interacts_with DB06144?
AL3810 , a multi-tyrosine kinase inhibitor , exhibits potent anti-angiogenic and anti-tumour activity via targeting VEGFR , FGFR and P09619 . Angiogenesis plays an important role in neoplastic transformation and progression as well as in the metastasis process of most human cancers . Herein , we identified AL3810 as a novel and orally bioavailable small molecular inhibitor with potent inhibitory activity against multiple tyrosine kinases involved in the process of angiogenesis . We found that AL3810 substantially inhibited the autophosphorylation of P35968 , PDGFRβ and P11362 in endothelial cells . Moreover , AL3810 exhibited potent anti-angiogenesis activity , manifested by significant inhibition of microvessel outgrowth of rat arterial ring and chickallantochorion membrane ( P62158 ) in ex vivo angiogenesis models . Daily dosing of AL3810 has shown broad-spectrum anti-tumour activity in human kidney , pancreas , liver cancer xenograft models . Importantly , immunohistochemistry results demonstrated that the anti-tumour activity of AL3810 was closely correlated with its anti-angiogenesis activity , as demonstrated by a decreased microvessel area and reduced microvessel numbers in tumour tissues . The overall pharmacological profiles of AL3810 are superior to sorafenib . The clinical trials of AL3810 will soon be launched in China . Identification of a potent inverse agonist at a constitutively active mutant of human Q9H244 receptor . Human platelets express two P2Y receptors : G(q)-coupled P2Y(1) , and G(i)-coupled P2Y(12) . Both P2Y(1) and P2Y(12) are ADP receptors on human platelets and are essential for ADP-induced platelet aggregation that plays pivotal roles in thrombosis and hemostasis . Numerous constitutively active G protein-coupled receptors have been described in natural or recombinant systems , but in the P2Y receptors , to date , no constitutive activity has been reported . In our effort to identify G protein coupling domains of the human platelet ADP receptor , we constructed a chimeric hemagglutinin-tagged human P2Y(12) receptor with its C terminus replaced by the corresponding part of human P2Y(1) receptor and stably expressed it in Chinese hamster ovary- P04264 cells . It is interesting that the chimeric P2Y(12) mutant exhibited a high level of constitutive activity , as evidenced by decreased DB02527 levels in the absence of agonists . The constitutive activation of the chimeric P2Y(12) mutant was dramatically inhibited by pertussis toxin , a G(i) inhibitor . The constitutively active P2Y(12) mutant retained normal responses to 2-methylthio-ADP , with an EC(50) of 0.15 +/- 0.04 nM . The constitutively active P2Y(12) mutant caused Akt phosphorylation that was abolished by the addition of pertussis toxin . Pharmacological evaluation of several P2Y(12) antagonists revealed ( E ) -N-[1-[7-(hexylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d]-pyrimidin-3-yl]-1,5,6-trideoxy-beta-d-ribo-hept-5-enofuranuronoyl]-l-aspartic acid ( AR-C78511 ) as a potent P2Y(12) inverse agonist and 5'-adenylic acid , N-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]- , monoanhydride with (dichloromethylene)bis [ phosphonic acid ] ( AR-C69931MX ) as a neutral antagonist . In conclusion , this is the first report of a cell line stably expressing a constitutively active mutant of human platelet P2Y(12) receptor and the identification of potent inverse agonist . DB00114 values in cerebrospinal fluid : reference values and diagnosis of Q9NVS9 deficiency in paediatric patients . Our aim was to establish reference values for cerebrospinal fluid ( P04141 ) pyridoxal 5'-phosphate ( PLP ) in a paediatric population for the diagnosis of pyridox(am)ine 5'-phosphate oxidase ( Q9NVS9 ) deficiency . For reference values , P04141 samples from 113 paediatric controls ( age range : 1 day-18 years ) from Barcelona and London were analysed . Cerebrospinal fluid PLP and biogenic amine concentrations were analysed by HPLC with fluorescence and electrochemical detection . DB00114 concentrations in 4 patients with Q9NVS9 deficiency were determined . A negative correlation between P04141 PLP values and age of controls was observed in both populations ( r=-0.503 ; p < 0.0001 and r=-0.542 ; p=0.002 ) . Reference values were stratified into 4 ( Barcelona ) and 3 age groups ( London ) . For the newborn period , P04141 PLP reference intervals were 32-78 and 44-89 nmol/L for the Barcelona and London centers , respectively ) . No correlation was observed in the