interacts_with DB08910?
Modification of the reactivity of three amino-acid residues in elongation factor 2 during its binding to ribosomes and translocation . The accessibility of three amino acids of P13639 , located within highly conserved regions near the N- and C-terminal extremities of the molecule ( the E region and the DB02059 region , respectively ) to modifying enzymes has been compared within nucleotide-complexed P13639 and ribosomal complexes that mimic the pre- and posttranslocational ones : the high-affinity complex ( P13639 ) -nonhydrolysable GTP analog GuoPP[CH2]P ribosome and the low-affinity ( P13639 ) -GDP-ribosome complex , P13639 and ribosomes being from rat liver . We studied the reactivity of two highly conserved residues diphthamide-715 and DB00125 -66 , to diphtheria-toxin-dependent ADP-ribosylation and trypsin attack , and of a threonine that probably lies between residues 51 and 60 , to phosphorylation by a Ca2+/calmodulin-dependent protein kinase . DB03223 715 and this threonine residue were unreactive within the high-affinity complex but seemed fully reactive in the low-affinity complex . DB00125 -66 was resistant to trypsin in both complexes . The possible involvement of the E and DB02059 regions of P13639 in the interaction with ribosome in the two complexes is discussed . Inhibition of tumor necrosis factor signal transduction in endothelial cells by dimethylaminopurine . P01375 ( P01375 ) promotes diverse responses in endothelial cells that are important to the host response to infections and malignancies ; however , less is known of the postreceptor events important to P01375 action in endothelial cells than in many other cell types . Since phosphorylation cascades are implicated in cytokine signaling , the effects of the protein kinase inhibitor dimethylaminopurine ( DMAP ) on P01375 action in bovine aortic endothelial cells ( BAEC ) were investigated . In BAEC , P01375 promotes phosphorylation of eukaryotic initiation factor 4E ( P06730 ) , c-Jun N-terminal kinase ( JNK ) and ceramide-activated protein kinase activities , Jun-b expression , prostacyclin production , and , when protein synthesis is inhibited , cytotoxicity . DMAP abrogated or significantly attenuated each of these responses to P01375 , without affecting the specific binding of P01375 to its receptors . DB11320 , another agent active in the endothelium , promotes phosphorylation of elongation factor-2 ( P13639 ) and prostacyclin production , but not phosphorylation of P06730 in BAEC . DB11320 -stimulated P13639 phosphorylation was not inhibited and prostacyclin production was unaffected by DMAP . These observations demonstrate that a distinct signal transduction cascade , which can be selectively inhibited by DMAP , promotes the response of BAEC to P01375 . Thus , we have identified a reagent , DMAP , that may be useful for characterizing the P01375 signal transduction pathway . Essential erbB family phosphorylation in osteosarcoma as a target for DB05424 inhibition . BACKGROUND : The role of erbB tyrosine kinases , especially Her-2 , in osteosarcoma has engendered intense debate . Some investigators identified an association between low-level Her-2 expression , compared to none , and poor patient outcome . Others questioned the importance of apparent cytoplasmic expression of Her-2 , since membranous overexpression is associated with poor outcome in carcinomas . We previously demonstrated that primary osteosarcoma cells express cell-surface P00533 and Her-2 , with the p80 isoform of Her-4 localized to the nucleus . We wished to determine if erbB kinases in osteosarcoma were phosphorylated , and if this was required for growth . PROCEDURES : We cultured early passage osteosarcoma cell lines in the presence or absence of the pan-erbB inhibitor DB05424 and examined the phosphorylation status of P00533 , Her-2 , and Her-4 by immunohistochemistry , cell-based ELISA , flow cytometry and two dimensional Western blot . We also assessed the impact of DB05424 upon osteosarcoma growth and survival in vitro . RESULTS : P00533 , Her-2 , and Her-4 were constitutively phosphorylated in early passage osteosarcoma cells cultured in vitro . DB05424 abrogated erbB receptor phosphorylation and caused growth inhibition and apoptosis in a titratible fashion with concentrations of 1 muM or more . CONCLUSIONS : P00533 , Her-2 , and Her-4 are