glioblastoma and is required for tumor growth mechanistically, such upregulation is due to an increased stability induced by AKT activation via phosphorylation on residue S386.

In the HTR-PM pebble bed reactor heat is produced in a cylindrical core surrounded by a graphite reflector. The helium coolant flowing down through the core first flows up through 30 coolant channels in the reflector, cooling it. Heat is also transferred through the reflector in radial direction to the pressure vessel and other surroundings, which is the main heat loss mechanism during a loss of cooling accident. Usually heat transfer in the reflector region is modelled using a 2D axi-symmetric geometry, modelling the region containing the coolant channels as a homogenized mixture of coolant channel and graphite reflector using a porosity value, sometimes using very course meshes. In reality temperature gradients in azimuthal direction will exist around the coolant channels, possibly affecting both heat transfer to the coolant and heat transfer through the graphite around the coolant channels to the outer boundary. This paper investigates the accuracy of the 2D model by comparing calculations for a fine and course 2D mesh with a 3D mesh in which the coolant channel geometry is explicitly modelled. Two cases were investigated: one representing full power operation, and the other a loss of forced cooling incident with no helium flow through the coolant channels. The course 2D mesh resulted in large errors in the reflector temperature field for full power conditions, overestimating the temperature drop across the coolant channel region. The 2D fine mesh compared reasonably well with the 3D mesh, although it resulted in both an overestimation of the effective heat transfer rate to the coolant channels and an underestimation of the effective resistance to heat transfer in the reflector in the radial direction around the coolant channels. Especially the last can lead to an underestimation of reflector and core temperatures during a loss of coolant accident. To amend this problem, the conductivity of the graphite in the coolant channel region should be adjusted in the 2D porous model to compensate for the added effective resistance to heat transfer in radial direction due to the geometry.

In order to analyze the dynamic operation performance and safety characteristics of the steam cycle high temperature gas cooled reactor (HTR) systems, it is necessary to find the solution of the whole HTR systems with all coupled circuits, including the primary circuit, the secondary circuit, and the residual heat removal system (RHRS). Considering that those circuits have their own individual fluidity and characteristics, some existing code packages for independent circuits themselves have been developed, for example THEMRIX and TINTE code for the primary circuit of the pebble bed reactor, BLAST for once through steam generator. To solve the coupled steam cycle HTR systems, a feasible way is to develop coupling method to integrate these independent code packages. This paper presents several coupling methods, e.g. the equivalent component method between the primary circuit and steam generator which reflect the close coupling relationship, the overlapping domain decomposition method between the primary circuit and the passive RHRS which reflects the loose coupling relationship. Through this way, the whole steam cycle HTR system with multiple circuits can be easily and efficiently solved by integration of several existing code packages. Based on this methodology, a code package TINTE–BLAST–RHRS was developed. Using this code package, some operation performance of HTR–PM was analyzed, such as the start-up process of the plant, and the depressurized loss of forced cooling accident when different number of residual heat removal trains is operated.

Water ingress into the primary circuit is generally recognized as one of the severe accidents with potential hazard to the modular high temperature gas-cooled reactor, which will cause a positive reactivity introduction with the increase of steam density in reactor core to enhance neutron slowing-down, also the chemical corrosion of graphite fuel elements and the damage of reflector structure material. The increase of the primary pressure may result in the opening of the safety valves, consequently leading the release of radioactive isotopes and flammable water gas. The research on water ingress transient is significant for the verification of inherent safety characteristics of high temperature gas-cooled reactor. The 200 MWe high temperature gas-cooled reactor (HTR-PM), designed by the Institute of Nuclear and New Energy Technology of Tsinghua University, is exampled to be analyzed in this paper. The design basis accident (DBA) scenarios of double-ended guillotine break of single heat-exchange tube (steam generator heat-exchange tube rupture) are simulated by the thermal-hydraulic analysis code, and some key concerns which are relative to the amount of water into the reactor core during the blow-down transient are analyzed in detail. The results show that both of water mass and steam ratio of the fluid spouting from the broken heat-exchange tube are affected by break location, which will increase obviously with the broken location closing to the outlet of the heat-exchange tube. The double-ended guillotine rupture at the outlet of the heat-exchange will result more steam penetrates into the reactor core in the design basis accident of water ingress. The mass of water ingress will also be affected by the draining system. It is concluded that, with reasonable optimization on design to balance safety and economy, the total mass of water ingress into the primary circuit of reactor could be limited effectively to meet the safety requirements, and the pollution of radioactive isotopes releasing to the secondary circuit during the blow-down transient will be prevented.

Tumor-specific pyruvate kinase M2 (PKM2) is instrumental in both aerobic glycolysis and gene transcription. PKM2 regulates G1-S phase transition by controlling cyclin D1 expression. However, it is not known whether PKM2 directly controls cell cycle progression. We show here that PKM2, but not PKM1, binds to the spindle checkpoint protein Bub3 during mitosis and phosphorylates Bub3 at Y207. This phosphorylation is required for Bub3-Bub1 complex recruitment to kinetochores, where it interacts with Blinkin and is essential for correct kinetochore-microtubule attachment, mitotic/spindle-assembly checkpoint, accurate chromosome segregation, cell survival and proliferation, and active EGF receptor-induced brain tumorigenesis. In addition, the level of Bub3 Y207 phosphorylation correlated with histone H3-S10 phosphorylation in human glioblastoma specimens and with glioblastoma prognosis. These findings highlight the role of PKM2 as a protein kinase controlling the fidelity of chromosome segregation, cell cycle progression, and tumorigenesis.