different age groups between PLP values and biogenic amines metabolites . PLP values in neonates with Q9NVS9 deficiency were clearly decreased ( PLP=3.6 , 12.0 , 14.0 and 18.0 nmol/L ) compared with our reference ranges . In conclusion , reference values for P04141 PLP should be stratified according to age . No association was observed between PLP values and biogenic amines metabolites . In our 4 cases with Q9NVS9 deficiency , P04141 PLP values were clearly below the reference values . Synthesis and biological evaluation of novel oxindole-based RTK inhibitors as anti-cancer agents . Given that receptor tyrosine kinases ( RTKs ) have emerged as key regulators of all aspects of cancer development , including proliferation , invasion , angiogenesis and metastasis , the RTK family represents an important therapeutic target for anti-cancer drug development . Oxindole structure has been used in RTK inhibitors such as DB02058 and intedanib . In this study , two series of new heterocyclic compounds containing oxindole scaffold have been designed and synthesized , and their inhibitory activity against the proliferation of nine cancer cell lines has been evaluated . Among them , compounds 9a and 9b displayed the strongest anti-proliferative activity with the IC50s below 10μM . Flow cytometric analysis showed that the compounds 9a and 9b dose-dependently arrested the cell cycle at G0/ P55008 phase . Although the leading compounds DB02058 and intedanib targets P11362 , the kinase activity test revealed that these compounds only showed slight inhibitory activity on P11362 kinase . Further enzymatic test aided by molecular docking simulation in the DB00171 -binding site demonstrated that 9a and 9b are potent inhibitors of c-Kit kinase . These compounds are worthy of further evaluation as anticancer agents . In vitro induction of protein complexes between bevacizumab , P15692 -A¹⁶⁵ and heparin : explanation for deposits observed on endothelial veins in monkey eyes . PURPOSE : By investigating the effects of intravitreal bevacizumab on retinal vessels of monkeys , we found that bevacizumab accumulated locally at high concentration within individual blood vessels . It formed electron-dense fibrous deposits between endothelial cells and erythrocytes or granulocytes inducing retinal vein thrombosis . To better characterise the observed deposits , we investigated in vitro whether these deposits result from a complex between bevacizumab , vascular endothelial growth factor ( P15692 ) -A(165) and heparin . METHODS : Cynomolgus monkeys were intravitreally injected with 1.25 mg bevacizumab . The eyes were enucleated between 1 and 14 days after injection and investigated by electron microscopy and immunohistochemistry . Human umbilical vein endothelial cells ( HUVEC ) were incubated with bevacizumab , P15692 (165) and heparin at different concentrations . Treatments with ranibizumab served as control . DB00112 and ranibizumab were detected immunohistochemically using Cy-3 or immunogold labelled antibodies . RESULTS : Treated animals showed bevacizumab locally at high concentration within retinal blood vessels . Electron-dense deposits inside retinal vessels and between erythrocytes were detected in three out of four treated monkeys . In vitro , many globular aggregates heavily stained with anti-human IgG were only observed with equimolar amounts ( 240 nM ) of bevacizumab and P15692 (165) and 0.2 U/ml heparin and not after ranibizumab treatment . The immunogold labelling specifically localised ultrastructurally the complexes formed between bevacizumab , P15692 (165) and heparin at the surfaces of HUVEC cells . CONCLUSIONS : DB01109 promotes bevacizumab immune complex deposition on to endothelial cells . Our in vitro results could explain the presence of deposits observed on endothelial veins in monkey eyes intravitreally injected with bevacizumab . P04279 -110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome . The DNA methyltransferase ( P26358 ) inhibitor vidaza ( DB00928 ) in combination with the histone deacetylase inhibitor entinostat has shown promise in treating lung cancer and this has been replicated in our orthotopic lung cancer model . However , the effectiveness of P26358 inhibitors against solid tumors is likely impacted by their limited stability and rapid inactivation by cytidine deaminase ( P32320 ) in the liver . These studies were initiated to test the efficacy of P04279 -110 , a dinucleotide containing decitabine that is resistant to deamination by P32320 , as a