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Observation of high energy and very high emission from Gamma Ray Bursts (GRBs) is crucial to study the gigantic explosion and the underline processes. With a large field-of-view and almost full duty cycle, the Water Cherenkov Detector Array (WCDA), a sub-array of the Large High Altitude Air Shower Observatory (LHAASO), is appropriate to monitor the very high energy emission from unpredictable transients such as GRBs. Nevertheless, the main issue for an extensive air shower array is the high energy threshold which limits the horizon of the detector. To address this issue a new trigger method is developed in this article to lower the energy threshold of WCDA for GRB observation. The proposed method significantly improves the detection efficiency of WCDA for gamma-rays around the GRB direction at 10-300 GeV. The sensitivity of the WCDA for GRB detection with the new trigger method is estimated. The achieved sensitivity of the quarter WCDA array above 10 GeV is comparable with that of Fermi-LAT. The data analysis process and corresponding fluence upper limit for GRB 190719C is presented as an example.

The main scientific goal of LHAASO-WCDA is to survey gamma-ray sources with energy from 100 GeV to 30 TeV. To observe high-energy shower events, especially to measure the energy spectrum of cosmic rays from 100 TeV to 10 PeV, a dynamic range extension system (WCDA++) is designed to use a 1.5-inch PMT with a dynamic range of four orders of magnitude for each cell in WCDA-1. The dynamic range is extended by using these PMTs to measure the effective charge density in the core region of air shower events, which is an important parameter for identifying the composition of primary particles. The system has been running for more than one year. In this paper, the details of the design and performance of WCDA++ are presented.

The extension of the cosmic-ray spectrum beyond 1 petaelectronvolt (PeV; 1015 electronvolts) indicates the existence of the so-called PeVatrons—cosmic-ray factories that accelerate particles to PeV energies. We need to locate and identify such objects to find the origin of Galactic cosmic rays1. The principal signature of both electron and proton PeVatrons is ultrahigh-energy (exceeding 100 TeV) γ radiation. Evidence of the presence of a proton PeVatron has been found in the Galactic Centre, according to the detection of a hard-spectrum radiation extending to 0.04 PeV (ref. 2). Although γ-rays with energies slightly higher than 0.1 PeV have been reported from a few objects in the Galactic plane3–6, unbiased identification and in-depth exploration of PeVatrons requires detection of γ-rays with energies well above 0.1 PeV. Here we report the detection of more than 530 photons at energies above 100 teraelectronvolts and up to 1.4 PeV from 12 ultrahigh-energy γ-ray sources with a statistical significance greater than seven standard deviations. Despite having several potential counterparts in their proximity, including pulsar wind nebulae, supernova remnants and star-forming regions, the PeVatrons responsible for the ultrahigh-energy γ-rays have not yet been firmly localized and identified (except for the Crab Nebula), leaving open the origin of these extreme accelerators. Observations of γ-rays with energies up to 1.4 PeV find that 12 sources in the Galaxy are PeVatrons, one of which is the Crab Nebula.

In this paper, an initial pressure adjustable explosion vessel was developed, and the effect of negative pressure, positive pressure (0.2–1.8 atm) different initial ambient pressure on the explosive shock wave generated by the explosion of explosives was studied. The relationships between the specific impulse, shock wave velocity, the amount of explosive gas products and the ambient pressure were analyzed for different initial pressure environments. It was found that: the overpressure of the blast shock wave decreases with the initial ambient pressure of the explosion, and there exists a negative pressure environment with a dramatic pressure decrease near 0.6 atm, defined as the super-sensitive negative pressure Pcr. The propagation velocity of an explosive wave increases with a decrease in the ambient pressure, and the propagation velocity at a pressure of 1.8 atm is four times less than the velocity at a pressure of 0.2 atm. The production of explosive gas products did not change. The greater the initial pressure of the environment where the explosive is located, the smaller the ratio of the gas generated by the explosion to the initial force gas in the explosion vessel is, and the greater the impact on the propagation of shock waves is. The maximum attenuation of the first specific impulse i1 is 72.97% and the maximum attenuation of the second specific impulse i2 is 72.39%. The experiments provide reference data for high-altitude military confrontation, high-altitude weapons and ammunition development, and deep-earth protection engineering.

A topological meron features a non-coplanar structure, whose order parameters in the core region are perpendicular to those near the perimeter. A meron is half of a skyrmion, and both have potential applications for information carrying and storage. Although merons and skyrmions in ferromagnetic materials can be readily obtained via inter-spin interactions, their behaviour and even existence in ferroelectric materials are still elusive. Here we observe using electron microscopy not only the atomic morphology of merons with a topological charge of 1/2, but also a periodic meron lattice in ultrathin PbTiO3 films under tensile epitaxial strain on a SmScO3 substrate. Phase-field simulations rationalize the formation of merons for which an epitaxial strain, as a single alterable parameter, plays a critical role in the coupling of lattice and charge. This study suggests that by engineering strain at the nanoscale it should be possible to fabricate topological polar textures, which in turn could facilitate the development of nanoscale ferroelectric devices. Merons are topological structures, but these have yet to be directly observed in ferroelectrics. Here, by epitaxially straining PbTiO3 on a SmScO3 substrate, electron microscopy and phase-field modelling allow the morphology and distribution of merons to be observed.

