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The X protein of hepatitis B virus (HBx) has been specifically implicated in the development of hepatocellular carcinoma (HCC). Clinical associations of HBx isoforms with chronic hepatitis and HCC have not been well studied. HBx has two roles in liver cells, namely pro-apoptotic and anti-apoptotic. In this report, we examined the role of Ser31-HBx in HCC and chronic hepatitis. Using the case-control study, we determined risks of chronic hepatitis and HCC conferred by hepatitis B virus (HBV) containing Ser31-HBx that was phosphorylated by Akt. Ser31-HBx isoforms conferred 3.23-fold risk of HCC in male and 3.36-fold risk in female. Ser31 isoforms were associated with 3.12-fold risk of chronic hepatitis and 3.43-fold risk of cirrhosis and also associated with higher HBV viral load and replication efficiency and lower rate of HBe loss. To determine the mechanism, we found that Ser31-HBx constituted an oncogenic circuit with Akt and cooperated with ras to transform NIH3T3 cells in contrast to non-Ser31-HBxs that did not transduce oncogenic signals. Our results give a clue to account for an underlying cause of HBx-mediated hepatocarcinogenesis. It appears that Ser31 phosphorylation of HBx by Akt plays an important role. The current study provides an example of association of HBV genome variations with risks of HCC and chronic hepatitis.

Objective In line with Smith's (1986) cognitive-affective model of athletic burnout, the purpose of this study was to examine the conjunctive effects of athletes' resilience and coaches' social support on the relationship between life stress and burnout. Design Cross-sectional, self-report survey. Methods A total of 218 student-athletes (Mage = 20.04 yrs, SD = 1.32; males = 159, females = 59) participating in team and individual sports completed life stress, resilience, coaches' social support, and athlete burnout scales. Hierarchical multiple regression analyses with one- two- and three-way interactions examined disjunctive and conjunctive moderations. Results Resilience and coaches' social support conjunctively moderated the stress-burnout relationship. Specifically the interaction of athletes' resilience with coaches' informational and tangible social support moderated athletes' stress-burnout relationship in high and low life stress conditions. Conclusions We suggest coaches provide useful social support and foster athletes' resilience to prevent stress-induced burnout in athletes.

Gemcitabine is an effective anti-cancer agent against solid tumors. The pharmacological mechanism of gemcitabine is known as incorporation into DNA and thereby inhibition of DNA synthesis. When used in metronomic chemotherapy of cancer, the agent may inhibit angiogenesis. It is still uncertain whether the agent can inhibit tumor growth by a mechanism other than DNA incorporation. In this report, we show that gemcitabine causes telomere shortening by stabilizing TRF2 that is required for XPF-dependent telomere loss. Overexpression of TRF2 in the absence of gemcitabine also causes telomere shortening with simultaneous association of TRF2 with XPF/ERCC1. Our study provides a new mechanism by which gemcitabine exerts its anti-tumor activity.

Differential evolution (DE) is a simple and effective global optimization algorithm. It has been successfully applied to solve a wide range of real-world optimization problems. However, DE has shown some weaknesses, especially the long computational times because of its stochastic nature. This drawback sometimes limits its application to optimization problems. Therefore we propose the 2-Opt based DE (2-Opt DE) which is inspired by 2-Opt algorithms to accelerate DE. The novel mutation schemes of 2-Opt DE, DE/2-Opt/1 and DE/2-Opt/2 are substituted for mutation schemes of the original DE namely DE/rand/1 and DE/rand/2. We also provide a comparison of 2-Opt DE to DE. A comprehensive set of 19 benchmark functions is employed for experimental verification. The experimental results confirm that 2-Opt DE outperforms the original DE in terms of solution accuracy and convergence speed.

