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Lung cancer is the leading cause of cancer-associated death, with a global 5-year survival rate20%. Early metastasis and recurrence remain major challenges for lung cancer treatment. The stemness property of cancer cells has been suggested to play a key role in cancer plasticity, metastasis and drug-resistance, and is a potential target for drug development. In this study, we found that in non-small cell lung cancer (NSCLC), BMI1 and MCL1 play crucial roles of cancer stemness including invasion, chemo-resistance and tumour initiation. JNK signalling serves as a link between oncogenic pathway or genotoxicity to cancer stemness. The activation of JNK, either by mutant EGFR or chemotherapy agent, stabilized BMI1 and MCL1 proteins through suppressing the expression of E3-ubiquitin ligase HUWE1. In lung cancer patient samples, high level of BMI1 is correlated with poor survival, and the expression of BMI1 is positively correlated with MCL1. A novel small-molecule, BI-44, was developed, which effectively suppressed BMI1/MCL1 expressions and inhibited tumour formation and progression in preclinical models. Targeting cancer stemness mediated by BMI1/MCL1 with BI-44 provides the basis for a new therapeutic approach in NSCLC treatment.

Complaint behaviours are the key to the competition in an online market when service quality is a major concern of consumers. An understanding of complaint intentions can provide insight into a negative service experience and in turn, effectively redress consumer's problems. It is our purpose to examine the determinants of complaint intentions in the online shopping. When online consumers essentially involve the purchase of products/services and the use of web-based technologies, two major issues particularly arise in this context, exchange behaviour and technology use. This study thus integrates justice perception and expectation–confirmation model (ECM) of information system continuance to understand customer satisfaction and in turn, complaint intentions. Data were collected for online consumers with negative service experiences. The results of testing the structural model indicated that distributive and interactional justices significantly contribute to customer satisfaction and complaint intentions, ...

Higher plants have both high- and low-affinity nitrate uptake systems. These systems are generally thought to be genetically distinct. Here, we demonstrate that a well-known low-affinity nitrate uptake mutant of Arabidopsis, chl1, is also defective in high-affinity nitrate uptake. Two to 3 hr after nitrate induction, uptake activities of various chl1 mutants at 250 microM nitrate (a high-affinity concentration) were only 18 to 30% of those of wild-type plants. In these mutants, both the inducible phase and the constitutive phase of high-affinity nitrate uptake activities were reduced, with the inducible phase being severely reduced. Expressing a CHL1 cDNA driven by the cauliflower mosaic virus 35S promoter in a transgenic chl1 plant effectively recovered the defect in high-affinity uptake for the constitutive phase but not for the induced phase, which is consistent with the constitutive level of CHL1 expression in the transgenic plant. Kinetic analysis of nitrate uptake by CHL1-injected Xenopus oocytes displayed a biphasic pattern with a Michaelis-Menten Km value of approximately 50 microM for the high-affinity phase and approximately 4 mM for the low-affinity phase. These results indicate that in addition to being a low-affinity nitrate transporter, as previously recognized, CHL1 is also involved in both the inducible and constitutive phases of high-affinity nitrate uptake in Arabidopsis.

Pin1 was the first prolyl isomerase identified that is involved in cell division. The mechanism by which Pin1 acts as a negative regulator of mitotic activity in G2 phase remains unclear. Here, we found that Aurora A can interact with and phosphorylate Pin1 at Ser16, which suppresses the G2/M function of Pin1 by disrupting its binding ability and mitotic entry. Our results also show that phosphorylation of Bora at Ser274 and Ser278 is crucial for binding of Pin1. Through the interaction, Pin1 can alter the cytoplasmic translocation of Bora and promote premature degradation by β-TrCP, which results in a delay in mitotic entry. Together with the results that Pin1 protein levels do not significantly fluctuate during cell-cycle progression and Aurora A suppresses Pin1 G2/M function, our data demonstrate that a gain of Pin1 function can override the Aurora-A-mediated functional suppression of Pin1. Collectively, these results highlight the physiological significance of Aurora-A-mediated Pin1 Ser16 phosphorylation for mitotic entry and the suppression of Pin1 is functionally linked to the regulation of mitotic entry through the Aurora-A-Bora complex.