Eight dissociation constants of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis (methylene phosphonic acid) (DOTMP, H8L) were determined for the first time by potentiometric titration in water using the CHEMEQUI program. The stability constants of Ga3+ complexes with deprotonated forms of DOTMP were determined. The stability constant of the Ga3+ complex with the fully deprotonated DOTMP ligand, lg KML equal to 27.8, is higher than the corresponding constant for the Ga3+ complex with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), the ligand most widely used in radiopharmacy; it is also higher than the constant for the Ga3+ complex with plasma protein transferrin, which makes the DOTMP ligand very promising for the use in radiopharmacy.

In this study, which is a continuation of our earlier work, the effect of double-atom vacancy defects (DAVD) on the elastic properties of single-layered graphene sheets (SLGS)-polymer nanocomposites is assessed by the multiscale modeling. According to the latter approach, the polymer matrix is modeled by finite element approach, while the SLGS and interphase layer are simulated at the atomistic scale by the molecular structural mechanics approach. In view of the Lennard–Jones potential concept, it is assumed that the SLGS and polymer matrix are related by van der Waals reciprocity. The fact that the elastic modulus of a polymer with 5% volume fraction of SLGS is increased by 17 times is demonstrated by numerous simulation results. It is also shown that the elastic modulus of SLGS-polymer nanocomposites with DAVDs is deteriorated with an increase in the number of DAVDs and improved with the increased volume fraction of SLGS.

A molecular structural mechanics approach is used to study the effect of double-atom vacancy defects (DAVD) on the elastic properties of zigzag and armchair single-layered graphene sheets (SLGS). To this end, the space frame structure is also adopted to model the interatomic forces of the C–C bonds. The numerical simulation results obtained via the finite element method strongly suggest that double-atom vacancy defects reduce the elastic module of SLGS, which effect weakens with graphene size. Finally, the elastic modulus and Poisson’s ratio of SLGS are found to decrease with the number of DAVDs.

Texture, mechanical anisotropy and microstructure of aged Al–Zn–Mg, Al–Zn–Mg–0.1Sc–0.1Zr and Al–Zn–Mg–0.25Sc–0.1Zr (wt.%) alloy sheets were investigated by tensile tests and electron microscopy. Sc and Zr additions do not change the texture of homogenized and cold rolled alloys, but transfer the cube texture of the aged Al–Zn–Mg alloy into β-fiber rolling texture. With increasing Sc and Zr additions, the strength significantly increases, and mechanical anisotropy is enhanced. The strength is highest parallel to the rolling direction, whereas it is lowest at a 45° angle to the rolling direction. The higher strength is mainly due to grain boundary strengthening and precipitation strengthening caused by Al3ScxZr1-x nano-particles. The stronger mechanical anisotropy is ascribed to the rolling texture, due to the inhibitory effect of Al3ScxZr1–x on recrystallization. A new model was successfully established to reveal the interrelation between Sc and Zr additions, texture and yield strength anisotropy of Al–Zn–Mg sheets.

Based on the principle of hot stamping, a simulation model of hot stamping is proposed. The blank contour line of U-shaped part is optimized by using a multiple iterative algorithm. By comparison of the simulated and experimental data, the multiple iterative optimization algorithm is verified. Moreover, the blank contour lines of a bumper and the B-pillar of Numisheet 2008 were optimized. The results obtained indicate that the multiple iterative method for optimizing the initial blank contour line has high calculating speed and accuracy. The hot stamping part contour lines match the ideal part contour lines quite well.

The welding of thick high strength aluminum alloy plate was exceedingly difficult. Traditional arc welding was prone to softening the welded joints and involves multilayer; meanwhile, multi-pass welding may cause great residual welding stress, and deformation resulted in dampening the wide expansion of the welding structure of thick high strength aluminum alloy plates. Therefore, it was urgent to develop advanced materials and welding technologies to enhance the comprehensive mechanical properties of welded joints. Fiber laser boasted the advantages such as perfect monochromaticity and high quality light beam. In order to decrease the thermal loss of the welding heat source on the matrix, small power fiber laser and super narrow gap groove were applied for the effective welding of the 20-mm thick 7A52 aluminum alloy. The welding adopted multilayer and single pass welding with the groove width no wider than 4 mm. The weld was composed of four layers and the size was no wider than 4.5 mm, which was basically consistent with the widths of the whole. The parent metal was welded with 5183 alloy and 5E06 alloy. Fiber optical microscope, scanning electron microscope (SEM), transmission electron microscope (TEM), and tensile testing machine were employed to investigate the influence of Er-Zr microalloying aluminum alloy welding wires upon the microstructure and mechanical properties of the welded joints.

Although elastic strains, particularly inhomogeneous strains, are able to tune, enhance or create novel properties of some nanoscale functional materials, potential devices dominated by inhomogeneous strains have not been achieved so far. Here we report a fabrication of inhomogeneous strains with a linear gradient as giant as 106 per metre, featuring an extremely lower elastic energy cost compared with a uniformly strained state. The present strain gradient, resulting from the disclinations in the BiFeO3 nanostructures array grown on LaAlO3 substrates via a high deposition flux, induces a polarization of several microcoulomb per square centimetre. It leads to a large built-in electric field of several megavoltage per metre, and gives rise to a large enhancement of solar absorption. Our results indicate that it is possible to build up large-scale strain-dominated nanostructures with exotic properties, which in turn could be useful in the development of novel devices for electromechanical and photoelectric applications., Inherent elastic strains are useful to tune the physical properties of functional materials but it is difficult to build. Here, Tang et al. report a fabrication of inhomogeneous strains with a linear gradient as giant as 106 per meter in a BiFeO3 nanostructure array grown on a LaAlO3 substrate.