The PTEN tumor suppressor is frequently mutated or deleted in cancer and regulates glucose metabolism through the PI3K-AKT pathway. However, whether PTEN directly regulates glycolysis in tumor cells is unclear. We demonstrate here that PTEN directly interacts with phosphoglycerate kinase 1 (PGK1). PGK1 functions not only as a glycolytic enzyme but also as a protein kinase intermolecularly autophosphorylating itself at Y324 for activation. The protein phosphatase activity of PTEN dephosphorylates and inhibits autophosphorylated PGK1, thereby inhibiting glycolysis, ATP production, and brain tumor cell proliferation. In addition, knockin expression of a PGK1 Y324F mutant inhibits brain tumor formation. Analyses of human glioblastoma specimens reveals that PGK1 Y324 phosphorylation levels inversely correlate with PTEN expression status and are positively associated with poor prognosis in glioblastoma patients. This work highlights the instrumental role of PGK1 autophosphorylation in its activation and PTEN protein phosphatase activity in governing glycolysis and tumorigenesis.

To assess the effectiveness of abdominal acupuncture at the endocrine and metabolic level in patients with obesity-type polycystic ovary syndrome (PCOS).Eighty-six women from the First Affiliated Hospital of Guangzhou Medical College with a diagnosis of PCOS (body-mass index [BMI] ≥25 kg/m(2)) were randomly assigned to receive 6 months of abdominal acupuncture (once a day) or oral metformin (250 mg three times daily in the first week, followed by 500 mg three times daily thereafter). BMI, waist-to-hip ratio (WHR), ovarian volume, menstrual frequency, homeostasis model assessment for insulin resistance (HOMA-IR), and Ferriman-Gallwey score were measured at the beginning of the study and after 6 months of treatment. Luteotrophic hormone (LH), testosterone, follicle-stimulating hormone (FSH), fasting blood glucose, 2-hour Postprandial blood glucose, fasting insulin, 2-hour postprandial blood insulin, total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were also assessed.According to the results at baseline and 6 months, BMI, WHR, Ferriman-Gallwey score, ovarian volume, luteotrophic hormone, ratio of luteotrophic hormone to follicle-stimulating hormone, testosterone, LDL-C, triglycerides, total cholesterol, fasting blood glucose, 2-hour postprandial blood glucose, fasting insulin, 2-hour postprandial blood insulin, and HOMA-IR were reduced significantly in the two groups (p0.05). Menstrual frequency and HDL-C (p0.05) increased significantly in both groups; follicle-stimulating hormone also increased in both groups, but the change was not significant (p0.05). The acupuncture group showed considerable advantages over the metformin group in terms of reduced BMI and WHR and increases in menstrual frequency (p0.05).Abdominal acupuncture and metformin improved the endocrine and metabolic function of patients with obesity-type PCOS. Abdominal acupuncture may be more effective in improving menstrual frequency, BMI, and WHR, with few adverse effects.

Protein tyrosine phosphatase (PTP)–proline-, glutamate-, serine-, and threonine-rich sequence (PEST) is ubiquitously expressed and is a critical regulator of cell adhesion and migration. PTP-PEST activity can be regulated transcriptionally via gene deletion or mutation in several types of human cancers or via post-translational modifications, including phosphorylation, oxidation, and caspase-dependent cleavage. PTP-PEST interacts with and dephosphorylates cytoskeletal and focal adhesion-associated proteins. Dephosphorylation of PTP-PEST substrates regulates their enzymatic activities and/or their interaction with other proteins and plays an essential role in the tumor cell migration process.

In thermal hydraulics designing and safety analysis of the High Temperature gas-cooled Reactor-Pebble Bed (HTR-PM), the THERMIX code was used to study the behavior of helium in the primary coolant system. Once the helium leaks out of the primary loop through a break on the pressure boundary or an inadvertent open relief valve, it is difficult to simulate the conditions of the room where the release occurred with THERMIX. In this paper, the latest version of RELAP5/MOD4 was used to simulate the behavior of the helium released to the containment rooms. A RELAP5/MOD4 input deck of the HTR-PM, consisting of the core, the primary coolant system, the secondary loop and the containment, was developed and evaluated in this paper. Based on the model, this paper simulated the accidents consequences of large breaks or small breaks near the inlet or the outlet of the helium circulator located inside the steam generator pressure vessel. The calculating results illustrate that the temperature of the helium flowing into the reactor building through the break was no more than 280°C even after an un-isolating large break. The analysis shows that the systems function to scram the reactor and to monitor the core temperature and pressure after accidents would not be affected by breaks.

Dietary fructose is primarily metabolized in the liver. Here we demonstrated that hepatocellular carcinoma (HCC) cells compared to normal hepatocytes largely reduce fructose metabolism rate and reactive oxygen species level, resulting from c-Myc–dependent and heterogeneous nuclear ribonucleoprotein (hnRNP) H1 and H2-mediadited switch from high-activity fructokinase (KHK)-C to low-activity KHK-A isoform expression. Importantly, KHK-A acts as a protein kinase, phosphorylating and activating phosphoribosyl pyrophosphate synthetase 1 (PRPS1) to promote the pentose phosphate pathway-dependent de novo nucleic acid synthesis and HCC formation. Furthermore, c-Myc, hnRNPH1/2, and KHK-A expression levels and PRPS1 T225 phosphorylation levels correlate with each other in HCC specimens and are associated with poor prognosis for HCC. These findings reveal a pivotal mechanism underlying the distinct fructose metabolism between HCC cells and normal hepatocytes and highlight the instrumental role of KHK-A protein kinase activity in promoting de novo nucleic acid synthesis and HCC development.

In the glycolysis pathway, pyruvate kinase (PK) and phosphoglycerate kinase 1 (PGK1) are the only 2 ATP-generating enzymes. PK is a rate-limiting glycolytic enzyme that catalyzes the conversion of ...