constitutively phosphorylated in early passage osteosarcoma cells in tissue culture , and erbB signaling provides essential growth and anti-apoptotic signals to osteosarcoma cells . This suggests that erbB overexpression is not required for erbB to promote malignancy , but rather that overexpression is one of several mechanisms that generate unregulated erbB signaling . Prominence of central sphingosine-1-phosphate receptor-1 in attenuating aβ-induced injury by fingolimod . FTY720 ( fingolimod ) , the sphingosine-1-phosphate ( Q14703 ) analogue , has been experimentally indicated to exert substantial ameliorating effects in animal models of Alzheimer 's disease ( AD ) . The present work aims to answer whether central P21453 ( P21453 ) plays significant role in the impact of fingolimod in AD . To verify the prominence of central FTY720 phosphorylation , DMS ( sphingosine kinase inhibitor ) was infused intracerebrally in parallel with systemic FTY720 administration to prevent central formation of FTY720-P as the recognized active ligand for S1PRs . The corresponding P21453 modulation was also investigated using the pharmacological blockage of central P21453 by W123 . Both DMS and W123 were efficiently capable of suppressing FTY720-ameliorating effects in AD animals , either on memory deficit or on P36551 -II and P01375 -α expression . Our data conclude that experimental benefits of FTY720 in the context of AD depend on central P21453 modulation , as well as on Q14703 kinase activity in the brain . DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti-inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo-controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin-induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 , IL-1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein-1alpha , macrophage inflammatory protein-1beta , monocyte chemoattractant protein-1 ( P13500 ) , interferon-inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti-inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels . Critical role of P21453 and integrin β4 in P14210 /c- DB00134 -mediated increases in vascular integrity . Vascular endothelial cell ( EC ) barrier integrity is critical to vessel homeostasis whereas barrier dysfunction is a key feature of inflammatory disorders and tumor angiogenesis . We previously reported that hepatocyte growth factor ( P14210 ) -mediated increases in EC barrier integrity are signaled through a dynamic complex present in lipid rafts involving its receptor , c- DB00134 . We extended these observations to confirm that P21453 ( sphingosine 1-phosphate receptor 1 ) and integrin β4 ( P16144 ) are essential participants in P14210 -induced EC barrier enhancement . Immunoprecipitation experiments demonstrated P14210 -mediated recruitment of c- DB00134 , P16144 and P21453 to caveolin-enriched lipid rafts in human lung EC with direct interactions of c- DB00134 with both P21453 and P16144 accompanied by c- DB00134 -dependent P21453 and P16144 transactivation . Reduced P21453 expression ( siRNA ) attenuated both P16144 and Rac1 activation as well as c- DB00134 / P16144 interaction and resulted in decreased transendothelial electrical resistance . Furthermore , reduced P16144 expression attenuated P14210 -induced c- DB00134 activation , c- DB00134 / P21453 interaction , and effected decreases in Q14703 - and P14210 -induced EC barrier enhancement . Finally , the c- DB00134 inhibitor , DB05030 , suppressed P14210 -induced c- DB00134 activation as well as P21453 and P16144 transactivation . These results support a critical role for P21453 and P16144 transactivation as rate-limiting events in the transduction of P14210 signals via a dynamic c- DB00134 complex resulting in enhanced EC barrier integrity . Acute kidney injury and inflammatory immune reconstitution syndrome in mixed genotype ( A/E ) hepatitis B virus co-infection in HIV-associated lymphoma . We report a first case of HIV-associated lymphoma ( P42357 ) presenting with acute kidney injury ( AKI ) and inflammatory immune reconstitution syndrome ( IRIS ) . A 39-year-old male , treated with nonsteroidal anti-inflammatory drugs ( NSAIDs ) for one month prior to admission , developed AKI , left testicular tumor , and recurrent swelling of the right parotid gland . A resected testicular tumor exhibited features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma . Renal biopsy showed hydro-degeneration of renal tubules , interstitial inflammatory cells , and a small number of lymphoma cells in the sub-capsule , compatible with acute interstitial nephritis . DB00117 renal dysfunction rapidly recovered following chemotherapy and combination antiretroviral therapy ( cART ) . He developed pneumonia concomitantly with a decrease in HIV-RNA level and an increase in P01730 + cells after the first cycle of chemotherapy , which spontaneously resolved after the second cycle of chemotherapy without additional anti-infection drugs ; thus , his pneumonia fulfilled the diagnostic criteria for IRIS . We suggest that IRIS may frequently develop during chemotherapy for P42357 , but may be overlooked . He was coinfected with hepatitis B virus ( HBV ) , which genotypes known as is associated with liver-related mortality and response to antiviral therapy ; recently , an intimate interplay between HIV and HBV in the onset of lymphoma has been reported . Therefore , we addressed the HBV genotype in the patient . The analysis revealed that he exhibited a mixed genotype ( A/E ) not native to Japan and primarily found in Europe and North America or West Africa . These findings suggest that universal vaccination for juveniles against HBV is warranted in Japan . P05231 , P01579 and P01375 production by liver-associated T cells and acute liver injury in rats administered concanavalin A . The relationship between the development of acute hepatitis and the production of P01375 P01579 and P05231 by liver-associated T lymphocytes following intravenous injection of concanavalin A ( Con A ) was studied in rats . Following a single injection of Con A , there was a dose and time-dependent correlation in the serum levels of serum alanine aminotransferase ( ALT ) , P05231 , P01579 and P01375 . These increases correlated with an increase in the numbers of P01730 + , CD8+ and CD25+ T cells in blood and P01730 + and CD25+ T cells in the liver perfusate , but not with CD8+ T cells in liver perfusate . Increased levels of P05231 , P01579 and P01375 were constitutively produced by liver-associated P01730 + T cells when cultured . In Con A-stimulated cultures , liver-associated P01730 + T cells secreted increasing levels of P01375 in a time-dependent manner following Con A injection , but P01375 production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h . Histological examination of the liver revealed fatty change , hepatocyte degeneration and necrosis , with an associated cell infiltrate of neutrophils and P01730 + T cells both in the portal areas and around the central veins . These results support the hypothesis that Con A-induced liver damage is mediated by P01730 + T cells acting within the liver , at least in part through the secretion of P01375 , P01579 and P05231 . Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC-4047 ( Actimid , DB08910 ) have been used as anti-inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor-alpha ( P01375 ) , interleukins ( IL ) 1-beta , 6 , 12 , and granulocyte macrophage-colony stimulating factor ( GM- P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti-angiogenic , anti-proliferative , and pro-apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies . Cbl-b is a negative regulator of inflammatory cytokines produced by IgE-activated mast cells . c-Cbl and Cbl-b E3 ubiquitin ligases are abundantly expressed in hemopoietic cells where they negatively regulate the activity and levels of many cell surface receptors and associated signaling molecules . By comparing bone marrow-derived mast cells from c-Cbl and Cbl-b-deficient mice it has recently been shown that Cbl-b is the dominant family member for negatively regulating signaling responses from high-affinity IgE receptors . In this study , we suggest that a possible reason for the greater enhancement of IgE receptor signaling in Cbl-b-deficient mice is the relatively higher levels of Cbl-b protein over c-Cbl in mast cells compared with other hemopoietic cells . We also directly compare mast cells from c-Cbl and Cbl-b-deficient mice and find that loss of Cbl-b , but not c-Cbl , increases cell growth , retards receptor internalization , and causes the sustained tyrosine phosphorylation of Syk and its substrates . However , loss of Cbl-b does not enhance the activation of P29323 or Akt , nor does it promote a greater