A series of ambient self-crosslinkable acrylic resin/protein composite emulsions (PA–Ps) were prepared by copolymerizing the functional monomer acetyl acetylethyl methacrylate (AAEM) with methyl acrylate, butyl acrylate and acrylic acid, and then protein crosslinking agents such as gelatin and casein were also added. The PA–P films were characterized by Fourier transform IR spectroscopy, contact angles, differential scanning calorimeter, thermogravimetric analysis, antisolvent testing and physicomechanical testing. Influences of AAEM and protein dosages on properties of composite films were examined in detail. The results indicate that influences of AAEM and protein on PA–P films are diverse on solvent resistance, physicomechanical properties and thermal properties. With enhancement of AAEM and protein dosages, hardness, solvent resistance to tetrahydrofuran and glass transition temperature (Tg) of PA–P films are markedly enhanced, but the decomposing temperatures (Td) are decreased. Tensile strengths are evidently reinforced while elongations at break are lessened. Suitable AAEM and protein dosages could render PA–P films with good water resistance.

DNA damage activates nuclear Abl tyrosine kinase to stimulate intrinsic apoptosis in cancer cell lines and mouse embryonic stem cells. To examine the in vivo function of nuclear Abl in apoptosis, we generated Abl-μNLS (μ, mutated in nuclear localization signals) mice. We show here that cisplatin-induced apoptosis is defective in the renal proximal tubule cells (RPTC) from the Ablμ/μmice. When injected with cisplatin, we found similar levels of platinum in the Abl+/+and the Ablμ/μkidneys, as well as similar initial inductions of p53 and PUMAα expression. However, the accumulation of p53 and PUMAα could not be sustained in the Ablμ/μkidneys, leading to reductions in renal apoptosis and tubule damage. Co-treatment of cisplatin with the Abl kinase inhibitor, imatinib, reduced the accumulation of p53 and PUMAα in the Abl+/+but not in the Ablμ/μkidneys. The residual apoptosis in the Ablμ/μmice was not further reduced in the Ablμ/μ; p53-/-double-mutant mice, suggesting that nuclear Abl and p53 are epistatic to each other in this apoptosis response. Although apoptosis and tubule damage were reduced, cisplatin-induced increases in phospho-Stat-1 and blood urea nitrogen were similar between the Abl+/+and the Ablμ/μkidneys, indicating that RPTC apoptosis is not the only factor in cisplatin-induced nephrotoxicity. These results provide in vivo evidence for the pro-apoptotic function of Abl, and show that its nuclear localization and tyrosine kinase activity are both required for the sustained expression of p53 and PUMAα in cisplatin-induced renal apoptosis. © 2013 Macmillan Publishers Limited.

Cytoplasmic STAT3, after activation by growth factors, translocates to different subcellular compartments, including nuclei and mitochondria, where it carries out different biological functions. However, the precise mechanism by which STAT3 undergoes mitochondrial translocation and subsequently regulates the tricarboxylic acid (TCA) cycle-electron transport chain (ETC) remains poorly understood. Here, we clarify this process by visualizing STAT3 acetylation in starved cells after serum reintroduction or insulin stimulation. CBP-acetylated STAT3 undergoes mitochondrial translocation in response to serum introduction or insulin stimulation. In mitochondria, STAT3 associates with the pyruvate dehydrogenase complex E1 (PDC-E1) and subsequently accelerates the conversion of pyruvate to acetyl-CoA, elevates the mitochondrial membrane potential, and promotes ATP synthesis. SIRT5 deacetylates STAT3, thereby inhibiting its function in mitochondrial pyruvate metabolism. In the A549 lung cancer cell line, constitutively acetylated STAT3 localizes to mitochondria, where it maintains the mitochondrial membrane potential and ATP synthesis in an active state.

About 10% of people infected with Mycobacterium tuberculosis develop active tuberculosis (TB), and Th1 effector cells and Th1 cytokines play key roles in controlling M. tuberculosis infection. Here, we hypothesise that this susceptibility to M. tuberculosis infection is linked to increased T regulatory (Treg) cells and Th2 cytokines in TB patients. To test this, we recruited 101 participants (71 TB patients, 12 non-TB pulmonary diseases and 18 healthy subjects) and investigated Treg cells and Th1/Th2 cytokines in peripheral blood. CD4(+)CD25(+) T cells and CD4(+)CD25(+)FoxP3(+) T cells significantly increased and IL-5 dramatically decreased in TB patients relative to healthy subjects. CD8(+)CD28(-) T cells, IFN-gamma, TNF-alpha, IL-10 and IL-4 significantly increased in patients with culture and sputum smear-positive pulmonary TB (PTB(+)) compared with healthy subjects. CD4(+)CD25(+)FoxP3(+) and CD8(+)CD28(-) T cells significantly decreased in PTB(+) after one month of chemotherapy. CD4(+), CD4(+)CD25(+) and CD8(+)CD28(+) T cells significantly increased in extra-pulmonary TB patients after one month of chemotherapy. These findings suggest that M. tuberculosis infection induces circulating CD4(+)CD25(+)FoxP3(+) and CD8(+)CD28(-) T cell expansion, which may be related to the progression of M. tuberculosis infection, and that the balance between effector immune responses and suppression immune responses is essential to control M. tuberculosis infection.