Background/Aims HCV NS5A appears to play an important role in HCV resistance to IFN-α but the molecular mechanism is not fully elucidated. Most studies regarding the involvement of signal transducer and activator of transcription 1 (STAT1) in inhibition of IFN-α signaling by NS5A were performed in non-hepatic cell lines and their relevance may be debatable. Methods We analyzed the effects of NS5A on IFN-α signaling through STAT1 phosphorylation in three hepatocyte-derived cell lines, Hep3B, J5 and Huh7. Interaction of NS5A and STAT1 was also investigated with co-immunoprecipitation and confocal microscopy. Results IFN-α induces STAT1 activation in Hep3B cells in a dose- and time-dependent manner. Transient or stable NS5A expression inhibits STAT1 phosphorylation in a dose-dependent manner in hepatocyte-derived cell lines, whereas the levels of STAT1 phosphorylation remain unchanged in non-hepatocyte HeLa and COS7 cells despite increasing amounts of NS5A. The NS5A may interact with STAT1, specifically, the N-terminal 488 amino acids of STAT1. Furthermore, NS5A inhibits activation of interferon-stimulated gene factor 3 (ISGF3) and interferon-stimulated response element (ISRE)-driven gene expression, as demonstrated by electrophoretic mobility shift assay and luciferase assay, respectively. Conclusions NS5A may interact with STAT1 and inhibit IFN-α signaling through suppression of STAT1 phosphorylation specifically in hepatocyte-derived cells.

In this study, four different types of helical composite springs were made of structures including unidirectional laminates (AU), rubber core unidirectional laminates (UR), unidirectional laminates with a braided outer layer (BU), and rubber core unidirectional laminates with a braided outer layer (BUR), respectively. It aims to investigate the effects of rubber core and braided outer layer on the mechanical properties of the aforementioned four helical springs. According to the experimental results, the helical composite spring with a rubber core can increase its failure load in compression by about 12%; while the spring with a braided outer layer can not only increase its failure load in compression by about 18%, but also improve the spring constant by approximately 16%. The helical spring with a BUR structure has the highest mechanical properties among those considered herein, its failure load in compression approximately equals 336.2 kgf, and the spring constant is almost 16.27 kgf/mm.

Human sorcin,Mr22-kDa/pI5.3, was identified in HOB1 lymphoma cells resistant to 1.0 μ M vincristine (designated HOB1/VCR1.0). The protein was purified and polyclonal antibody against it was produced. Using antibody to precipitate sorcin from32P-labeled cell extract, the SDS–PAGE-resolved human sorcin was not phosphorylated in contrast to the report of A. M. van der Blieket al.((1986)EMBO J.5, 3201–3208) in which the authors emphasized hamster sorcin might be phosphorylated through a cAMP-dependent protein kinase. Although sorcin had not been found among proteins of parental HOB1 cells labeled by [35S]methionine and resolved by 2-D PAGE, it could be immunoprecipitated from the cytosolic extract of the same cells.In vitrophosphorylation study did not reveal an enhanced phosphoprotein located in the area of 22 kDa, either. A 521-bp human sorcin cDNA fragment synthesized by PCR was used to screen cDNA library constructed from mRNA of HOB1/VCR1.0 cells. Human sorcin cDNA encoded 198 amino acids, 10 among which have been replaced in hamster sorcin. Of the 10 amino acid changes, 6 involve serine's in human sorcin compared to hamster's 1. These data suggest a difference in phosphorylation state between the two species. The results of Southern blot indicate the sorcin gene was amplified in HOB1/VCR1.0 cells under the pressure of high concentration of vincristine but not secondary to themdrgene amplification. 2-step PCR, exhibiting the gene could be latently expressed in parental HOB1 cells, confirms the above result of immunoprecipitation. Interestingly, HOB1/VCR0.5 cells (resistant to 0.5 μ M vincristine) do not show amplification of the gene but do have increased expression of the protein. When this cell line was cultured in 0.1 μ M vincristine for a period of time, the protein's expression amount reverted to the latent level. These results suggest that sorcin should have a place in mediating resistance of HOB1 cells to vincristine.