calcium response . Furthermore , loss of Cbl-b or c-Cbl does not increase levels of the Syk or Lyn protein tyrosine kinases . Most notable , however , is the extremely large increase in the production of proinflammatory cytokines P01375 , P05231 , and P13500 by Cbl-b(-/-) mast cells compared with levels produced by c-Cbl(-/-) or wild-type cells . This marked induction , which appears to be restricted to these three cytokines , is dependent on IgE receptor activation and correlates with enhanced O15111 phosphorylation . Thus , Cbl-b functions as a potent negative regulator of cytokines that promote allergic and inflammatory reactions . P01375 inhibits flow and insulin signaling leading to NO production in aortic endothelial cells . Endothelial cells release nitric oxide ( NO ) acutely in response to increased " flow " or fluid shear stress ( FSS ) , and the increase in NO production is correlated with enhanced phosphorylation and activation of endothelial nitric oxide synthase ( P29474 ) . Both vascular endothelial growth factor and FSS activate endothelial protein kinase B ( P31749 ) by way of incompletely understood pathway(s) , and , in turn , P31749 phosphorylates P29474 at DB00133 -1179 , causing its activation . In this study , we found that either FSS or insulin stimulated insulin receptor substrate-1 ( P35568 ) tyrosine and serine phosphorylation and increased P35568 -associated phosphatidylinositol 3-kinase activity , phosphorylation of P31749 DB00133 -473 , phosphorylation of P29474 DB00133 -1179 , and NO production . Brief pretreatment of bovine aortic endothelial cells with tumor necrosis factor-alpha ( P01375 ) inhibited the above described FSS- or insulin-stimulated protein phosphorylation events and almost totally inhibited FSS- or insulin-stimulated NO production . These data indicate that FSS and insulin regulate P29474 phosphorylation and NO production by overlapping mechanisms . This study suggests one potential mechanism for the development of endothelial dysfunction in disease states with alterations in insulin regulation and increased P01375 levels . Potent and selective inhibition of human nitric oxide synthases . Inhibition by non-amino acid isothioureas . DB02539 was a potent competitive inhibitor of human nitric oxide synthase ( NOS ) , with Ki values of 17 , 36 , and 29 nM for the inducible ( i ) , endothelial ( e ) , and neuronal ( n ) isozymes , respectively . Unlike some potent inhibitors of NOS , no time dependence was observed . DB02539 was not a detectable substrate for P29474 . DB02539 was also a potent inhibitor of mouse P35228 ( Ki value of 5.2 nM ) , and its binding perturbed the spectrum of P35228 consistent with its altering the environment of the bound heme . The optimum binding of S-ethyl- and S-isopropylisothiourea relative to 70 other analogs suggested that these alkyl substitutions fit into a small hydrophobic pocket . Most isothioureas were 2-6-fold selective for the human P35228 ( Ki for P35228 versus Ki for P29474 ) , with one being 19-fold selective . The cyclized mimics of S-ethylisothiourea , 2-NH2-thiazoline , and 2-NH2-thiazole , were also competitive inhibitors of human NOS . A third structural class of inhibitors , bisisothioureas , were , in general , the most selective in their inhibition of human P35228 . S,S'-(1,3-Phenylenebis(1,2-ethanediyl))bisisothiourea was 190-fold selective ( Ki value of 0.047 microM against P35228 versus 9.0 microM against P29474 ) . These results demonstrate that potent and selective inhibition of human NOS isozymes is achievable . P50579 is required for P19526 initiation and proliferation . In a chemical screening , we tested the antiangiogenic effects of fumagillin derivatives and identified fumagillin as an inhibitor of definitive hematopoiesis in zebrafish embryos . DB02640 is known to target methionine aminopeptidase II ( MetAP2 ) , an enzyme whose function in hematopoiesis is unknown . We investigated the role of MetAP2 in hematopoiesis by using zebrafish embryo and human umbilical cord blood models . Zebrafish metap2 was expressed ubiquitously during early embryogenesis and later in the somitic region , the caudal hematopoietic tissue , and pronephric duct . metap2 was inhibited by morpholino and fumagillin treatment , resulting in increased mpo expression at 18 hours postfertilization and reduced c-myb expression along the ventral wall