DNA damage can, but does not always, induce cell death. While several pathways linking DNA damage signals to mitochondria-dependent and -independent death machineries have been elucidated, the connectivity of these pathways is subject to regulation by multiple other factors that are not well understood. We have proposed two conceptual models to explain the delayed and variable cell death response to DNA damage: integrative surveillance versus autonomous pathways. In this review, we discuss how these two models may explain the in vivo regulation of cell death induced by ionizing radiation (IR) in the developing central nervous system, where the death response is regulated by radiation dose, cell cycle status and neuronal development.

We present a detailed description of a novel dye-doped cholesteric LC cell that exhibits polarization-independent diffraction based on a photochromic mechanism. The photochromic phase grating exhibited over 90% polarization independence of the writing beams, and over 90% polarization-independent self and probe diffractions were observed. No external ac or dc field is needed for operation. Unpolarized light can also be used for writing-in beam and/or read-out beam, making this method immediately suitable for applications of light modulation. To our knowledge this cell represents the first example of polarization-independent photochromic phase modulation and light diffraction, for both writing and probe beams, in an anisotropic liquid crystalline material.

Two-year-old young spruce (Picea koraiensis Nakai) plants were grown in a climatic chamber during three summer months at double atmospheric CO2 concentration, sufficient content of soil inorganic nitrogen, and diurnal variation of temperature and illuminance, which simulate natural growth conditions. The control plants were grown in another climatic chamber under the same conditions, but at atmospheric CO2 concentration (350 ppm). CO2 exchange was measured with a Li-Cor 6400 infra-red gas analyzer in attached leaves placed in a climatic chamber in the morning under growth conditions and saturating light 1200 µE/(m2 s) in June, July, and August. In addition, dry weights of needles, leafless shoot parts of plant, fraction of thick (more than 0.5 mm in diameter) and thin (less than 0.5 mm in diameter) roots were recorded. The data were used to plot CO2 exchange rates as a function of carbon dioxide concentration and to calculate the increment of shoot and root phytomass. The maximum gas exchange rates in the treated and control plants similarly depended on CO2 concentration. The slope of the CO2 dependence curve, which corresponded to the kinetic characteristic Vm /KM of photosynthetic carboxylation, increased monotonically during the experiment. To the end of observation period, the proportion of thick roots in plant phytomass significantly increased in the plants grown at double atmospheric CO2 concentration, as compared to the control plants. Thus, the increase in the rate of photosynthetic gas exchange in plants grown for three months at double atmospheric CO2 concentration was only due to the increase in CO2, the substrate of Rubisco carboxylation activity. We found no differences in the CO2 characteristic for Rubisco between the treated and control plants. The ratio of needle to thin roots in the treated and control plants was similar and did not change during the experiment. The excess of photoassimilates in the treated, as compared to the control plants, was preferentially used for thick root growth. This result shows that photosynthesis in young spruce forests can deposit excess atmospheric CO2 in the soil horizon in the form of thick root phytomass.

Two-year old birch (Betula platyphylla Suk.) seedlings were grown in climatic chambers for 7 weeks under various conditions: (1) ambient CO2 concentration (350 ppm) and an ordinary nitrogen content in soil (2 mM NH4NO3); (2) ambient CO2 concentration and a high nitrogen rate (16 mM NH4NO3); (3) doubled CO2 concentration (700 ppm) and ordinary nitrogen content, and (4) doubled CO2 concentration and a high nitrogen rate. Doubled CO2 concentration in combination with the high nitrogen rate activated mostly seedling growth, e.g., stem thickening and leaf initiation. In this treatment, the maximum rate of apparent photosynthesis (A max) was twice as high as in control seedlings. At doubled CO2 concentration and ordinary nitrogen content, we observed the phenomenon of stomata absence from the upper leaf surface and doubling their number on the lower surface, whereas, at doubled CO2 concentration and a high nitrogen rate, stomata partition was essentially similar as in control leaves. The conclusion is that, when the balance between CO2 concentration and nitrogen rate is shifted, doubled CO2 concentration exerts a morphotropic effect on differentiation of young epidermal tissue.

Genotoxic agents or inflammatory cytokines activate cellular stress responses and trigger programmed cell death. We have identified a signal transduction module, including three nuclear proteins that participate in the regulation of cell death induced by chemotherapeutic agents and tumor necrosis factor (TNF). In this nuclear signaling module, retinoblastoma protein (Rb) functions as an inhibitor of apoptotic signal transduction. Inactivation of Rb by phosphorylation or caspase-dependent cleavage/degradation is required for cell death to occur. Rb inhibits the Abl tyrosine kinase. Thus, Rb inactivation is a pre-requisite for Abl activation by DNA damage or TNF. Activation of nuclear Abl and its downstream effector p73 induces mitochondriadependent cell death. The involvement of these nuclear signal transducers in TNF induced apoptosis, which does not require new gene expression, indicates that nuclear events other than transcription can contribute to extrinsic apoptotic signal transduction.

