This paper investigates the dynamical processes through which the Tibetan Plateau (TP) influences the East Asian summer monsoon (EASM) within the framework of the moist static energy (MSE) budget, using both observations and atmospheric general circulation model (AGCM) simulations. The focus is on the most prominent feature of the EASM, the so-called meiyu-baiu (MB), which is characterized by a well-defined, southwest-northeast elongated quasi-stationary rainfall band, spanning from eastern China to Japan and into the northwestern Pacific Ocean between mid-June and mid-July.Observational analyses of the MSE budget of the MB front indicate that horizontal advection of moist enthalpy, and primarily of dry enthalpy, sustains the front in a region of otherwise negative net energy input into the atmospheric column. A decomposition of the horizontal dry enthalpy advection into mean, transient, and stationary eddy fluxes identifies the longitudinal thermal gradient due to zonal asymmetries and the meridional stationary eddy velocity as the most influential factors determining the pattern of horizontal moist enthalpy advection. Numerical simulations in which the TP is either retained or removed show that the TP influences the stationary enthalpy flux, and hence the MB front, primarily by changing the meridional stationary eddy velocity, with reinforced southerly wind over the MB region and northerly wind to its north. Changes in the longitudinal thermal gradient are mainly confined to the near downstream of the TP, with the resulting changes in zonal warm air advection having a lesser impact on the rainfall in the extended MB region.

The breast attains its maximum development during pregnancy and lactation. After menopause the breast regresses in both nulliparous and parous women containing lobular structures that have been designated lobules type 1. Despite the similarity in the lobular composition of the breast at menopause, the fact that nulliparous women are at higher risk of developing breast cancer than parous women, indicates that Lobules type 1 in these two groups of women might be biologically different, or exhibit different susceptibility to carcinogenesis. Based on these observations it was postulated that the Lobule type 1 found in the breast of nulliparous women and of parous women with breast cancer never went through the process of differentiation, retaining a high concentration of epithelial cells that are targets for carcinogens and therefore susceptible to undergo neoplastic transformation, these cell are called Stem cells 1, whereas Lobules type 1 structures found in the breast of early parous postmenopausal women free of mammary pathology, on the other hand, are composed of an epithelial cell population that is refractory to transformation called Stem cells 2. It was further postulated that the degree of differentiation acquired through early pregnancy has changed the "genomic signature" that differentiates the Lobule type 1 from the early parous women from that of the nulliparous women by shifting the Stem cell 1 to a Stem cell 2 that is refractory to carcinogenesis, making this the postulated mechanism of protection conferred by early full term pregnancy. The identification of a putative breast stem cell (Stem cell 1) has reached in the last decade a significant impulse and several markers also reported for other tissues have been found in the mammary epithelial cells of both rodents and humans. Although still more work needs to be done in order to better understand the role of the Stem cell 2 and its interaction with the genes that confer it a specific signature, collectively, the data presently available provides evidence that pregnancy, through the process of cell differentiation, shifts the Stem cell 1 to Stem cell 2, cells that exhibit a specific genomic signature that could be responsible for the refractoriness of the mammary gland to carcinogenesis.