Many types of human tumour cells overexpress the dual-specificity phosphatase Cdc25A. Cdc25A dephosphorylates cyclin-dependent kinase and regulates the cell cycle, but other substrates of Cdc25A and their relevant cellular functions have yet to be identified. We demonstrate here that EGFR activation results in c-Src-mediated Cdc25A phosphorylation at Y59, which interacts with nuclear pyruvate kinase M2 (PKM2). Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2-dependent β-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop. Cdc25A-mediated PKM2 dephosphorylation promotes the Warburg effect, cell proliferation and brain tumorigenesis. In addition, we identify positive correlations among Cdc25A Y59 phosphorylation, Cdc25A and PKM2 in human glioblastoma specimens. Furthermore, levels of Cdc25A Y59 phosphorylation correlate with grades of glioma malignancy and prognosis. These findings reveal an instrumental function of Cdc25A in controlling cell metabolism, which is essential for EGFR-promoted tumorigenesis., Protein phosphatase Cdc25 controls cell cycle transitions by dephosphorylating CDK substrates. Here, the authors show that the Cdc25A isoform regulates glycolysis through dephosphorylation of pyruvate kinase PKM2, resulting in β-catenin activation and consequent upregulation of the transcription of glycolytic genes.

The double-ended guillotine break (DEGB) of the horizontal coaxial gas duct accident is a serious air ingress accident of the high temperature gas-cooled reactor pebble-bed module (HTR-PM). Because the graphite is widely used as the structure material and the fuel element matrix of HTR-PM, the oxidation analyses of this severe air ingress accident have got enough attention in the safety analyses of the HTR-PM. The DEGB of the horizontal coaxial gas duct accident is calculated by using the TINTE code in this paper. The results show that the maximum local oxidation of the matrix graphite of spherical fuel elements in the core will firstly reach3.75⁎104 mol/m3at about 120 h, which means that only the outer 5 mm fuel-free zone of matrix graphite will be oxidized out. Even at 150 h, the maximum local weight loss ratio of the nuclear grade graphite in the bottom reflectors is only 0.26. Besides, there is enough time to carry out some countermeasures to stop the air ingress during several days. Therefore, the nuclear grade graphite of the bottom reflectors will not be fractured in the DEGB of the horizontal coaxial gas duct accident and the integrity of the HTR-PM can be guaranteed.

Pyruvate kinase M2 (PKM2) is upregulated in multiple cancer types and contributes to the Warburg effect by unclear mechanisms. Here we demonstrate that EGFR-activated ERK2 binds directly to PKM2 Ile 429/Leu 431 through the ERK2 docking groove and phosphorylates PKM2 at Ser 37, but does not phosphorylate PKM1. Phosphorylated PKM2 Ser 37 recruits PIN1 for cis-trans isomerization of PKM2, which promotes PKM2 binding to importin α5 and translocating to the nucleus. Nuclear PKM2 acts as a coactivator of β-catenin to induce c-Myc expression, resulting in the upregulation of GLUT1, LDHA and, in a positive feedback loop, PTB-dependent PKM2 expression. Replacement of wild-type PKM2 with a nuclear translocation-deficient mutant (S37A) blocks the EGFR-promoted Warburg effect and brain tumour development in mice. In addition, levels of PKM2 Ser 37 phosphorylation correlate with EGFR and ERK1/2 activity in human glioblastoma specimens. Our findings highlight the importance of nuclear functions of PKM2 in the Warburg effect and tumorigenesis.

We investigate the formation of high-order polarization vortex spatial solitons. The high-order polarization vortex solitons have novel polarization states which are different from fundamental polarization vortex solitons and have rotational symmetry only in intensity. It is proved that the polarization vortex solitons cannot carry vortex phase. The existence domain and dynamical characteristic of these high-order polarization vortex solitons in Bessel optical lattices are discussed in detail.

Air ingress into to the core after the primary circuit depressurization due to large breaks of the pressure boundary is considered as one of the severe hypothetical accidents for the high temperature gas-cooled reactor (HTR). If the air source and the natural convection cannot be impeded, the continuous graphite oxidation reaction along with the formation of burnable gas mixtures resulting in the corrosion of the fuel elements and the reflectors might damage the reactor structure integrity and endanger the reactor safety. In order to study the effects of air flow driven by natural convection as well as to investigate the corrosion of graphite, the NACOK (Naturzug im Core mit Korrosion) facility was built at Julich Research Center in Germany. A complete 2A-rupture of the coaxial duct in the HTR primary system, as well as the chimney effect caused by breaks in both upper and lower parts of the pressure boundary was simulated in the test facility. Several series of experiments and the related code validations (TINTE, DIREKT, THERMIX/REACT, etc.) have been performed on this facility since the 1990s. In this paper, the latest NACOK air ingress experiment, carried out on October 23, 2008 to simulate the chimney effect, was preliminarily analyzed at NRG with the SPECTRA code, as well as at INET, Tsinghua University of China with the TINTE code. The calculating results of air flow rate of natural convection, time-dependent graphite corrosion, and temperature distribution are compared with the NACOK test results. The preliminary code-to-experiment and code-to-code validation successfully proves the code capability to simulate and predict the air-ingress accident. In addition, more research work, including parameter sensitivity analysis, modeling refinement, code amelioration, etc., should be performed to improve the simulation accuracy in the future.

Along with the further ongoing design procedures of a large demonstration power plant of Chinese 200 MWe high temperature gas-cooled reactor pebble-bed module (HTR-PM), three-dimensional (3-D) analysis is necessary for studying the reactor characteristics under some special unsymmetrical conditions. Compared with the well established two-dimensional thermal-hydraulics code THERMIX, a new three-dimensional system analysis code ATTICA3D (Advanced Thermal hydraulics Tool for In-vessel & Core Analysis in 3D), developed by IKE of University of Stuttgart on the basis of TH3D, is used to perform the steady state calculation and transient analysis of a depressurized loss of coolant accident (DLOCA) for the HTR-PM. After a brief introduction of the reactor primary circuit, the above two codes, including correlative typical parameters and relevant formulae are described in detail. Then an ATTICA3D model, which keeps consistent with the THERMIX model as much as possible, is constructed according to the preliminary design of the HTR-PM. Based on the cylindrically symmetrical power distribution, the comparisons of the two-dimensional calculations between ATTICA3D and THERMIX indicate, that the main results including pressure drop and temperature distribution show good agreement. Furthermore, considering one set of small absorber spheres (SAS) dropping into the side reflectors resulting in an asymmetric distribution of the nuclear power, a three-dimensional calculation for the steady state is implemented to basically show the good 3-D simulation capabilities of ATTICA3D, which will be helpful to the next refined design stage for the HTR-PM project. It should be pointed out that the current 3-D simulation results illustrated in this paper are still preliminary, and more research work, e.g., comparison with experimental data or with some commercial CFD codes, needs to be carried out in order to further validate the ATTICA3D code and study the special 3-D characteristics of the HTR-PM in the future.