We studied a large hospitalized cohort of patients aged 55 years and over with acute ischemic stroke to identify the frequency and predictors of poststroke dementia. A total of 434 consecutive patients with ischemic stroke were enrolled in this study. During admission, the demographic data, vascular risk factors, stroke features, and neurological status information were collected. All subjects were examined by a battery of neuropsychological tests during admission and 3 months after stroke. Logistic regression analysis was used to find the predictors of poststroke dementia. (1) The frequency of poststroke dementia was 27.2%, that of stroke-related dementia was 21.6%, and that of dementia after first-ever stroke was 22.7% 3 months after stroke. (2) Univariate analysis indicated that older age, low educational level (≤ 6 years), everyday drinking, diabetes mellitus, atrial fibrillation, prior stroke, left carotid territory infarction, embolism, multiple stroke lesions, dysphasia, and gait impairment were more frequent in the patients with poststroke dementia. (3) Multivariate analyses demonstrated that age (OR 1.179, 95%CI 1.130–1.230), low educational level (OR 1.806, 95 %CI 1.024–3.186), everyday drinking (OR 3.447, 95 %CI 1.591–7.468), prior stroke (OR 2.531, 95 %CI 1.419–4.512), atrial fibrillation (OR 3.475, 95%CI 1.712–7.057), dysphasia (OR 5.873, 95 %CI 2.620–13.163), and left carotid territory infarction (OR 1.975, 95%CI 1.152–3.388) were associated with poststroke dementia. The frequency of dementia is about one-forth of patients with ischemic stroke 3 months after stroke. Independent predictors of poststroke dementia include age, low educational level, everyday drinking, prior stroke, dysphasia, atrial fibrillation, and left carotid territory infarction.

The stability problem of a rock slope containing a wedge resting on two intersecting discontinuities is of great interest in rock slope engineering. It is a statistically indeterminate problem with two extra unknowns according to the force (stress) equilibrium analysis. The widely used limit equilibrium methods in practice assume that the directions of the shear forces acting on the two discontinuities are parallel to their line of intersection. The validity of this assumption, however, has not been verified theoretically. This paper presents a general limit equilibrium method that determines the directions of the shear forces by using Pan’s “Maximum principle” and an upper bound method that applies the classic upper bound theorem of limit analysis to avoid making extra assumptions. The formulations of the two methods are derived. A non-symmetric wedge and a symmetric wedge are analyzed using the two derived methods. To further explore the influence on stability due to the direction of the shear force acting on the two discontinuities, three-dimensional finite-element analyses are also conducted. The results are compared and discussed.

Ionizing radiation (IR) induces DNA breakage to activate cell cycle checkpoints, DNA repair, premature senescence or cell death. A master regulator of cellular responses to IR is the ATM kinase, which phosphorylates a number of downstream effectors, including p53, to inhibit cell cycle progression or to induce apoptosis. ATM phosphorylates p53 directly at Ser15 (Ser18 of mouse p53) and indirectly through other kinases. In this study, we examined the role of ATM and p53 Ser18 phosphorylation in IR-induced retinal apoptosis of neonatal mice. Whole-body irradiation with 2 Gy IR induces apoptosis of postmitotic and proliferating cells in the neonatal retinas. This apoptotic response requires ATM, exhibits p53-haploid insufficiency and is defective in mice with the p53S18A allele. At a higher dose of 14 Gy, retinal apoptosis still requires ATM and p53 but can proceed without Ser18 phosphorylation. These results suggest that ATM activates the apoptotic function of p53 in vivo through alternative pathways depending on IR dose.

In this paper, we propose a modified extragradient method for solving variational inequalities (VI) which has the following nice features: (i) The generated sequence possesses an expansion property with respect to the starting point; (ii) the existence of the solution to a VI problem can be verified through the behavior of the generated sequence from the fact that the iterative sequence diverges to infinity if and only if the solution set is empty. Global convergence of the method is guaranteed under mild conditions. Our preliminary computational experience is also reported.

Udgivelsesdato: 2003-Aug-7 Protein kinase CK2 is a serine/threonine protein kinase involved in various aspects of cellular regulation. The regulatory beta-subunit of CK2 exerts a central role not only in mediating formation of tetrameric CK2 complexes but also as a docking partner for several protein kinases. In this study, CK2beta is found to interact with the human cell cycle checkpoint kinase Chk1. The Chk1-interacting region of CK2beta is localized at the C-terminus and the complex between CK2beta and Chk1 is devoid of the catalytic CK2alpha-subunit. The interaction between CK2beta and Chk1 leads to an increase in the Cdc25C phosphorylation activity of Chk1. The screening of several cell lines has revealed that the association between CK2beta and Chk1 also occurs in vivo at a different degree. Collectively, these studies confirm the implication of the regulatory beta-subunit of protein kinase CK2 in cell cycle regulation and identify a novel mechanism for the activation of Chk1 protein kinase.

Recent studies have shown that RB can inhibit apoptosis, independently of its ability to block cell proliferation. This poses the question of how cells choose to grow or to die when RB becomes inactivated. RB is phosphorylated following mitogenic stimulation, but it is degraded in response to death stimuli. Most sporadic cancers also inactivate RB by phosphorylation, rather than losing RB entirely--possibly to exploit the survival advantage conferred by RB under stress. Drawing from the different mechanisms of RB inactivation, we propose two models for ways in which cells use RB to make the choice of life versus death.