Although prominent FRAT/GBP exhibits a limited degree of homology to Axin, the binding sites on GSK3 for FRAT/GBP and Axin may overlap to prevent the effect of FRAT/GBP in stabilizing beta-catenin in the Wnt pathway. Using a yeast two-hybrid screen, we identified a novel protein, GSK3beta interaction protein (GSKIP), which binds to GSK3beta. We have defined a 25-amino acid region in the C-terminus of GSKIP that is highly similar to the GSK3beta interaction domain (GID) of Axin. Using an in vitro kinase assay, our results indicate that GSKIP is a good GSK3beta substrate, and both the full-length protein and a C-terminal fragment of GSKIP can block phosphorylation of primed and nonprimed substrates in different fashions. Similar to Axin GID(381-405) and FRATtide, synthesized GSKIPtide is also shown to compete with and/or block the phosphorylation of Axin and beta-catenin by GSK3beta. Furthermore, our data indicate that overexpression of GSKIP induces beta-catenin accumulation in the cytoplasm and nucleus as visualized by immunofluorescence. A functional assay also demonstrates that GSKIP-transfected cells have a significant effect on the transactivity of Tcf-4. Collectively, we define GSKIP as a naturally occurring protein that is homologous with the GSK3beta interaction domain of Axin and is able to negatively regulate GSK3beta of the Wnt signaling pathway.

Background: The purpose of the study was to investigate the morphologic changes of distraction osteogeriesis performed on the mandible in growing minipigs. Methods: Eighteen piglets were divided into four groups. In group A (n = 6), animals received unilateral osteotomy and the distractor device was activated for 2 weeks after a 1-week latency period. In group B (n = 6), animals underwent the osteotomy procedure and distractor placement. In group C (n = 3), animals received the distractor, and in group D (n = 3), only four reference pins were placed. After completion of distraction, the head portions were sent for computed tomography scanning. The coordinates of each selected mandibular landmark were recorded on three-dimensional computed tomographic reconstruction images for further mathematical linear and angular measurements to quantify morphologic changes. Results: The sagittal length related to gonial region was increased in group A but decreased in group B. Although all groups had the tendency of increased ramus width, it was only significant in group B. The distraction also reduced the gonial angle and elevated the ramus inclination to the Frankfort horizontal plane at the operated side. On the contrary, osteotomy alone opened the gonial angle and flattened the ramus inclination. Conclusions: Distraction could lengthen the mandibles in growing minipigs by reducing the gonial angle and displacing the mandible posteriorly. This effect, which allows for developing a prominent gonial angle, could be further explored in treating syndromic patients with the deficiency in the gonial region. A greater amount of overcorrection should be considered while treating growing patients because the mandibular osteotomy procedure itself seems to retard the growth.

The role of photosynthesis and transpiration in the desiccation-induced inhibition of acetylene reduction (nitrogen fixation) was investigated in soybean (Glycine max [L.] Merr. var. Beeson) using an apparatus that permitted simultaneous measurements of acetylene reduction, net photosynthesis, and transpiration. The inhibition of acetylene reduction caused by low water potentials and their aftereffects could be reproduced by depriving shoots of atmospheric CO2 even though the soil remained at water potentials that should have favored rapid acetylene reduction. The inhibition of acetylene reduction at low water potentials could be partially reversed by exposing the shoots to high CO2 concentrations. When transpiration was varied independently of photosynthesis and dark respiration in plants having high water potentials, no effects on acetylene reduction could be observed. There was no correlation between transpiration and acetylene reduction in the CO2 experiments. Therefore, the correlation that was observed between transpiration and acetylene reduction during desiccation was fortuitous. We conclude that the inhibition of shoot photosynthesis accounted for the inhibition of nodule acetylene reduction at low water potentials.