Protein tyrosine phosphatase (PTP)-PEST is a critical regulator of cell adhesion and migration. However, the mechanism by which PTP-PEST is regulated in response to oncogenic signaling to dephosphorylate its substrates remains unclear. Here, we demonstrate that activated Ras induces extracellular signal-regulated kinase 1 and 2-dependent phosphorylation of PTP-PEST at S571, which recruits PIN1 to bind to PTP-PEST. Isomerization of the phosphorylated PTP-PEST by PIN1 increases the interaction between PTP-PEST and FAK, which leads to the dephosphorylation of FAK Y397 and the promotion of migration, invasion, and metastasis of v-H-Ras-transformed cells. These findings uncover an important mechanism for the regulation of PTP-PEST in activated Ras-induced tumor progression.

It is generally accepted that spermatozoa capacitation is associated with protein kinase A-mediated tyrosine phosphorylation. In our previous study, we identified the fibrous sheath CABYR binding protein (FSCB), which was phosphorylated by PKA. However, the phosphorylation status of FSCB protein during spermatozoa capacitation should be further investigated. To this aim, in this study, we found that phosphorylation of this 270-kDa protein occurred as early as 1 min after mouse spermatozoa capacitation, which increased over time and remained stable after 60 min. Immunoprecipitation assays demonstrated that the tyrosine and Ser/Thr phosphorylation of FSCB occurred during spermatozoa capacitation. The extent of phosphorylation and was closely associated with the PKA activity and spermatozoa motility characteristics. FSCB phosphorylation could be induced by PKA agonist DB-cAMP, but was blocked by PKA antagonist H-89.Therefore, FSCB contributes to spermatozoa capacitation in a tyrosine-phosphorylated format, which may help in further elucidating the molecular mechanism of spermatozoa capacitation.

The embryonic pyruvate kinase M2 (PKM2) isoform is highly expressed in human cancer. In contrast to the established role of PKM2 in aerobic glycolysis or the Warburg effect, its non-metabolic functions remain elusive. Here we demonstrate, in human cancer cells, that epidermal growth factor receptor (EGFR) activation induces translocation of PKM2, but not PKM1, into the nucleus, where K433 of PKM2 binds to c-Src-phosphorylated Y333 of β-catenin. This interaction is required for both proteins to be recruited to the CCND1 promoter, leading to HDAC3 removal from the promoter, histone H3 acetylation and cyclin D1 expression. PKM2-dependent β-catenin transactivation is instrumental in EGFR-promoted tumour cell proliferation and brain tumour development. In addition, positive correlations have been identified between c-Src activity, β-catenin Y333 phosphorylation and PKM2 nuclear accumulation in human glioblastoma specimens. Furthermore, levels of β-catenin phosphorylation and nuclear PKM2 have been correlated with grades of glioma malignancy and prognosis. These findings reveal that EGF induces β-catenin transactivation via a mechanism distinct from that induced by Wnt/Wingless and highlight the essential non-metabolic functions of PKM2 in EGFR-promoted β-catenin transactivation, cell proliferation and tumorigenesis.

DNA replication is initiated by assembly of the kinase cell division cycle 7 (CDC7) with its regulatory activation subunit, activator of S-phase kinase (ASK), to activate DNA helicase. However, the mechanism underlying regulation of CDC7-ASK complex is unclear. Here, we show that ADP generated from CDC7-mediated MCM phosphorylation binds to an allosteric region of CDC7, disrupts CDC7-ASK interaction, and inhibits CDC7-ASK activity in a feedback way. EGFR- and ERK-activated casein kinase 2α (CK2α) phosphorylates nuclear phosphoglycerate kinase (PGK) 1 at S256, resulting in interaction of PGK1 with CDC7. CDC7-bound PGK1 converts ADP to ATP, thereby abrogating the inhibitory effect of ADP on CDC7-ASK activity, promoting the recruitment of DNA helicase to replication origins, DNA replication, cell proliferation, and brain tumorigenesis. These findings reveal an instrumental self-regulatory mechanism of CDC7-ASK activity by its kinase reaction product ADP and a nonglycolytic role for PGK1 in abrogating this negative feedback in promoting tumor development.

Water ingress into the primary circuit is generally recognized as one of the severe accidents with potential hazard to the modular high temperature gas-cooled reactor adopting steam-turbine cycle, which will cause a positive reactivity introduction, as well as the chemical corrosion of graphite fuel elements and reflector structure material. Besides, increase of the primary pressure may result in the opening of the safety valves, consequently leading the release of radioactive isotopes and flammable water gas. The analysis of such a kind of important and particular accident is significant to verify the inherent safety characteristics of the modular HTR plants. Based on the preliminary design of the 200 MWe high temperature gas-cooled reactor pebble-bed modular (HTR-PM), the design basis accident of a double-ended guillotine break of one heating tube and the beyond design basis accident of a large break of the main steam collection plate have been analyzed by using TINTE code, which is a special transient analysis program for high temperature gas-cooled reactors. Some safety relevant concerns, such as the fuel temperature, the primary loop pressure, the graphite corrosion, the water gas releasing amount, as well as the natural convection influence on the condition of failing to close the blower flaps, have been studied in detail. The calculation results indicate that even under some severe hypothetical postulates, the HTR-PM is able to keep the inherent safeties of the modular high temperature gas-cooled reactor and has a relatively good natural plant response, which will not result in environmental radiation hazard.