Two proteins with M r values of 170 kDa and 200 kDa, respectively, were identified in HOB1 lymphoma cells resistant to 1.0 μM vincristine (designated HOB1/VCR1.0) by Western blot. Using anti-P-glycoprotein monoclonal antibody to immunoprecipitate the protein from the 32 P-labeled extract of HOB1/VCR1.0 cells, the major form of the protein was in the area of 200 kDa. When the cells were cultured in 0.5 μM vincristine for 72 h, the major form shifted to the area of 170 kDa. Northern blot analysis of the mdr transcription showed the gene had been overexpressed to a maximum in the cells resistant to 0.5 μM vincristine. [ 3 H]Vincristine uptake study showed the cells with hyperphosphorylated P-glyceprotein accumulated only half the amount of the agent after 60 min of incubation as compared with those with hypophosphorylated protein. The current study suggests hyperphosphorylated P-glycoprotein is a form by which the cells can effectively exploit the protein when it can not be induced any more.

A multidrug-resistant lymphoma cell line resistant to 1.0 microM vincristine (designated HOB1/VCR1.0) was established. The tubulins of parental and resistant cell lines were purified by ion-exchange chromatography. Two-dimensional polyacrylamide gel electrophoresis of tubulins showed a decrease in the basic component of beta-tubulin in the HOB1/VCR1.0 cell line; native isoelectric focusing of tubulins showed decreased expression of two more basic tubulin dimers in the same cell line. The [3H]vincristine-tubulin binding studies were performed by filtration and HPLC and displayed the tubulin of HOB1/VCR1.0 cells having a weaker binding affinity to vincristine than those of parental HOB1 and HOB1/VCR0.5 cells. The binding constant Ka of purified tubulin to vincristine, calculated from the slope of the Scatchard curve, for parental HOB1 cells was 5.6 x 10(6), and that for HOB1/VCR1.0 cells was 3.1 x 10(6). The Scatchard kinetics was also used to determine the binding ability of the purified tubulins to [3H]colcemid: the Kas for parental and HOB1/VCR1.0 cells were 3.9 x 10(5) and 2.0 x 10(5), respectively. The current study suggests that high-level resistant cells, HOB1/VCR1.0, tend to express fewer tubulin isoforms of stronger binding affinities to antimitotic agents; that is, they preserve weak drug-binding forms rather than produce additional species. This may be a mechanism for the cells to protect themselves from drug injury when the P-glycoprotein cannot efficiently pump out the agent of high concentration within the cells.

In this paper, we shall design a systolic algorithm for generating all N! permutations of N objects. The algorithm is time efficient, generates all permutations in lexicographic order, and can be execuded on a simple computation model (systolic array). Futhermore, because the algorithm is systolic, it is suitable for VLSI implementation.

Permutation generation is an important problem in combinatorial computing. In this paper we present an optimal parallel algorithm to generate all N! permutations of N objects. The algorithm is designed to be executed on a very simple computation model that is a linear array with N identical processors. Because of the simplicity and regularity of the processors, the model is very suitable for VLSI implementation. Another advantageous characteristic of this design is that it can generate all the permutations in minimal change order.

An MDR cell line resistant to 1.0 μM vincristine (designated HOB1/VCR 1.0 ) was established. The growth rate of HOB1/VCR 1.0 cells was slow. The cells did not go into active proliferation although the drug treatment was released for two months (revertant cells). The HOB1/VCR 1.0 cell line and its revertant were resistant to a high dose of vincristine (up to 20 μM). These two cell lines showed a decrease in expression of the hyperphosphorylated form of the retinoblastoma protein, of which the hypophosphorylated form has been considered to be a tumor suppressor. Similar phenomena were observed in the parental cells surviving brief treatment with a lethal dose of vincristine (0.05 μM). The current study gives the impression that self-inhibited growth rate may participate in the initial drug resistance before the expression of P-glycoprotein when tumor cells are suddenly exposed to chemotherapeutic agents.