Diurnal variation in algal nitrogen fixation was studied in Lake Mendota, Wisconsin, during the summers of 1971 to 1973. Approximately two-thirds of the daily acetylene reduction in the surface decimeter occurred before noon. The decline in acetylene reduction (nmoles/liter·hr) near midday was partially because the algae relocated themselves at greater depths. However, acetylene reducing activity (nmoles per A 663 unit chlorophyll a per hour) also decreased as midday approached. Occasionally algae would resurface near the end of the day. On average, acetylene reduction (nmoles per liter per hour) was maximum at about 0900 Central standard time in the top decimeter, and acetylene reduction between 0830 and 0930 Central standard time represented 13% of the total daily acetylene reduction. Furthermore, acetylene reduction in the top decimeter, on average, represented 3.6% of the total acetylene reduction in the column. Calculation of the contribution by nitrogen fixation to a lake9s fixed nitrogen budget is discussed.

An apparatus was designed that permitted acetylene reduction (N(2) fixation) by root nodules to be measured in situ simultaneously with net photosynthesis, dark respiration, and transpiration of the shoot in soybean plants (Glycine max [L.] Merr. var. Beeson). Tests showed that acetylene reduction was linear with time for at least 5 hours, except for the first 30 to 60 minutes. Endogenous ethylene production did not affect the measurements. Successive determinations of acetylene reduction could be made without apparent aftereffects on the plant.This apparatus was used to investigate the effects of soil flooding and desiccation on acetylene reduction under conditions where soil, nodule, and leaf water potentials could be measured. No acetylene reduction was detectable in flooded soil or in soil desiccated to a water potential of -19.5 bars. Between these extremes, acetylene reduction displayed a sharp optimum. Removing the soil eliminated the inhibitory effects of flooding, suggesting that rates of gas exchange were restricted between the nodules and the atnosphere at soil water potentials above -2 bars.As the soil desiccated further, acetylene reduction decreased, and the decrease was correlated with decreases in photosynthesis and transpiration. Although dark respiration was inhibited, it was not affected to the extent that acetylene reduction, photosynthesis, or transpiration were. Consequently, it was concluded that photosynthesis, transpiration, or some direct effect on the nodules other than that caused by respiration were most likely to account for the inhibition of acetylene reduction at soil water potentials below -2 bars.

Nitrogen fixation (acetylene reduction) and the growth of blue-green algae were studied in Green Bay (Lake Michigan) during summer 1972. Where concentrations of all nutrients were high Microcystis predominated. As combined nitrogen concentrations decreased Aphanixomenon increased. Aphanixomenon showed increasing C&-reducing efficiency as the NH&+ + NOa- concentration declined, but its standing crop decreased with declining P concentration. At 40 km from the Fox River diatoms were predominant. Increased algal growth and nitrogen fixation in 1972, as compared to 1971, correlated with higher phosphate concentrations. Almost half as much nitrogen was added to the bay by fixation as was delivered by the Fox River during the same period.

Five phenolic compounds produced by decomposing rice straw and sterile extracts of decomposing rice straw in soil were very inhibitory to growth of three strains ofRhizobium. The effects were additive and in several instances synergistic. The phenolic compounds also reduced nodule numbers and hemoglobin content of the nodules in two bean (Phaseolus vulgaris) varieties. Extracts of decomposing rice straw in soil (same concentration as in the soil) significantly reduced N2 fixation (acetylene reduction) in Bush Black Seeded beans. This may explain in part the great reduction in soybean yields in Taiwan following rice crops when the rice stubble is left in the field.

Lead (300 mum) and cadmium (18 mum) inhibit pod fresh weight in soybeans (Glycine max L.) by 35%. Eighteen micromolar cadmium caused a 30% decline in nitrogenase activity by day 52 (the day on which maximum activity was measured) and a 71% inhibition by day 59. The heavy metals depressed photosynthetic rates; when photosynthesis was depressed by 60%, as measured on the day of peak photosynthesis activity, carbohydrate did not accumulate in the nodules. The reduction of pod fresh weight correlated with the effect of lead and cadmium on several other aspects of plant metabolism (shoot, root, leaf, and nodule dry weight; nodule ammonia, protein and carbohydrate content).