Summary EGFR activates phosphatidylinositide 3-kinase (PI3K), but the mechanism underlying this activation is not completely understood. We demonstrated here that EGFR activation resulted in lysine acetyltransferase 5 (KAT5)-mediated K395 acetylation of the platelet isoform of phosphofructokinase 1 (PFKP) and subsequent translocation of PFKP to the plasma membrane, where the PFKP was phosphorylated at Y64 by EGFR. Phosphorylated PFKP binds to the N-terminal SH2 domain of p85α, which is distinct from binding of Gab1 to the C-terminal SH2 domain of p85α, and recruited p85α to the plasma membrane resulting in PI3K activation. PI3K-dependent AKT activation results in enhanced phosphofructokinase 2 (PFK2) phosphorylation and production of fructose-2,6-bisphosphate, which in turn promotes PFK1 activation. PFKP Y64 phosphorylation–enhanced PI3K/AKT-dependent PFK1 activation and GLUT1 expression promoted the Warburg effect, tumor cell proliferation, and brain tumorigenesis. These findings underscore the instrumental role of PFKP in PI3K activation and enhanced glycolysis through PI3K/AKT-dependent positive-feedback regulation.

Within the framework of a Coordinated Research Project on Evaluation of High Temperature Gas-Cooled Reactor Performance (CRP-5) initiated by the International Atomic Energy Agency (IAEA), the calculation of steady-state temperature distribution of the 10MW High Temperature Gas-Cooled Reactor-Test Module (HTR-10) under its initial full power experimental operation has been defined as one of the benchmark problems. This paper gives the investigation results obtained by different countries who participate in solving this benchmark problem. The validation works of the THERMIX code used by the Institute of Nuclear and New Energy Technology (INET) are also presented. For the benchmark items defined in this CRP, various calculation results correspond well with each other and basically agree the experimental results. Discrepancies existing among various code results are preliminarily attributed to different methods, models, material properties, and so on used in the computations. Temperatures calculated by THERMI...

Pressurized and Depressurized Loss Of Forced Cooling (PLOFC and DLOFC) are two important design basis accidents for high temperature gas-cooled reactors. Analysis of the reactor characteristic behaviors during LOFC can provide useful reference to the physics, thermohydraulic and structure designs of the reactor core, and can also verify the design of the Residual Heat Removal System (RHRS). The 200 MWe High Temperature gas-cooled Reactor Pebble-bed Module project (HTR-PM), designed by the Institute of Nuclear and New Energy Technology (INET) of Tsinghua University in China, is characterized by its inherent safety features, such as shutdown ability via negative temperature coefficients of reactivity, passive mechanism of decay heat removal and so on. In this paper, two cases of loss of forced cooling accidents have been analyzed by using THERMIX code based on the preliminary design of the HTR-PM. With respect to the DLOFC, the effects of related key parameters on the maximum temperatures of fuel element and the reactor pressure vessel (RPV), as well as the decay heat removal by the RHRS are studied in detail. From the calculation results, it is shown that, in the LOFC accidents, the maximum temperatures of the fuel element and the RPV are below the safety limits and the RHRS can effectively remove the decay heat from the core, so as to keep the reactor in a safe state. As compared with the PLOFC accident, the DLOFC accident will lead to a much higher fuel element temperature but lower RPV temperatures and RHRS heat load. The analyses also illustrate that the decay heat level, the emissivity of RPV and water-cooling panel, and the average temperature of the water-cooling panel, play important roles in the DLOFC accident.

Background Surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS) is a powerful tool to detect biomarkers of many diseases. The purpose of this study is to evaluate SELDI-TOF MS as a potential tool for identifying serological biomarkers of acute myocardial infarction (AMI) at an early stage. Methods Serum samples were collected from rats after they had received left anterior descending coronary artery (LAD) ligation at 5, 15, 30, 60, 120, 240 and 360 min, respectively. These samples, along with serum samples from the sham-operated and uninjured control animals, were processed and analyzed with CM-10 ProteinChip and SELDI-TOF MS. Levels of myocardial creatine kinase isoenzyme MB (CKMB) activity and cardiac troponin I (cTnI) concentration were measured with respective commercial kits. Histological changes were examined after HE staining. Results Three peaks with m / z 7586 Da, 7564 Da and 9583 Da, which were only found in the operated groups, were termed specific peaks. The peaks with m / z 7586 and 7564 Da had the sensitivity of 97.0% and specificity of 97.0% in the ≥15 min operated groups. Four peaks with m / z 4983, 5140, 8075, and 9423 Da were novel tissue unspecific injury related peaks in response to injury. Four peaks with m / z 4400, 4542, 8400 and 7666 Da exhibited more than 2 fold peak height alterations. In contrast, the significant increase of CKMB activity and cTnI concentration in the serum could not be detected until 4 h after the ligation. Conclusions The specific peaks and unspecific injury related peaks detected by SELDI-TOF MS with CM-10 ProteinChip may be used as the biomarkers for early diagnosis of AMI.

BACKGROUND. Early diagnosis of nasopharyngeal carcinoma (NPC) remains a challenge. Serum protein profiling is a promising approach for the classification of cancer versus noncancer samples. The objective of the current study was to assess the feasibility of mass spectrometry-based protein profiling and a classification tree algorithm for discriminating between patients with NPC and noncancer controls. METHODS. Serum samples from patients with NPC and noncancer controls were analyzed by using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). The study was divided into a preliminary training set and a blind test set: A preliminary training set and a classification tree of spectra derived from 55 patients with NPC and a group of 60 noncancer controls were used to develop a proteomic model that discriminated cancer from noncancer effectively. Then, the validity of the classification tree was challenged with a blind test set, which included another 25 patients with NPC and 28 noncancer controls. RESULTS. Four protein peaks at 4097 daltons (Da), 4180 Da, 5912 Da, and 8295 Da were chosen automatically as a biomarker pattern in the training set that discriminated cancer from noncancer with sensitivity of 94.5% and specificity of 96.7%. When the SELDI marker pattern was tested with the blinded test set, it yielded a sensitivity of 92%, a specificity of 92.9%, and an accuracy rate of 92.5%. The accuracy of 2 protein peaks (4581 Da and 7802 Da) was 80% for predicting stage I and II NPC and 86% for predicting stage III and IV NPC. CONCLUSIONS. The high sensitivity and specificity obtained by the serum protein profiling approach demonstrated that SELDI-TOF-MS combined with a tree analysis model both can facilitate discriminating between NPC and noncancer controls and can provide an innovative clinical diagnostic platform to improve the detection of NPC. Cancer 2008. © 2007 American Cancer Society.