single agent and in combination with entinostat . Evaluation of in vivo plasma concentrations and pharmacokinetic properties of P04279 -110 showed rapid conversion to decitabine and a plasma half-life of 4 hr . P04279 -110 alone or in combination with entinostat reduced tumor burden of a K-ras/p53 mutant lung adenocarcinoma cell line ( Calu6 ) engrafted orthotopically in nude rats by 35 % and 56 % , respectively . P04279 -110 caused widespread demethylation of more than 300 gene promoters and microarray analysis revealed expression changes for 212 and 592 genes with P04279 -110 alone or in combination with entinostat . Epigenetic therapy also induced demethylation and expression of cancer testis antigen genes that could sensitize tumor cells to subsequent immunotherapy . In the orthotopically growing tumors , highly significant gene expression changes were seen in key cancer regulatory pathways including induction of P38936 and the apoptotic gene Q13323 . Moreover , P04279 -110 in combination with entinostat caused widespread epigenetic reprogramming of Q15910 -target genes . These preclinical in vivo findings demonstrate the clinical potential of P04279 -110 for reducing lung tumor burden through reprogramming the epigenome . Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8-hydroxy-DPAT ( 8-OH-DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3-10 , 10-17 or 17-24 ) were injected daily with 1 mg/kg 8-OH-DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye-opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10-17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17-24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin 's influence in brain development . Efficacy of liraglutide as a follow-up therapy after resolution of glucotoxicity with intensive insulin therapy . OBJECTIVE : To assess the utility of liraglutide , a P43220 agonist , as additional therapy following resolution of glucotoxicity with insulin therapy . METHODS : The subjects were 13 Japanese patients with short-duration type 2 diabetes mellitus ( 2.0 ± 2.1 years ) . At first , treatment with insulin therapy consisted of bolus insulin before each meal and basal insulin at bed time commenced to improve every preprandial glucose levels below 130 mg/dL . Then , insulin therapy was replaced with liraglutide monotherapy in case in which 50 % or more self-monitoring of blood glucose ( SMBG ) tests revealed preprandial glucose levels of less than 130 mg/dL at least for one month . DB06655 dosing was initiated at 0.3 mg/day and increased in weekly or biweekly increments of 0.3 mg/day , to the maximum permissible dose ( in Japan ) of 0.9 mg/day . The participants were treated with liraglutide for 24 weeks . RESULTS : The average insulin therapy period was 13.2 ± 5.4 weeks , and insulin therapy significantly improved HbA1c values from 12.4 % ± 1.6 % to 6.8 % ± 0.9 % ( P < 0.05 ) . After improvement of hyperglycemia with insulin therapy and switching to liraglutide monotherapy for 24 weeks , HbA1c values remained constant ( 6.2 % ± 1.0 % at week 24 ) and the rates of hypoglycemic episodes significantly decreased ( P < 0.05 ) . CONCLUSIONS : These data suggest that liraglutide is proposed as an alternative follow-up therapy subsequent to eliminate glucotoxicity with insulin therapy . Tp53-associated growth arrest and DNA damage repair gene expression is attenuated in mammary epithelial cells of rats fed whey proteins . Dietary protection from mammary cancer is likely coordinated through multiple signaling pathways , based on the known heterogeneity of the disease and the distinct origins of mammary tumor cells . The present study examined the modulatory effects of dietary intake of whey protein hydrolysate ( WPH ) relative to casein ( CAS ) , on mammary epithelial cell resistance to endogenous DNA damage using Tp53 gene expression and signaling as a read-out , and on systemic proapoptotic and immune surveillance activity , in young adult female Sprague-Dawley rats . Rats were fed AIN-93G diets made with CAS or WPH as the sole protein source beginning at gestation d 4 . At postnatal day ( P01160 ) 50 , mammary glands of rats fed WPH had lower levels of activated Tp53 and p38 mitogen-activated protein kinase proteins , and reduced transcript levels for Tp53-associated DNA damage repair , growth arrest , and proapoptotic genes than those of CAS-fed rats . Serum from WPH-fed rats had greater apoptotic activity in MCF-7 tumor cells than that from rats fed CAS . Serum levels of monocyte chemoattractant