of dorsal aorta at 36 hours postfertilization . It also disrupted intersegmental vessels in Tg(fli1:gfp) embryos without affecting development of major axial vasculatures . Inhibition of MetAP2 in CB P28906 (+) cells by fumagillin had no effect on overall clonogenic activity but significantly reduced their engraftment into immunodeficient nonobese diabetes/severe combined immunodeficiency mice . metap2 knock-down in zebrafish and inhibition by fumagillin in zebrafish and human CB P28906 (+) cells inhibited P62158 Kinase II activity and induced P29323 phosphorylation . This study demonstrated a hitherto-undescribed role of MetAP2 in definitive hematopoiesis and a possible link to noncanonical Wnt and P29323 signaling . Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk . The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions . We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain ( P31749 , P23560 , O75052 , P36544 , P21964 , Q96EV8 , Q99259 , Q14832 , Q99466 , Q02297 , O43272 , P49798 , P01375 ) interacted with serious obstetric complications to influence risk for schizophrenia . A family-based study of transmission disequilibrium was conducted in 116 trios . Twenty-nine probands had at least one serious obstetric complication ( OC ) using the McNeil-Sjostrom Scale , and many of the OCs reported were associated with the potential for fetal hypoxia . Analyses were conducted using conditional logistic regression and a likelihood ratio test ( LRT ) between nested models was performed to assess significance . Of the 13 genes examined , four ( P31749 ( three SNPs ) , P23560 ( two SNPs ) , Q96EV8 ( one SNP ) and Q14832 ( one SNP ) ) showed significant evidence for gene-by-environment interaction ( LRT P-values ranged from 0.011 to 0.037 ) . Although our sample size was modest and the power to detect interactions was limited , we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia . c-Jun N-terminal kinase and Akt signalling pathways regulating tumour necrosis factor-α-induced interleukin-32 expression in human lung fibroblasts : implications in airway inflammation . Airway inflammatory diseases such as chronic obstructive pulmonary disease ( P48444 ) and asthma are associated with elevated expression of interleukin-32 ( P24001 ) , a recently described cytokine that appears to play a critical role in inflammation . However , so far , the regulation of pulmonary P24001 production has not been fully established . We examined the expression of P24001 by tumour necrosis factor-α ( P01375 -α ) in primary human lung fibroblasts . Human lung fibroblasts were cultured in the presence or absence of P01375 -α and/or other cytokines/Toll-like receptor ( TLR ) ligands or various signalling molecule inhibitors to analyse the expression of P24001 by quantitative RT-PCR and ELISA . Next , activation of Akt and c-Jun N-terminal kinase ( JNK ) signalling pathways was investigated by Western blot . P24001 mRNA of four spliced isoforms ( α , β , γ and δ ) was up-regulated upon P01375 -α stimulation , which was associated with a significant P24001 protein release from P01375 -α-activated human lung fibroblasts . The combination of interferon-γ and P01375 -α induced enhanced P24001 release in human lung fibroblasts , whereas P05112 , Q16552 , Q8TAD2 and TLR ligands did not alter P24001 release in human lung fibroblasts either alone , or in combination with P01375 -α . Furthermore , the activation of Akt and JNK pathways regulated P01375 -α-induced P24001 expression in human lung fibroblasts , and inhibition of the Akt and JNK pathways was able to suppress the increased release of P24001 to nearly the basal level . These data suggest that P01375 -α may be involved in airway inflammation via the induction of P24001 by activating Akt and JNK signalling pathways . Therefore , the P01375 -α/ P24001 axis may be a potential therapeutic target for airway inflammatory diseases . Cross-talk between PKA-Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . DB01656 , a phosphodiesterase (PDE)4-selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up-regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up-regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners . We also found that protein kinase A catalytic subunit β ( PKA-Cβ ) and nuclear factor-κB ( NF-κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA-Cβ phosphorylates p65 in a