A new type of control rod driving system, the hydraulic control rod driving system (HCRDS) with a hole-hole step cylinder, has been applied in the 5-MW nuclear heating reactor of Tsinghua University for several years and has performed well all along. A second-generation HCRDS has been developed based on operational experience, and further improvements are being carried out. This paper focuses on the first-generation HCRDS, analyzing in detail its working performance in an unstable state. The control rod stability after minute perturbation and the operation of the control rod in an incline state have been theoretically calculated. The study proves the self-lock design characteristic of the system. The calculated results also indicate that the control rod step-up, step-down, and scram operations function properly. The theoretical analysis proves the HCRDS reliable and safe, establishing a baseline for further research and development for wide use in portable seawater distillation systems.

This paper discusses the behavior of the hydraulic control rod driving system (HCRDS) in cyclical swing. The first generation HCRDS with the hole–hole step cylinder, the important driving component, has been applied in 5 MW nuclear heating reactor for several years and run well all along. The second generation with the chamfer-hole step cylinder has also been developed and studied. The HCRDS working principle, as well as the particular design of the hole–hole step cylinder, has been introduced in the paper. The control rod (CR) behavior when HCDRS vacillating in certain swing and cycle has been analyzed subsequently. The calculating result indicates that the CR can keep its balance in such unstable state and the operation of driving CR upwards or downwards can function properly likewise. In cyclical swing, the CR can drop down quickly and meet the reactor shut-down needs. The theoretical analysis proves the HCRDS reliable and safe, establishing basement for its further research and wide use.

As a representative fluoroquinolone antibacterial, ciprofloxacin is frequently used to treat infections caused by bacteria such as E. coli. It is much meaningful to explore ciprofloxacin susceptibility and investigate a possible mechanism of drug susceptibility changes in E. coli ATCC25922 exposed to the environmental stress of simulated microgravity. The subculture of E. coli lasted for 7 days under simulated microgravity conditions (SMG) and normal microgravity (NG) conditions. On the 8th day, the cultures were divided into three groups: (1) NG group (continuous NG cultures); (2) SMG group (continuous SMG cultures); (3) SMCNG group (simulated microgravity change into normal gravity cultures). Ciprofloxacin (a final concentration of 0.125 μg/ml) sensitivity and expression of acrAB-tolC genes were detected in E. coli cells. The count and percentage of viable cells in the SMG cultures bacteria exposed to ciprofloxacin were higher than that in NG cultures and reduced to the levels of NG group when they were subcultivated from SMG to NG. The expressions of efflux pump genes (acrA, acrB and tolC) were upregulated in SMG culture and downregulated to the levels of NG group when they were subcultivated from SMG to NG. Susceptibility to ciprofloxacin and expression of acrAB-tolC genes in E. coli could be reversibly affected by SMG conditions. Over expression of efflux pump genes acrAB-tolC perhaps played an important role in decreased CIP susceptibility under SMG.

To investigate specific proteins in ultraviolet (UV)-induced acute damage of human fibroblasts using proteinchip with surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS).CM10 Proteinchip and SELDI-TOF-MS were used for detecting protein samples of non-irradiated group, UVA (2.5 J/cm(2))-irradiated group and UVB (100 mJ/cm(2))-irradiated group of normal human fibroblasts.Ten protein peaks were down-regulated and 8 protein peaks up-regulated in fibroblasts after UV irradiation. By searching in SWISS-PROT and TrEMBLE databases, the peaks of 11 320.1 and 8 574.3 accorded with those of caspase-7 precursor and cytochrome C oxidase polypeptide VIc precursor proteins.As a quick and convenient high-throughout proteomic analytic method, SELDI-TOF-MS plus proteinchip offers a unique platform for detecting dermal photodamage.

Directional cell motility is essential for normal development and physiology, although how motile cells spatiotemporally activate signaling events remains largely unknown. Here, we have characterized an adhesion and signaling unit comprised of protein tyrosine phosphatase (PTP)-PEST and the extracellular matrix (ECM) adhesion receptor β8 integrin that plays essential roles in directional cell motility. β8 integrin and PTP-PEST form protein complexes at the leading edge of migrating cells and balance patterns of Rac1 and Cdc42 signaling by controlling the subcellular localization and phosphorylation status of Rho GDP dissociation inhibitor 1 (RhoGDI1). Translocation of Src-phosphorylated RhoGDI1 to the cell's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin-bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1/Cdc42 in the cytoplasm. Collectively, these data reveal a finely tuned regulatory mechanism for controlling signaling events at the leading edge of directionally migrating cells.

Cholangiocarcinoma (CCA) is a common biliary malignancy. Despite continuing advances, novel indicators are urgently needed to identify patients with a poor prognosis. Several microRNAs (miRNAs) have been reported to be dysregulated in CCA tissues. The purpose of the current study was to explore the potential use of certain miRNAs as serum indicators. A total of 157 individuals, including103 CCA patients, were recruited into this study. We first used qRT-PCR to evaluate 5 CCA-related miRNAs in the serum of 95 individuals to identify significantly deregulated miRNAs. A logistic regression was used to analyse the potential variables influencing lymph node metastasis. Cox proportional hazards regression models were applied to determine the association between possible prognostic variables and overall survival (OS). We observed that decreased serum miR-106a confers a higher likelihood of lymph node metastasis [hazard ratio (HR) 18.3, 95% confidence interval (CI) 5.9–56.4, p p p

