Hypersensitivity to DNA cross-linking agents associated with up-regulation of glucose-regulated stress protein GRP78

We have shown previously that NAD/poly(ADP-ribose) polymerase-deficient cells that overexpress Mr 78,000 glucose-regulated stress protein (GRP78) are resistant to topoisomerase II inhibitors, such as etoposide, m-amsacrine, and doxorubicin. However, these cells have been found to be hypersensitive to DNA cross-linking agents, including melphalan, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). These observations prompted us to examine whether overexpression of GRP78 is associated with modulation of cytotoxicity of clinically useful DNA-cross-linking agents such as melphalan, BCNU, and cisplatin. We up-regulated GRP78 in V79 Chinese hamster cells by 2-5-fold using two independent approaches that include exposure to 6-aminonicotinamide, or 2-deoxyglucose. Subsequently, these GRP78-overexpressing cells were trypsinized, plated in regular medium without GRP78-inducing agents, and allowed a 5-h attachment time before being treated with melphalan, BCNU, or cisplatin for 1 h to determine clonogenic survivals. In addition, repair of DNA cross-links induced by those agents were determined by alkaline elution assay. Our results show that the GRP78-overexpressing V79 cells are hypersensitive to DNA cross-linking agents compared to the control V79 cells. Furthermore, repair of drug-induced DNA cross-links appears to be considerably slower in these cells relative to that found in control V79 cells. Thus, our results suggest that (a) up-regulation of GRP78 is associated with an impairment of DNA cross-link repair, (b) up-regulation of GRP78 is associated with potentiation of cytotoxicity induced by alkylating and platinating agents, and (c) up-regulation of GRP78 can be considered as a potentially useful tool to modulate the cytotoxicity of clinically useful alkylating and platinating agents.     

Experience-dependent cell survival in the maternal rat brain.

Postpartum maternal experience produces long-lasting changes in maternal behavior in the mother rat, which can be altered by early-life isolation. Postpartum experience also affects the regulation of adult neurogenesis in the neural circuit underlying maternal behavior, in a region-specific manner. Female rats were reared either with their mothers (MR) or in isolation in an artificial rearing (AR) paradigm. In adulthood, rats were mated and separated from their pups at birth. The following day, dams were injected with a mitotic marker and either allowed to interact with pups (maternal experience) or left alone. Results show that MR rats that acquire a later maternal experience show increases in cell survival in parts of the excitatory limb of the maternal neural network (bed nucleus of the stria terminalis and nucleus accumbens), but no changes in the inhibitory limb (amygdala). In comparison to AR inexperienced rats, AR maternally experienced rats show no increases in cell survival in the excitatory limb, but a striking reduction in cell survival in the inhibitory limb. The results suggest that early preweaning maternal isolation alters the structural plasticity that occurs following a postpartum maternal experience. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Microstructure,properties, and age hardening behavior of a thermomechanically processed ultralow-carbon Cu-bearing high-strength steel

An ultralow-carbon steel alloyed with Ni, Mn, Mo, and Cu and microalloyed with Nb and Ti was subjected to a three-stage controlled rolling operation followed by water quenching. The effect of thermomechanical processing on the microstructure, mechanical properties, and age-hardening behavior of the steel was evaluated. The precipitation behavior of Cu at different aging temperatures was studied by transmission electron microscopy (TEM) and differential scanning calorimetry (DSC). The high strength values obtained in the present steel are due to the fine-lath martensite structure along with tiny precipitates of microalloying carbide and carbonitride of Ti and Nb at all finish rolling temperatures (FRTs). The increased strength value at the lower FRT is due to the finer lath width and packet size of martensite. The large TiN particles and the coarse martensite-austenite (MA) constituents impaired the impact-toughness value of the steel at subambient temperature. On aging at different temperatures, a wide variation in structure and properties has been obtained. At low aging temperatures, coherent Cu particles form and a peak strength is obtained due to the formation of fine ε-Cu precipitates. On increasing aging temperatures, the Cu particle size increases, with a simultaneous decrease in dislocation density in the matrix resulting in a continuous decrease in strength.     

Transient steel quality under non-isothermal conditions in a multi-strand billet caster tundish: part II. Effect of a flow-control device

A mathematical model was built to simultaneously analyse the effects of non-isothermal conditions and flow-control device on steel quality in a real steelmaking tundish. Liquid steel was used as the operating liquid with a step-input of 23° in a full-scale delta-shaped multi-strand billet caster tundish fitted with a standard impact pad (SIP). The changes in flow pattern and temperature fields of liquid steel in the tundish under isothermal, step-up and step-down conditions were thoroughly studied. Similar to the case of a bare tundish, buoyancy effects were seen to dominate at regions away from the ladle shroud. The presence of SIP modified the flow patterns and resulted into markedly different values of RRI as compared to bare tundish. Finally, the calculated results were qualitatively compared to results obtained from a real steelmaking tundish.     