We report on the optical properties of nematic liquid crystal cells containing the commercially available liquid crystal E7 doped with the azo dye Disperse Red 1 at concentrations ranging from 0.3% to 1.0%. From polarized absorption measurements an order parameter of S=0.569 was obtained, thus showing that the dye molecules align themselves very well with the liquid crystal's director axis. Optical index gratings were written in the material by overlapping two coherent laser beams at 532 nm. Self-diffraction of the writing beams and diffraction of a probe beam at 670 nm were measured. First-order self-diffraction efficiencies and rise times were found to be linearly dependent upon the dye concentration with a maximum efficiency of 3.29% and a minimum rise time of 10.6 ms. The non-linear index coefficient, n 2, was calculated to be 7.6 × 10-3cm2W-1. The data are consistent with a grating formation based on trans–cis photoisomerism of the dye molecules that leads to a reorientation of the liquid crystal phase. These photonic devices are functional without the application of any external field, they are easily prepared, and have lifetimes in excess of two years without any indication of degradation when stored at ambient temperature.

In this paper, we propose a unified framework of extragradient-type methods for solving pseudomonotone variational inequalities, which allows one to take different stepsize rules and requires the computation of only two projections at each iteration. It is shown that the modified extragradient method of Ref. 1 falls within this framework with a short stepsize and so does the method of Ref. 2 with a long stepsize. It is further demonstrated that the algorithmic framework is globally convergent under mild assumptions and is sublinearly convergent if in addition a projection-type error bound holds locally. Preliminary numerical experiments are reported.

The Hepatocyte Growth Factor (HGF) and its receptor Met are physiological regulators of cell migration. HGF and Met have also been implicated in tumor progression and metastasis. We show here that the tyrosine kinase inhibitor STI571 has a stimulatory effect on HGF-induced migration and branching morphogenesis in thyroid cancer but not in primary or immortalized thyroid epithelial cells. These stimulatory effects of STI571 are observed at a concentration that is clinically relevant. The STI571-enhanced motile response can be correlated with an increase in the Met receptor tyrosine phosphorylation as well as ERK and Akt activation by HGF. Interestingly, one of the targets of STI571, namely the c-Abl tyrosine kinase, is activated by HGF and is recruited at the migrating edge of thyroid cancer cells. These data suggests that c-Abl and/or STI571-inhibited tyrosine kinases can negatively regulate the Met receptor to restrain the motile response in thyroid cancer cells.

The chimeric BCR-ABL oncoprotein is the molecular hallmark of chronic myelogenous leukemia (CML). BCR-ABL contains nuclear import and export signals but it is localized only in the cytoplasm where it activates mitogenic and anti-apoptotic pathways. We have found that inhibition of the BCR-ABL tyrosine kinase, either by mutation or by the drug STI571, can stimulate its nuclear entry. By combining STI571 with leptomycin B (LMB) to block nuclear export, we trapped BCR-ABL in the nucleus and the nuclear BCR-ABL tyrosine kinase activates apoptosis. As a result, the combined treatment with STI571 and LMB causes the irreversible and complete killing of BCR-ABL transformed cells, whereas the effect of either drug alone is fully reversible. The combined treatment with STI571 and LMB also preferentially eliminates mouse bone marrow cells that express BCR-ABL. These results indicate that nuclear entrapment of BCR-ABL can be used as a therapeutic strategy to selectively kill chronic myelogenous leukemia cells.

The c-abl proto-oncogene encodes a protein tyrosine kinase that is distributed in the nucleus and the cytoplasm of proliferating cells. In the nucleus, c-Abl activity is negatively regulated by the retinoblastoma protein (RB) and positively regulated by DNA damage signals. Activation of the c-Abl kinase by DNA damage requires the function of ATM, which regulates cell cycle checkpoint, DNA repair and apoptosis in response to DNA damage. Cells lacking c-Abl can activate cell cycle checkpoints and DNA repair, but show defects in apoptosis. The apoptosis defect of c-Abl deficient cells is correlated with a defect in the induction and activation of p73, which is a functional homologue of the p53 tumor suppressor protein and has pro-apoptotic activity. The inhibition of c-Abl by RB is consistent with RB's ability to block apoptosis; while the activation of c-Abl by ATM is consistent with ATM's ability to activate cell death. The oncogenic Bcr-Abl tyrosine kinase is a potent inhibitor of apoptosis, and it is retained exclusively in the cytoplasm of transformed cells. Interestingly, when Bcr-Abl is trapped inside of the nucleus through a combined disruption of its cytoplasmic retention and its nuclear export, this oncogenic Abl kinase induces apoptosis. Taken together, the current results support a role for the nuclear c-Abl tyrosine kinase in the regulation of apoptosis. Whether the cytoplasmic c-Abl kinase can actively inhibit apoptosis remains to be determined; however, a deliberate retention of c-Abl in the cytoplasm could potentially contribute to the attenuation of apoptosis response.