DB02527 -dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA-Cβ-induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor . The anti-androgen drug dutasteride renders triple negative breast cancer cells more sensitive to chemotherapy via inhibition of HIF-1α-/ P15692 -signaling . BACKGROUND : Triple negative breast cancer ( TNBC ) is characterized by lack of expression of both estrogen and progesterone receptor as well as lack of amplification of P04626 . Patients with TNBC carry an unfavorable prognosis compared to other breast cancer subtypes given that endocrine or P04626 targeted therapies are not effective , rendering chemotherapy the sole effective treatment option to date . Therefore , there is a high demand for additional novel treatment options . FINDINGS : We previously published a list of genes showing both higher gene expression rates in TNBC and , in addition , are known to encode targets of non-oncologic drugs . P18405 , which encodes the type-1 isoform of the steroid-5alpha-reductase , which is involved in androgen metabolism , was found to be one of these genes . DB01126 is a dual blocker of both the type-1 and type-2 isoform of P18405 and is indicated in the treatment of benign prostate hyperplasia . Treatment of TNBC cell lines with dutasteride was associated with a dose-dependent decrease in cell viability , altered protein expression of P15692 and HIF-1α and increased chemosensitivity . CONCLUSION : Our results demonstrate that the P18405 -corresponding anti-androgenic drug dutasteride might act as a combinatorial therapeutic option besides standard chemotherapy in highly aggressive TNBC . Effects of an alpha 7-nicotinic agonist on default network activity in schizophrenia . BACKGROUND : 3-(2,4-dimethoxybenzylidene)-anabaseine ( DB05708 ) is a partial agonist at α7 nicotinic acetylcholine receptors that has been evaluated clinically for treatment of schizophrenia . This study examined the effects of DB05708 on default network activity as a biomarker for drug effects on pathologic brain function associated with schizophrenia . METHODS : Placebo and two doses of DB05708 were administered in a random , double-blind crossover design during a Phase 2 study of DB05708 . Functional magnetic resonance imaging was performed on 16 nonsmoking patients with schizophrenia while they performed a simple eye movement task . Independent component analysis was used to identify the default network component . Default network changes were evaluated in the context of a polymorphism in P36544 , the α7-nicotinic acetylcholine receptor subunit gene , which was previously found to be associated with schizophrenia . RESULTS : Compared with placebo , both 150 and 75 mg twice daily DB05708 altered default network activity , including a reduction in posterior cingulate , inferior parietal cortex , and medial frontal gyrus activity and an increase in precuneus activity . The most robust difference , posterior cingulate activity reduction , was affected by P36544 genotype . CONCLUSIONS : The observed DB05708 -related changes are consistent with improved default network function in schizophrenia . Pharmacogenetic analysis indicates mediation of the effect through the α7-nicotinic receptor . These results further implicate nicotinic cholinergic dysfunction in the disease and suggest that default network activity may be a useful indicator of biological effects of novel therapeutic agents . [ Cellular adhesion signal transduction network of tumor necrosis factor-alpha induced hepatocellular carcinoma cells ] . OBJECTIVE : To systemically explore the cellular adhesion signal transduction network of tumor necrosis factor-alpha ( P01375 -α ) -induced hepatocellular carcinoma cells with bioinformatics tools . METHODS : Published microarray dataset of P01375 -α-induced HepG2 , human transcription factor database HTRI and human protein-protein interaction database HPRD were used to construct and analyze the signal transduction network . RESULTS : In the signal transduction network , MYC and SP1 were the key nodes of signaling transduction . Several genes from the network were closely related with cellular adhesion. P00533 ( P00533 ) is a possible key gene of effectively regulating cellular adhesion during the induction of P01375 -α . CONCLUSION : P00533 is a possible key gene for P01375 -α-induced metastasis of hepatocellular carcinoma .