protein ( MCP ) -1 were higher in WPH- than in CAS-fed rats . MCF-7 cells treated with CAS serum + recombinant rat P13500 had apoptotic activity and Tp53 and P38936 gene expression levels comparable to those treated with WPH serum or recombinant P13500 . Results indicate that mammary glands of rats fed a WPH diet are more protected from endogenous DNA damage than are those of CAS-fed rats , and identify P13500 as a potential serum biomarker for the positive effects of healthy diets . State of the art of new Q9H244 antagonists . The interaction of ADP with its platelet receptor Q9H244 plays a crucial role in platelet activation and thrombogenesis . This article reviews the pharmacology and clinical trials of specific antagonists of Q9H244 . DB00758 is a thienopyridine with proven antithrombotic efficacy , but it has some important drawbacks : ( a ) it is a pro-drug that needs to be metabolized to its active metabolite ; ( b ) it has a delayed onset and offset of action and ( c ) there is high inter-individual variability in pharmacological response . Prasugrel is also a thienopyridine , with faster onset of action and a more uniform inhibition of platelet function compared to clopidogrel , accounting for lower incidence of ischemic events in patients with acute coronary syndromes ( ACS ) undergoing percutaneous coronary intervention ( P05154 ) and higher incidence of both non-CABG-related bleeding complications . Two direct and reversible Q9H244 antagonists , DB06441 and ticagrelor , are characterized by rapid onset and reversal of platelet inhibition . DB06441 is not superior to clopidogrel in preventing thrombotic events in patients undergoing P05154 . DB08816 is superior to clopidogrel in preventing major adverse cardiac events in ACS patients , but , like prasugrel , is associated with a higher frequency of non-CABG-related bleeding complications . A shorter period of drug discontinuation before surgery is necessary in ticagrelor-treated patients compared to clopiodgrel-treated patients to limit the severity of post-surgical bleeding . P27487 deficiency preserves cardiac function via P0C6A0 signaling in rats subjected to myocardial ischemia/reperfusion . Dipeptidyl peptidase-4 ( P27487 ) enzyme inhibition has been reported to increase plasma glucagon-like peptide-1 ( P0C6A0 ) level for controlling postprandial glucose concentration . Both P27487 inhibitors and P0C6A0 analog have been approved for antihyperglycemic agents . In addition to the insulinotropic effect , P0C6A0 signaling was reported to modulate cardiac function . P27487 inhibition was shown to improve survival rate after myocardial infarction in mice , but the precise mechanism remains unknown . We aimed to compare the cardiovascular responses of ischemia/reperfusion ( I/R ) between wild-type and P27487 -deficient rats and investigate the underlying mechanism . Rats were subjected to 45 min of coronary artery occlusion , followed by reperfusion for 2 h . Cardiac function was characterized by analyzing pressure-volume loops . As compared to wild-type rats , after I/R , P27487 -deficient rats had better cardiac performance in association with less infarct size and cardiac injury markers ( LDH , P01160 , and DB04899 ) , which could be attenuated by exendin-(9-39) , a P43220 antagonist . Exendin-(9-39) could diminish the increased phosphorylation levels of myocardial AKT and GSK-3β as well as the higher expression of P14672 in post-infarcted P27487 -deficient rats . However , exendin-(9-39) could not completely abrogate the less infarct size in P27487 -deficient rats as compared with that in wild-type rats , implicating the involvement of P43220 -independent pathway . In summary , this study demonstrated that the benefit of cardiac protective action against I/R injury was demonstrated in P27487 -deficient rats , which is mediated through both P43220 -dependent and receptor-independent mechanisms . Adolescent exposure to oxytocin , but not the selective oxytocin receptor agonist TGOT , increases social behavior and plasma oxytocin in adulthood . There are indications that exposing adolescent rodents to oxytocin ( OT ) may have positive " trait-changing " effects resulting in increased sociability and decreased anxiety that last well beyond acute drug exposure and into adulthood . Such findings may have relevance to the utility of OT in producing sustained beneficial effects in human psychiatric conditions . The present study further examined these effects using an intermittent regime of OT exposure