This study explores the roles of Bax and other Bcl-2 family members play in arsenic trioxide (As(2)O(3))-induced apoptosis. We showed that As(2)O(3) treatment triggered Bax conformational change and subsequent translocation from cytosol to mitochondria to form various multimeric homo-oligomers in IM-9 cells. On the other hand, human leukemic Jurkat cells deficient in Bax showed dramatically reduced apoptosis in response to As(2)O(3). Stable overexpression of Bcl-2 in IM-9 cells (IM-9/Bcl-2) inhibited As(2)O(3)-mediated Bax activation and apoptosis, and this inhibition could be partially averted by cell-permeable Bid-Bcl-2 homology (BH)3 peptide. Meanwhile, Bax conformational change and oligomerization induced by As(2)O(3) were not inhibited by the pancaspase inhibitor z-VAD-fmk, although Bid cleavage could be completely abolished. Bax activation by As(2)O(3) seemed to require stress-induced intracellular reactive oxygen species (ROS), since the ROS scavengers (N-acetyl-L-cysteine and lipoic acid) could completely block the conformational change and translocation of Bax from cytosol to mitochondria. These data suggest that As(2)O(3) might exert the cell killing in part by inducing Bax activation through a Bcl-2-suppressible pathway in hematopoietic cells that is caspase independent and intracellular ROS regulated.

A simplified mathematical model was developed for the Hydraulic Control Rod Driving System (HCRDS) of a 200 MW nuclear heating reactor, which incorporated the design of its chamfer-hole step cylinder, to analyze its seismic response characteristics. The control rod motion was analyzed for different sine-wave vibration loadings on platform vibrator. The vibration frequency domain and the minimum acceleration amplitude of the control rod needed to cause the control rod to step to its next setting were compared with the design acceleration amplitude spectrum. The system design was found to be safety within the calculated limits. The safety margin increased with increasing frequency.

Nature 480, 118–122 (2011); doi:10.1038/nature10598 In the Methods section of this Letter, the description of immunohistochemical (IHC) analysis did not clearly describe the scoring system we used. To avoid confusion, the assignment of proportion scores should have been described as follows: “0 if 0% of the tumour cells showed positive staining, 0.1–1.0 if 0.1% to 1% of cells were stained, 1.1–2.0 if 1.1% to 10% stained, 2.1–3.0 if 11% to 30% stained, 3.1–4.0 if 31% to 70% stained, and 4.1–5.0 if 71% to 100% stained. (Each percentage range of the stained tumour section is further divided into ten smaller percentage ranges and represented by corresponding non-integral scores, such as 3.1 representing 31%–34%). We rated the intensity of staining on a scale of 0 to 3: 0, negative; 1, weak; 2, moderate; and 3, strong.

Overcoming metabolic stress is a critical step in tumor growth. Acetyl coenzyme A (acetyl-CoA) generated from glucose and acetate uptake is important for histone acetylation and gene expression. However, how acetyl-CoA is produced under nutritional stress is unclear. We demonstrate here that glucose deprivation results in AMP-activated protein kinase (AMPK)-mediated acetyl-CoA synthetase 2 (ACSS2) phosphorylation at S659, which exposed the nuclear localization signal of ACSS2 for importin α5 binding and nuclear translocation. In the nucleus, ACSS2 binds to transcription factor EB and translocates to lysosomal and autophagy gene promoter regions, where ACSS2 incorporates acetate generated from histone acetylation turnover to locally produce acetyl-CoA for histone H3 acetylation in these regions and promote lysosomal biogenesis, autophagy, cell survival, and brain tumorigenesis. In addition, ACSS2 S659 phosphorylation positively correlates with AMPK activity in glioma specimens and grades of glioma malignancy. These results underscore the significance of nuclear ACSS2-mediated histone acetylation in maintaining cell homeostasis and tumor development.

Autophagy is crucial for maintaining cell homeostasis. However, the precise mechanism underlying autophagy initiation remains to be defined. Here, we demonstrate that glutamine deprivation and hypoxia result in inhibition of mTOR-mediated acetyl-transferase ARD1 S228 phosphorylation, leading to ARD1-dependent phosphoglycerate kinase 1 (PGK1) K388 acetylation and subsequent PGK1-mediated Beclin1 S30 phosphorylation. This phosphorylation enhances ATG14L-associated class III phosphatidylinositol 3-kinase VPS34 activity by increasing the binding of phosphatidylinositol to VPS34. ARD1-dependent PGK1 acetylation and PGK1-mediated Beclin1 S30 phosphorylation are required for glutamine deprivation- and hypoxia-induced autophagy and brain tumorigenesis. Furthermore, PGK1 K388 acetylation levels correlate with Beclin1 S30 phosphorylation levels and poor prognosis in glioblastoma patients. Our study unearths an important mechanism underlying cellular-stress-induced autophagy initiation in which the protein kinase activity of the metabolic enzyme PGK1 plays an instrumental role and reveals the significance of the mutual regulation of autophagy and cell metabolism in maintaining cell homeostasis.

To study the influence of hypergravity exposure after 30-days simulated weightlessness on the expression of chemokine CCL20 and its receptor CCR6 in lingual mucosa of rhesus macaque.Twenty-three male rhesus monkeys were divided according to the random number method into one control group (A, n = 3) and three experimental groups, including the weightlessness group (B, n = 3), the hypergravity group (C, n = 3) and hypergravity exposure after 30-days simulated weightlessness group (D, n = 14), which was further divided into four subgroups according to the values of overload as: +11 Gx/270s group (D1, n = 3), +13 Gx/230s group (D2, n = 4) and +15 Gx/200s group (D3, n = 4) and +13 Gx/230s with 9-days recovery group (D4, n = 3). Histopathological changes of lingual mucosa were observed by hematoxylin-eosin staining and the expressions of CCL20 and CCR6 were detected by immunohistochemistry (IHC) and quantitative real-time PCR (Q-PCR).Histological observation showed that no significant histopathological changes were found in the lingual mucosa in all experimental groups of the animals, however, there were more infiltrated lymphocyte and neutrophils in the experimental groups. The immunohistochemical scores of CCL20 in group C, group D2 and group D3 were 1.30 ± 0.11, 1.68 ± 0.62 and 2.26 ± 1.00, respectively, significantly higher than that in A group (0.47 ± 0.12, P0.05). The immunohistochemical scores of CCR6 expression in those three groups were 4.40 ± 1.48, 6.67 ± 2.04 and 7.02 ± 2.11, respectively, also remarkably higher than that in A group (1.33 ± 0.66, P0.05). As far as the mRNA expression was concerned, the expressions of CCL20 and CCR6 had similar change trend with their protein expressions.Hypergravity exposure after 30-days simulated weightlessness will not lead to significant pathological changes in lingual mucosa, but can induce the expression of chemokine CCL20 and its receptor CCR6.