Effect of Bonding Temperature on Interfacial Reaction and Mechanical Properties of Diffusion-Bonded Joint Between Ti-6Al-4V and 304 Stainless Steel Using Nickel as an Intermediate Material

An investigation was carried out on the solid-state diffusion bonding between Ti-6Al-4V (TiA) and 304 stainless steel (SS) using pure nickel (Ni) of 200-μm thickness as an intermediate material prepared in vacuum in the temperature range from 973 K to 1073 K (700 °C to 800 °C) in steps of 298 K (25 °C) using uniaxial compressive pressure of 3 MPa and 60 minutes as bonding time. Scanning electron microscopy images, in backscattered electron mode, had revealed existence of layerwise Ti-Ni-based intermetallics such as either Ni₃Ti or both Ni₃Ti and NiTi at titanium alloy-nickel (TiA/Ni) interface, whereas nickel-stainless steel (Ni/SS) diffusion zone was free from intermetallic phases for all joints processed. Chemical composition of the reaction layers was determined in atomic percentage by energy dispersive spectroscopy and confirmed by X-ray diffraction study. Room-temperature properties of the bonded joints were characterized using microhardness evaluation and tensile testing. The maximum hardness value of ~800 HV was observed at TiA/Ni interface for the bond processed at 1073 K (800 °C). The hardness value at Ni/SS interface for all the bonds was found to be ~330 HV. Maximum tensile strength of ~206 MPa along with ~2.9 pct ductility was obtained for the joint processed at 1023 K (750 °C). It was observed from the activation study that the diffusion rate at TiA/Ni interface is lesser than that at the Ni/SS interface. From microhardness profile, fractured surfaces and fracture path, it was demonstrated that failure of the joints was initiated and propagated apparently at the TiA/Ni interface near Ni₃Ti intermetallic phase.     

Health-care utilization by disabled persons: a survey in rural Bangladesh

The purpose of the present study was to examine the utilization of health services by disabled persons in rural Bangladesh and to identify associated factors to inform the development of appropriate health services. Household surveys were conducted in two villages of Bangladesh by a trained primary-care specialist who lived in the study area for 4 months. About 81% of the sample had utilized some form of health care with more than half consulting unqualified practitioners of modern medicine. Disabled persons whose families perceived they were disabled were 14 times more likely than others to seek treatment. Being male and in the economically productive age group, having an acquired disability and having some form of belief about disability causation were associated with utilization. The conclusions of the study are that social and cultural barriers prevent certain groups, notably women and demographically dependent age groups, from accessing health care. Those who are economically beneficial to the family usually utilize health services. A combination of educational and economic initiatives such as a disability benefits allowance would strongly promote the health of disabled persons and create a general awareness of disability in Bangladesh. A long-term programme which includes disability training for health-care workers and use of financial institutions and existing local government infrastructure for intensive rehabilitation will improve quality of life for disabled persons and is proposed for urgent implementation.     

The comparison of the surface area of porous and non-porous solids as determined by diffusional flow and nitrogen adsorption

The Knudsen equation for the diffusional flow of gases through capillaries, together with the Kozeny concept of a packed bed of powder being similar to a bundle of narrow tortuous capillaries, were used to evaluate the surface area of powders packed in a diffusion tube.The surface areas calculated by this steady-state diffusion method were larger than the areas determined by permeametry. The simple diffusion method gave comparable surface areas, for porous and non-porous powders, to that obtained by low temperature nitrogen adsorption.     

Glycosphingolipids of human plasma lipoproteins

The content and structure of glycosphingolipids (GSL) in human plasma lipoproteins were studies. The quantitative distribution of the neutral GSL(Glc-Cer, Gal-Glc-Cer, Gal-Gal-Glc-Cer, and GalNAc-Gal-Gal-Glc-Cer) and the principal ganglioside (AcNeu-Gal-Glc-Cer) within the different lipoprotein classes was similar to that of whole plasma. The total amounts (μmol glucose/100 ml plasma) of GSL in the plasma lipoproteins of three normal subjects were VLDL (very low density lipoproteins) (trace to 0.46), LDL (low density lipoproteins) (1.08–1.48), HDL₂ (high density lipoproteins₂) (0.62–0.85), and HDL₃ (high density lipoproteins₃) (trace to 0.28). In subjects with Lp(a) lipoproteins, HDL₂ rather than HDL₃ contained most of the GSL in HDL. When the data were corrected for differences in the plasma concentrations of the lipoproteins, the total amounts of GSL(nmol glucose/mg lipoprotein cholesterol) were VLDL(trace to 21.20), LDL(11.70–15.36), HDL₂(8.50–9.10), and HDL₃(3.12). No GSL were detected in lipoprotein deficient plasma. Mass spectrometry of the trimethylsilyl derivatives of the GSL in LDL showed major fragment ions characteristic of their individual structural components. The elevated plasma levels of the GSL(2–18 fold), in a homozygote for familial hypercholesterolemia, resided in LDL which contained an absolute increase (per mg lipoprotein cholesterol) of GSL. Most, if not all, of the plasma GSL are associated with plasma lipoproteins and may have an important role in their biological functions.