cells; C-6 cells; SchizophreniaSchizophrenia is a chronic psychiatric illness with two major types of symptoms-positive or psychotic symptoms, such as hallucinations and delusions, and negative or deficit symptoms, such as amotivation, apathy, and asociality. Approximately 1% of the population suffers from schizophrenia (Kaplan and Sadock 1988). The serendipitous discovery of chlorpromazine four decades ago not only provided the first efficacious therapeutic intervention, but also opened horizons into research about the etiology and therapy of this disease. It was soon hypothesized that chlorpromazine and similar drugs worked by being pharmacological antagonists of the neurotransmitter dopamine (Seeman et al. 1976;Creese et al. 1976), a hypothesis that ultimately provided the foundation for the commonly accepted division of dopamine receptors into two classes (Garau et al. 1978), now often called D 1 and D 2 (Kebabian and Calne 1979).During the past decade, molecular cloning studies have resulted in the identification of several genes coding for dopamine receptors. There now are at least two From the Departments of Pharmacology (CP, RBM) and Psychiatry (CPL, RBM), and Medicinal Chemistry (RBM), Curricula in Toxicology (CPL, RBM), and Neurobiology (MML, RBM), UNC Neuroscience Center (CPL, CP, MML, RBM), University of North Carolina School of Medicine, Chapel Hill, North Carolina; and Molecular Neuropharmacology Section (CM, DJ, JAS, AMG, DRS), National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland.Address correspondence to: Dr. Cindy Lawler, CB #7250; UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7250. Received April 17, 1998; revised August 27, 1998; accepted September 21, 1998. (Zhou et al. 1990;Monsma et al. 1990;Sunahara et al. 1990;Dearry et al. 1990) and D 1B (Tiberi et al. 1991) or D 5 (Sunahara et al. 1991], both of these linked functionally to stimulation of cAMP synthesis, and preferentially recognizing 1-phenyl-tetrahydrobenzazepines (e.g., SCH23390). The D 2 -like receptors come from at least three genes and include multiple splice variants. The D 2 -like receptors [D 2S (Bunzow et al. 1988), D 2L (Giros et al. 1989;Monsma et al. 1989), D 3 (Sokoloff et al. 1990, and D 4 ] sometimes are linked to inhibition of cAMP synthesis and have a different pharmacological specificity from the D 1 -like receptors (i.e., having much higher affinity for spiperone or sulpiride).The traditional view of antipsychotic drug efficacy posits a primary role for pharmacological antagonism of D 2 -like receptors. Despite the demonstrable effectiveness of dopamine D 2 receptor antagonists, however, a substantial number (up to 20%) of patients are considered unresponsive to these typical antipsychotics (Kane et al. 1988). Furthermore, the typical antipsychotics have significant and serious side effects that make them less than optimal therapeutic agents (see Peacock and Gerlach 1996). For example, they cause acute drug-induced parkinsonian symptoms (...

Exposure of D1 dopamine receptors to agonists results in rapid desensitization of the receptor-stimulated accumulation of cAMP. It is believed that agonist-induced phosphorylation of the receptor plays a critical role in the processes that underlie this phenomenon. To investigate the role of agonist-induced receptor phosphorylation, a FLAG epitope was added to the amino terminus of the rat D1 dopamine receptor and this construct was stably expressed in C6 glioma cells. It was found that the D1 receptor was stoichiometrically phosphorylated under basal conditions and that its phosphorylation state was increased by 2- to 3-fold upon exposure of the cells to dopamine for 10 min. The dopamine-induced receptor phosphorylation could be blocked by D1-selective antagonists but was unaffected by inhibitors of either protein kinase A or protein kinase C. The incorporation of phosphate into the receptor was rapid but transient, despite the continued presence of dopamine. A comparison of the rates of receptor phosphorylation approximately ion (t(1/2) < 1 min) and dopamine-induced desensitization (t(1/2) approximately 7 min) revealed that receptor phosphorylation was not the rate limiting step for receptor desensitization. Upon removal of dopamine, the receptor was rapidly dephosphorylated (t(1/2) approximately 10 min) and this was not blocked by agents (i.e., concanavalin A or hypertonic sucrose) that inhibit D1 receptor internalization. Using specific inhibitors, the phosphatase involved in D1 receptor dephosphorylation was shown not to correlate with the recently identified "G protein-coupled receptor phosphatase" (Proc Natl Acad Sci USA 92:8343-8347, 1995). These results suggest that the phosphorylated D(1) receptor is processed through a novel recovery pathway and that internalization is not required for receptor dephosphorylation.

Seasonal changes in demands, supplies, and also in the operating conditions of a chemical process may call for different system structures to optimize the performance of its heat exchanger network (HEN). To produce a multiperiod HEN design, the traditional approach is to solve a single mathematical program that minimizes the total annual cost (TAC). This objective function, that is, TAC, is usually the sum of the annualized capital costs and annual utility costs determined according to given durations of all periods in a year. As a result, the conventional designs are often suboptimal, since the period lengths may have to be adjusted in response to the unexpected disturbances during actual operations. A new design approach is taken in the present study to circumvent the aforementioned drawback. In particular, a single-period model is first constructed and solved to produce the optimal design for each period individually. A timesharing strategy is then applied to integrate all such single-period designs so as to reduce the overall capital investment as much as possible while still keeping the utility consumption rates in every period at the minimum levels. In addition to their economic benefits, the new designs should be considered to be more flexible, since they are optimal despite unforeseen changes in the operation schedule. Finally, the numerical results of extensive case studies are also reported in this paper to demonstrate the effectiveness of the proposed approach. ■ INTRODUCTIONHeat exchanger network (HEN) synthesis has been a wellstudied subject over the last three decades. The mathematical programming approaches for this task can be classified into two different types, that is, the sequential and simultaneous optimization strategies. 1−3 The former usually calls for decomposition of the design procedure into several consecutive steps so as to reduce the computation effort. Such a practice inevitably leads to suboptimal solutions because the trade-off issues between energy consumption and capital expenditure cannot be properly addressed. Although this shortcoming can be overcome with the simultaneous strategy in principle, the required optimization runs may not always be convergent.In a realistic production environment, the demands, supplies, and also the operating conditions of a chemical process may undergo seasonal variations. Such changes could cause the operation of its HEN inefficient if the network structure is configured under a single-period assumption. Various design methods have already been developed to generate the optimal multiperiod HEN designs. On the basis of given process data, Floudas and Grossmann 4,5 first suggested to produce a feasible HEN design by separately achieving the minimum utility cost, the minimum number of units, and the minimum investment cost for each time period. Since the global optimum cannot be reached with such a sequential strategy, extensive subsequent studies have thus been performed in recent years to develop effective simultaneous approaches.Aaltola 6 first d...

MicroRNAs (miRNAs) have been shown to play an important role in diverse biological processes and cancer progression. The objective of the present study was to investigate the role of miR-497 in ovarian cancer angiogenesis. We found that miR-497 expression was downregulated in human ovarian cancer tissues, and the low miR-497 expression was significantly associated with increased angiogenesis. Functionally, exogenous expression of miR-497 suppressed the ability of ovarian cancer cells to promote capillary tube formation of endothelial cells. We further disclosed that miR-497 exerted its function of anti-angiogenesis by suppressing VEGFA expression in ovarian cancer cells and, in turn, impairing the VEGFR2-mediated PI3K/AKT and MAPK/ERK pathways. Our findings suggest that downregulation of miR-497 may contribute to angiogenesis in ovarian cancer. miR-497 may be a promising candidate target for prevention and treatment of ovarian cancer.