In Philadelphia chromosome (Ph1)-positive human leukemia, the c-Abl tyrosine kinase is activated by fusion to sequences encoded by the breakpoint cluster region (bcr) gene. Two major types of Bcr-Abl fusion proteins have been found in human leukemia. Fusion of the N-terminal 426 amino acids of Bcr generates p190(Bcr-Abl) which is mostly found in acute lymphocytic leukemia (ALL), whereas fusion of the N-terminal 902 or 927 amino acids of Bcr generates p210(Bcr-Abl) mostly found with chronic myelogenous leukemia (CML). Previous studies have demonstrated that both the Bcr and the Abl functional domains contribute to the oncogenic activity of Bcr-Abl proteins. Present in both p190 and p210 is the N-terminal coiled-coil of Bcr (aa 1-63), which is shown here to be functionally replaceable with the leucine zipper of the yeast transcription factor GCN4. The ZIP-Bcr-Abl protein transforms Rat-1/myc cells, is autophosphorylated on tyrosine and localized predominantly to actin filaments. Thus, formation of homo-oligomers through either Bcr or GCN4 coiled-coil can activate the tyrosine kinase and F-actin binding functions of Abl. We also found that a Bcr-Abl fusion containing only Bcr amino acids (1-191) can efficiently transform Rat-1/myc cells. Fusion of additional Bcr sequences (aa 192-923) did not affect the transformation of Rat-1/myc cells but progressively reduced the disruptive effect on the actin cytoskeleton. In particular, the Dbl homology domain present in p210(Bcr-Abl) but not in p190(Bcr-Abl) contributes to the stabilization of actin fibers. The modulatory effect of Bcr sequences on actin structure may underlie the apparent pathogenic variations between the different Bcr-Abl fusion proteins.

Deletions of chromosomal region 9p21 are among the most common genetic alterations observed during the clonal evolution of high grade malignant gliomas. Structural and functional evidence has suggested that homozygous deletion involving CDKN2A (the genetic locus encoding the cyclin-dependent kinase inhibitor p16(NK4a)) is a mechanism of inactivation of this gene and that it can be a growth suppressor in human gliomas. However, the presence of other potential suppressor genes in the 9p21 region and the relatively large sizes of the deletions has made it difficult to be certain that the CDKN2A gene is their actual target. Here, we tested this hypothesis by determining the growth suppressive effects, cell cycle inhibitions, and the activities of seven naturally occurring glioma-derived CDKN2A alleles carrying point mutations and found that two of them were functionally compromised. To resolve discrepancies among the different existing functional assays, we developed an assay for p16(INK4a) function that allowed us to demonstrate that the expression of wild-type CDKN2A, but not alleles with inactivating mutations, prevents pRB phosphorylation in vivo in human glioma cells. These data suggest that CDKN2A is a critical target for mutational inactivation in human malignant gliomas.

The degradation products of basic fibroblast growth factor (bFGF) were isolated by ion exchange HPLC (HP-IEC) and characterized. The predominant product at pH 5 was a succinimide in place of aspartate15 as determined by LC/MS, N-terminal sequencing, and susceptibility to degradation at pH >6.5. The rate of appearance of the succinimidyl-bFGF at 22 °C was comparable to that reported for small peptides, consistent with a high flexibility predicted for asp15-gly. Tryptic mapping together with [3H]-methylation indicated that iso-aspartate was formed at the position of asp15. Size exclusion HPLC indicated the presence of intact and truncated dimers and trimers which associated through disulfide linkages. Two truncated monomer forms were found that co-eluted by HP-IEC; the cleavages were determined to be at asp28-pro and asp15-gly using LC/MS and N-terminal sequencing. These degradation products which occurred at sites that are away from receptor or heparin binding domains of bFGF remained bioactive in a cell proliferation assay.

Two crown ethers, di(tert-butylbenzo)-propyl-15-crown-5 polysiloxane (PSO-DTB-15C5) and dibenzo-propyl-15-crown-5 polysiloxane (PSO-DB-15C5) have been synthesized and coated onto fused-silica capillary columns. The chromatographic characteristics, including column efficiency, polarity, phase transition temperature, operating temperature range and selectivity, were studied.

An error in the PDB code occurred in the article published in the Journal of Biology [1]. In the legend to Figure One, instead of 1FW3, the correct PDB code is 3FW1.

Poly(vinyl amine) and alginate were used as the materials for microencapsulation. IW32 (a murine erythroleukemia cell line) cells were cultured within the capsules to a density of 8×107 cells/ml, 40 times that obtained in the free-cell culture. Erythropoietin accumulated in the microcapsule to a concentration of 7.0 U/ml, about three times that in the extra-capsular medium and 14 times the concentration found in the medium of free-cell culture.

In this paper we introduce the CM field in Sections 2 and 3 based on the paper by Wang and Peng(1985), and calculate the light curved in the CM field in Section 4. The result shows that P makes DELTAphi(CM) larger than DELTAphi(C) at theta is-an-element-or (cos-1 1/3 pi - cos-1 1/3) or (pi - cos-3 1/3, pi). Under a special circumstance which source, CM lens, and observer are in the same line, if we get DELTAphi\0=0, DELTAphi\0=cos-1 1/3 and DELTAphi\0=pi/2, we can determine the P(M) and Q(M) of the CM lens, M is the mass of the CM lens.

In this Letter, Einstein's equations of gravitational field have been used to calculate the metric of Einstein's disc. The known result has been obtained, but its physical significance is made very clear.