in adolescence , and using Long Evans rats , that are generally more sensitive to the acute prosocial effects of OT . As OT has substantial affinity for the vasopressin V1a receptor ( P37288 ) in addition to the oxytocin receptor ( OTR ) , we examined whether a more selective peptidergic OTR agonist - [ Thr4 , Gly7 ] -oxytocin ( TGOT ) - would have similar lasting effects on behavior . Male Long Evans rats received OT or TGOT ( 0.5-1mg/kg , intraperitoneal ) , once every three days , for a total of 10 doses during adolescence ( postnatal day ( P01160 ) 28-55 ) . Social and anxiety-related behaviors were assessed during acute administration as well as later in adulthood ( from P01160 70 onwards ) . OT produced greater acute behavioral effects than TGOT , including an inhibition of social play and reduced rearing , most likely reflecting primary sedative effects . In adulthood , OT but not TGOT pretreated rats displayed lasting increases in social interaction , accompanied by an enduring increase in plasma OT . These findings confirm lasting behavioral and neuroendocrine effects of adolescent OT exposure . However , the absence of such effects with TGOT suggests possible involvement of the P37288 as well as the OTR in this example of developmental neuroplasticity . Mechanism of interaction of niflumic acid with heterologously expressed kidney CLC-K chloride channels . CLC-K Cl(-) channels belong to the CLC protein family . In kidney and inner ear , they are involved in transepithelial salt transport . Mutations in ClC-Kb lead to Bartter 's syndrome , and mutations in the associated subunit barttin produce Bartter 's syndrome and deafness . We have previously found that 3-phenyl-CPP blocks hClC-Ka and rClC- P04264 from the extracellular side in the pore entrance . Recently , we have shown that niflumic acid ( DB04552 ) , a nonsteroidal anti-inflammatory fenamate , produces biphasic behavior on human CLC-K channels that suggests the presence of two functionally different binding sites : an activating site and a blocking site . Here , we investigate in more detail the interaction of DB04552 on CLC-K channels . Mutants that altered block by 3-phenyl-2-(p-chlorophenoxy)propionic acid ( CPP ) had no effect on DB04552 block , indicating that the inhibition binding site of DB04552 is different from that of 3-phenyl-CPP and flufenamic acid . Moreover , DB04552 does not compete with extracellular Cl(-) ions , suggesting that the binding sites of DB04552 are not located deep in the pore . Differently from ClC-Ka , on the rat homologue P51800 , DB04552 has only an inhibitory effect . We developed a quantitative model to describe the complex action of DB04552 on ClC-Ka . The model predicts that ClC-Ka possesses two DB04552 binding sites : when only one site is occupied , DB04552 increases ClC-Ka currents , whereas the occupation of both binding sites leads to channel block . Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early-onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 -3B , P01160 , and P36382 from 192 early-onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7.6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0.1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4.1 % ; with minor allele frequency < 0.1 ; P = .0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early-onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF . Localization of the vasopressin V1a and V2 receptors within the renal cortical and medullary circulation . DB00067 ( AVP ) is a potent vasoconstrictor that preferentially reduces renal medullary blood flow through the stimulation of the vasopressin V1a receptor ( P37288 ) . Studies have also shown that the vasopressin V2 receptor ( P30518 ) may modulate AVP-mediated vasoconstriction . At present , the distribution of the P37288 and P30518 within the renal cortical and medullary microcirculation has not been determined . This study was designed to localize the transcriptional and translational sites of the P37288 and P30518 in microdissected intrarenal vascular segments from both the cortex and medulla , specifically the interlobar , arcuate , and interlobular arteries ; afferent and efferent arterioles ; glomeruli ; and single outer medullary vasa recta capillaries using reverse transcription-polymerase chain reaction and Western blot analyses . The results indicated that P37288 mRNA and proteins were present in the isolated cortical or medullary vasculature , but the P30518 mRNA and proteins were not found . This study