Pyruvate kinase M2 (PKM2) is expressed at high levels during embryonic development and tumor progression and is important for cell growth. However, it is not known whether it directly controls cell division. Here, we found that Aurora B phosphorylates PKM2, but not PKM1, at T45; this phosphorylation is required for PKM2's localization and interaction with myosin light chain 2 (MLC2) in the contractile ring region of mitotic cells during cytokinesis. PKM2 phosphorylates MLC2 at Y118, which primes the binding of ROCK2 to MLC2 and subsequent ROCK2-dependent MLC2 S15 phosphorylation. PKM2-regulated MLC2 phosphorylation, which is greatly enhanced by EGF stimulation or EGFRvIII, K-Ras G12V, and B-Raf V600E mutant expression, plays a pivotal role in cytokinesis, cell proliferation, and brain tumor development. These findings underscore the instrumental function of PKM2 in oncogenic EGFR-, K-Ras-, and B-Raf-regulated cytokinesis and tumorigenesis.

Activation of epidermal growth factor receptor (EGFR), which occurs in many types of tumour, promotes tumour progression1,2. However, no extracellular antagonist of human EGFR has been identified. We found that human macrophage migration inhibitory factor (MIF) is O-GlcNAcylated at Ser 112/Thr 113 at its carboxy terminus. The naturally secreted and O-GlcNAcylated MIF binds to EGFR, thereby inhibiting the binding of EGF to EGFR and EGF-induced EGFR activation, phosphorylation of ERK and c-Jun, cell invasion, proliferation and brain tumour formation. Activation of EGFR through mutation or its ligand binding enhances the secretion of MMP13, which degrades extracellular MIF, and results in abrogation of the negative regulation of MIF on EGFR. The finding that EGFR activation downregulates its antagonist in the tumour microenvironment represents an important feedforward mechanism for human tumour cells to enhance EGFR signalling and promote tumorigenesis.

Pebble bed modular high temperature gas-cooled reactors (HTR), due to their characteristics of low power density, slender structure, large thermal inertia of fuel elements and reactor component materials (graphite), have good inherent safety features. However, the reflectors consisting of large piles of graphite blocks will form huge numbers of certain bypass gaps in the radial, axial and circumferential directions, thus affecting the effective cooling flow into the reactor core, which is one of the concerned issues of HTRs. According to the preliminary design of the Chinese high temperature gas-cooled reactor pebble-bed modular (HTR-PM), the thermal-hydraulic calculation model is established in this paper. Based on this model, considering different bypass flow, that is to say, different core cooling flow, fuel element temperature, outlet helium temperature and the core pressure drop in the normal operation, as well as the maximal fuel temperature during the depressurized loss of forced cooling (DLOFC) accident are analyzed. This study on bypass effects on the steady-state and transient phases can further demonstrate the HTR safety features.

The 10 MW High Temperature Gas-cooled Reactor-Test Module (HTR-10), which was designed, constructed and operated by the Institute of Nuclear and New Energy Technology (INET) of Tsinghua University, is the first High Temperature Gas-cooled Reactor (HTGR) in China. Stepping into the commissioning phase in April, 2000, the HTR-10 attained the first criticality in December, 2000 and achieved its full power operation in January, 2003. Up to now, the HTR-10 has been successfully operated for more than ten years with different power levels. During the relatively long period of commissioning and operation, various kinds of tests were carried out on this reactor. Within the scope of this paper, the commissioning stage, the operation history and the test implementation of the HTR-10 are briefly summarized. At this stage, the HTR-10 is the only pebble bed HTGR under operation in the world, so the measured data from this reactor are extremely valuable for verifying the inherent safety features incorporated in small modular HTGRs as well as for testing the computer programs employed in the HTGR design process. With the purpose of ensuring the code credibility, validation work using the HTR-10 operation and test data has been performed for several years in INET. What is more, these data were partly shared with different countries through some collaborative research projects related to code development and assessment. In this paper, progress of the HTR-10 measured data utilization is reviewed. Meanwhile, existing problems observed from the code-to-test as well as code-to-code comparisons are pointed out. In addition, possible reasons of such problems are discussed in detail.

Water ingress accident is one of the most severe accidents which must be analyzed in high temperature gas-cooled reactor pebble-bed modular (HTR-PM). The droplet could enter the primary circuit under the design basis accident of a double-ended guillotine break of a heat transfer tube. This paper simulates the behavior of single droplet evaporation and movement in the steam generator by numerical methods. Based on the structure characteristics of steam generator, the life time of droplet and the distance that the single droplet could move have been analyzed. The important parameters such as the droplet diameter, helium temperature, helium pressure and helium velocity which have an influence on the behavior of droplet evaporation and movement have also been discussed in detail. The preliminary numerical simulation results indicate that the droplet diameter, helium velocity and helium temperature play an important role in the life time of droplet in the accident situation in the primary circuit. Helium pressure has a little effect on droplet evaporation in practical situation. The numerical simulation results demonstrate that only certain droplets with a diameter in certain range could arrive to the bottom of the steam generator pressure vessel (SGPV) and enter into the steam generator annular channel after collision with the bottom of the SGPV. The distance that the single droplet could move in the primary circuit is decided by a various complex factors such as the structure of the primary circuit, the droplet diameter and helium velocity. The preliminary analyses indicate that there is little probability for the single droplet to enter into the reactor core of the HTR-PM.