Recent high magnetic field, far infrared transmission and photoconductivity experiments on shallow donor impurities (Si) doped in the centers of the wells, the centers of the barriers and the edges of the wells in GaAs/AlGaAs multiple-quantum-well (MQW) structures are described. For donors doped in the centers of the wells, transitions to various high excited states have been observed. The assignment of these transitions and their relationship to the hydrogenic transitions in bulk (three dimensional) semiconductors is discussed. The edge-doped samples show dramatic differences in line shape for otherwise identical samples doped at the top and bottom of the GaAs wells. It is concluded from comparison with model calculations that the Si donors are redistributed along the growth direction, and such modeling should permit the determination of the impurity distribution non-destructively. Samples doped in the centers of the barriers show two lines at frequencies lower than that of the well-center impurities. The dominant line is due to electrons in the wells bound to their parent positive donor ions in the centers of the barriers. Possible origins of the weaker line are discussed.

Gleevec inhibits the oncogenic BCR–ABL tyrosine kinase in chronic myelogenous leukaemia and thus safely and effectively suppresses this human cancer. Gleevec also inhibits the normal cellular ABL, a downstream effector of the Eph-receptors, which mediate repulsive cell–cell interactions to regulate axon guidance, angiogenesis and epithelial homeostasis. New work shows that Eph-dependent tumour suppression requires ABL and is blocked by Gleevec, thus cautioning against the indiscriminate use of this drug in cancer therapy.

Magneto-studies have been carried out for several MOCVD grown GaN thin films and GaN/AlGaN heterostructures at magnetic fields up to 30 T and at temperatures between 4.2 K to 100 K. Electron cyclotron resonance was observed in two heterostructures with high mobilities (μ > 2000 cm2/V-s), the effective mass obtained from the cyclotron resonance measurement is 0.23±0.01 m0, where m0 is the mass of free electron. For Si-doped thin film GaN there was no sign of electron cyclotron resonance even when samples were heated up to 100 K. However, a Is to 2p+ absorption line was observed for Si-doped GaN samples. A binding energy of 29 meV and low frequency dielectric constant of 10.4 is obtained.

ATM and NBS1 are genes that are mutated in two different human diseases. Cells from patients with these diseases show similarities, including increased chromosome breakage, so ATM and NBS1 might work together in DNA repair. Indeed, ATM phosphorylates NBS1 in several places — events needed for the cellular response to DNA breaks.

The corresponding author submitted this article [1] to Molecular Cancer on an assumption that the manuscript had been lost during its previous transmission to Cancer Biology and Therapy. In fact it had been received by that journal and was published there, simultaneously [2]. The authors are therefore retracting the version published in this journal based on the fact that it was initially submitted to the other journal first. The author is deeply sorry for any inconvenience this may have caused to the editorial staff and readers.

Rhabdomyosarcoma is a common malignancy in children. There are two major types of rhabdomyosarcomas, the embryonal and the alveolar, differing in cytogenetic and morphologic features. The alveolar type of rhabdomyosarcoma is frequently associated with chromosome translocation t(2, 13) and poor clinical prognosis. Pathogenesis of rhabdomyosarcoma remains obscure, and especially it occurs in the location where skeletal muscle is absent. We report here that there is a high frequency of association of rhabdomyosarcoma with ataxia telangiectasia mutated (ATM) gene mutation/deletion. Totally 17 cases of rhabdomyosarcoma specimens were studied by immunohistochemical or immunofluorescent staining with ATM antibody and revealed that 7 of the 17 cases were negative for ATM expression (41%). Further analyses of rhabdomyosarcoma cell lines with RT-PCR revealed that in Rh30 cells, an alveolar rhabdomyosarcoma cell line, there are three separate deletions/mutations of the ATM mRNA. Western blotting analysis of the Rh30 cellular extract with anti-ATM antibody showed that there is an aberrant form of ATM protein within the Rh30 cells that are smaller than normal control. These results suggest a link of ATM gene deletion/mutation with rhabdomyosarcoma, and since ATM kinase is a crucial regulatory protein in DNA damage repair signaling pathway, and ATM deletion/mutation may contribute to pathogenesis of rhabdomyosarcoma.

This paper deals with the effects of air leakage from intake to return airways through a series of stoppings on the analysis of coal mine ventilation. The mathematical model which assumes continuous leakage along adjoining intake and return airways is reviewed, and a new mathematical approach is presented based upon the concentrated leakage through individual stoppings. The procedure incorporating the new method in the analysis of coal mine ventilation networks is also discussed.

Three distinct forms of lipolytic enzyme were identified in a commercialCandida lipase preparation. Two of these lipases (lipases A & C) were isolated and characterized. Lipase A had a higher optimal reaction pH and a better thermal stability than those of lipase C. Lipase A and C displayed different acyl chain length specificity on the lipolysis of p-nitrophenol esters.

Solving ventilation networks of natural air splitting is a classical problem in mine ventilation. A common approach to this problem is to formulate it based on Kirchhoff's voltage and current laws and obtain the solution by an iterative technique known as the Hardy Cross method. In this paper, it is shown that the problem can be formulated and analysed as an unconstrained optimization (minimization) problem. The computational experience with the method of conjugate gradients is also discussed.