Interleukin-1 triggers the down-regulation of several hepatic cytochrome P450 gene products, but the cellular signaling pathways involved are not known. We have examined the role of sphingomyelin hydrolysis to ceramide in the suppression of CYP2C11, a major constitutive form of cytochrome P450, by interleukin-1. Treatment of rat hepatocytes cultured on matrigel with interleukin-1␤ caused a rapid turnover of sphingomyelin and an increase in cellular ceramide, with no change in cellular phosphatidylcholine. The ceramide was composed mainly of a D-erythro-sphingosine backbone, suggesting that it was derived from sphingolipid hydrolysis rather than from increased de novo synthesis. Treatment of the cells with either N-acetyl-D-erythro-sphingosine (C 2 -ceramide) or bacterial sphingomyelinase suppressed the expression of CYP2C11 and induced the expression of the interleukin-1-responsive ␣ 1 -acid glycoprotein mRNA. In contrast, the acute-phase gene ␤-fibrinogen, which is induced by interleukin-6 but not by interleukin-1, did not respond to C 2 -ceramide. N-Acetyl-D-erythro-sphinganine mimicked the effect of C 2 -ceramide on CYP2C11, but not on ␣ 1 -acid glycoprotein expression. These results are consistent with a role for ceramide or a related sphingolipid in mediating the down-regulation of CYP2C11, the induction of ␣ 1 -acid glycoprotein, and perhaps other cellular effects of interleukin-1 in hepatocytes.Stimulation of the immune system during an infection or inflammation results in an impairment of hepatic drug metabolism and a decrease in the hepatic content of cytochrome P450, the family of enzymes that are responsible for the metabolism of many drugs and chemical toxins (2-4). The decrease in drug clearance can result in adverse reactions to normal doses of clinically important drugs, such as theophylline (5), that have low therapeutic indices.At least part of the decrease in P450 1 -catalyzed metabolism in response to inflammatory stimuli such as bacterial endotoxin is due to the down-regulation of multiple P450 gene products (6, 7), which appear to be manifested mainly at the transcriptional level (8). The down-regulation of P450 genes is accompanied by a well characterized induction of hepatic plasma proteins (such as fibrinogen and ␣ 1 -acid glycoprotein (9), which are called the "positive acute-phase proteins") and a decreased synthesis of "negative acute-phase proteins" (such as albumin (9)). Cytokines, together with glucocorticoids, are the major humoral mediators of the acute phase of host defense after injury and infection (9). Numerous in vivo and in vitro studies have shown that IL-1␤ plays a key role in inducing many of the acute-phase proteins at both transcriptional and post-transcriptional levels (9), whereas others are induced mainly by the action of interleukin-6 (9). A role for IL-1␤ in the down-regulation of P450 genes has been inferred from several studies in which injection of IL-1␤ in vivo reduced the expression of various P450 gene products (10 -13). However, until now, studies on the mec...

Ethinyl estradiol (EE) is a strong hepatic promoter and weak complete hepatocarcinogen. Among the effects on rat liver caused by chronic exposure to non-hepatotoxic doses of EE is an initial, transient increase in hepatocyte growth followed by a subsequent inhibition (mitosuppression) of basal and/or induced liver growth. To investigate the mechanism of EE-induced mitosuppression, we performed a differential display and identified 10 genes whose expression was increased 2- to 4-fold in EE-induced, mitosuppressed livers (Chen et al., Carcinogenesis, 17, 2783-2786, 1996). We found that one of these clones was homologous to nuclear genome-encoded mitochondrial ATP synthase subunit E. Here, we describe the identification of two additional cDNAs representing transcripts whose levels were elevated during EE-induced mitosuppression as mitochondrial DNA-encoded cytochrome c oxidase subunit III and ATP synthase 6. In addition, we found that EE, estradiol and the estradiol catechol metabolites, 4-OH-estradiol and 2-OH-estradiol, increased the levels of these and other mitochondrial genome-encoded transcripts in human hepatoma HepG2 cells. We also observed that this increase can be blocked by inhibition of cytochrome P450-mediated estrogen metabolism, and that this increase is accompanied by increased mitochondrial superoxide production, which reflects increased respiratory chain activity.

Ethinyl estradiol (EE) is a strong promoter of hepatocarcinogenesis. Treatment of rats with EE and other hepatic promoters induces a mitosuppressed state characterized by decreased hepatocyte turnover and reduced growth responsiveness. Previously, we identified several nuclear and mitochondrial genome-encoded mitochondrial genes whose transcripts were increased during EE-induced hepatic mitosuppression in rats and in EE-treated HepG2 cells (Chen et al. Carcinogenesis, 17, 2783-2786, 1996 and Carcinogenesis, 19, 101-107, 1998). In both cultured rat hepatocytes and HepG2 cells, EE increased respiratory chain activity (reflected by increased mitochondrial superoxide production detected as increased lucigenin-derived chemiluminescence (LDCL). In this paper, we provide additional characterizations of these effects. Increased LDCL was detected in mitochondria isolated from EE-treated rats, documenting that these estrogen effects on mitochondrial function are not confined to cells in culture. EE and estradiol (E2) increased LDCL in cultured rat hepatocytes and HepG2 cells in a dose- (beginning at 0.25 microM levels) and time-dependent response. Inhibition of P450-mediated estrogen metabolism inhibited, while direct exposure to E2 catechol metabolites enhanced LDCL. Co-treatment with glutathione ester or with the specific antiestrogen, ICI 182708 inhibited LDCL. In contrast, estrogen-induced LDCL was enhanced by glutathione depletion, and by inhibition of catechol-o-methyltransferase. These results support a working hypothesis that in liver cells, increased respiratory chain activity induced by estrogen treatment requires both metabolism to catechols and an estrogen receptor-mediated signal transduction pathway.