suggests that the vasoconstrictor action of AVP within the renal medulla is mediated through the P37288 and that the modulatory P30518 -mediated vasodilation is probably through the release of paracrine hormones found within the renal interstitial or tubular cells . A common single nucleotide polymorphism can exacerbate long-QT type 2 syndrome leading to sudden infant death . BACKGROUND : Identification of infants at risk for sudden arrhythmic death remains one of the leading challenges of modern medicine . We present a family in which a common polymorphism ( single nucleotide polymorphism ) inherited from the father , combined with a stop codon mutation inherited from the mother ( both asymptomatic ) , led to 2 cases of sudden infant death . METHODS AND RESULTS : P51787 , Q12809 , Q14524 , P15382 , Q9Y6J6 , CACNA1c , CACNB2b , and P63252 genes were amplified and analyzed by direct sequencing . Functional electrophysiological studies were performed with the single nucleotide polymorphism and mutation expressed singly and in combination in Chinese ovary ( CHO- P04264 ) and COS-1 cells . An asymptomatic woman presenting after the death of her 2-day-old infant and spontaneous abortion of a second baby in the first trimester was referred for genetic analysis . The newborn infant had nearly incessant ventricular tachycardia while in utero and a prolonged QTc ( 560 ms ) . The mother was asymptomatic but displayed a prolonged QTc . Genetic screening of the mother revealed a heterozygous nonsense mutation ( P926AfsX14 ) in Q12809 , predicting a stop codon . The father was asymptomatic with a normal QTc but had a heterozygous polymorphism ( K897T ) in Q12809 . The baby who died at 2 days of age and the aborted fetus inherited both K897T and P926AfsX14 . Heterologous coexpression of K897T and P926AfsX14 led to loss of function of Q12809 current much greater than expression of K897T or P926AfsX14 alone . CONCLUSIONS : Our data suggest that a common polymorphism ( K897T ) can markedly accentuate the loss of function of mildly defective Q12809 channels , leading to long-QT syndrome-mediated arrhythmias and sudden infant death . DB00741 response to stress is associated with myocardial remodeling in salmonid fishes . Cardiac disease is frequently reported in farmed animals , and stress has been implicated as a factor for myocardial dysfunction in commercial fish rearing . DB00741 is a major stress hormone in teleosts , and this hormone has adverse effects on the myocardium . Strains of rainbow trout ( Oncorhynchus mykiss ) selected for divergent post-stress cortisol levels [ high responsive ( HR ) and low responsive ( LR ) ] have been established as a comparative model to examine how fish with contrasting stress-coping styles differ in their physiological and behavioral profiles . We show that the mean cardiosomatic index ( CSI ) of adult HR fish was 34 % higher than in LR fish , mainly because of hypertrophy of the compact myocardium . To characterize the hypertrophy as physiological or pathological , we investigated specific cardiac markers at the transcriptional level . HR hearts had higher mRNA levels of cortisol receptors ( MR , GR1 and GR2 ) , increased P53805 levels [ suggesting enhanced pro-hypertrophic nuclear factor of activated T-cell ( NFAT ) signaling ] and increased P15692 gene expression ( reflecting increased angiogenesis ) . Elevated collagen ( Col1a2 ) expression and deposition in HR hearts supported enhanced fibrosis , whereas the heart failure markers P01160 and DB04899 were not upregulated in HR hearts . To confirm our results outside the selection model , we investigated the effect of acute confinement stress in wild-type European brown trout , Salmo trutta . A positive correlation between post-stress cortisol levels and CSI was observed , supporting an association between enhanced cortisol response and myocardial remodeling . In conclusion , post-stress cortisol production correlates with myocardial remodeling , and coincides with several indicators of heart pathology , well-known from mammalian cardiology . Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( DB06144 ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4(3)-based assays were found to be the most economical but had high false-hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color-quenching problems but was expensive and still gave false hits . The nonradioactive Rb+ efflux assay was the most sensitive of all the assays evaluated and had the lowest false-hit rate . Cardiac channelopathies associated with infantile fatal ventricular arrhythmias : from the cradle to the bench . BACKGROUND : Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades , and postmortem analyses in P22304 victims have provided evidence of this association . However , the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear . METHODS AND RESULTS : Seven infants with potentially lethal arrhythmias at age < 1 year ( 5 males , age of onset 44.1 ± 72.1 days ) were genetically analyzed for P51787 , Q12809 , P15382 -5 , P63252 , Q14524 , P36382 , and P62158 by using denaturing high-performance liquid chromatography and direct sequencing . Whole-cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with Q14524 and Q12809 cDNA . In 5 of 7 patients , we identified 4 mutations ( p.N1774D , p.T290fsX53 , p.F1486del and p.N406K ) in Q14524 , and 1 mutation ( p.G628D ) in Q12809 . N1774D , F1486del , and N406K in Q14524 displayed tetrodotoxin-sensitive persistent late Na(+) currents . By contrast , Q14524 -T290fsX53 was nonfunctional . Q12809 -G628D exhibited loss of channel function . CONCLUSION : Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies . Functional assays revealed both gain and loss of channel function in Q14524 mutations , as well as loss of function associated with the Q12809 mutation . Q9Y6J6 forms potassium channels with P22001 and P51787 in the choroid plexus epithelium . Cerebrospinal fluid ( P04141 ) is crucial for normal function and mechanical protection of the CNS . The choroid plexus epithelium ( CPe ) is primarily responsible for secreting P04141 and regulating its composition by mechanisms currently not fully understood . Previously , the heteromeric P51787 - Q9Y6J6 K(+) channel was functionally linked to epithelial processes including gastric acid secretion and thyroid hormone biosynthesis . Here , using Kcne2(-/-) tissue as a negative control , we found cerebral expression of Q9Y6J6 to be markedly enriched in the CPe apical membrane , where we also discovered expression of P51787 . Targeted Kcne2 gene deletion in C57B6 mice increased CPe outward K(+) current 2-fold . The Kcne2 deletion-enhanced portion of the current was inhibited by XE991 ( 10 μM ) and margatoxin ( 10 μM ) but not by dendrotoxin ( 100 nM ) , indicating that it arose from augmentation of KCNQ subfamily and P22001 but not Q09470 K(+) channel activity . Kcne2 deletion in C57B6 mice also altered the polarity of CPe P51787 and P22001 trafficking , hyperpolarized the CPe membrane by 9 ± 2 mV , and increased P04141 [ Cl(-) ] by 14 % compared with wild-type mice . These findings constitute the first report of CPe dysfunction caused by cation channel gene disruption and suggest that Q9Y6J6 influences blood- P04141 anion flux by regulating P51787 and P22001 in the CPe . Efficacy and safety of vilazodone 20 and 40 mg in major depressive disorder : a randomized , double-blind , placebo-controlled trial . DB06684 is a selective serotonin reuptake inhibitor and P08908 partial agonist approved for major depressive disorder ( MDD ) treatment in adults . This was a 10-week , multicenter , double-blind , placebo-controlled and active-controlled , fixed-dose trial ( NCT01473381 ) . Adult patients with MDD ( Diagnostic and Statistical Manual of Mental Disorders , 4th ed. , text revision criteria ) were randomized 1 : 1 : 1 : 1 to vilazodone 20 or 40 mg/day , citalopram 40 mg/day , or placebo . Primary efficacy : Montgomery-Åsberg Depression Rating Scale ( MADRS ) ; secondary efficacy : Clinical Global Impressions-Severity and sustained response ( MADRS total score≤12 for at least the last two consecutive double-blind visits ) . The intent-to-treat population comprised 1133 patients , ( placebo=281 ; vilazodone 20 mg/day=288 ; vilazodone 40 mg/day=284 ; citalopram=280 ) . MADRS and Clinical Global Impressions-Severity score change from baseline to week 10 was significantly greater for vilazodone 20 mg/day , vilazodone 40 mg/day , and citalopram versus placebo . Sustained response rates were numerically higher , but not significantly different , in all active treatment groups versus placebo . The most common adverse events ( ≥5 % of vilazodone patients , twice the rate of placebo ) were diarrhea , nausea , vomiting ( vilazodone 40 mg/day only ) , and insomnia . Improved sexual function ( Changes in Sexual Functioning Questionnaire scores ) was seen in all groups ; between-group differences were not significant . DB06684 20 and 40 mg/day demonstrated efficacy and tolerability in the treatment of MDD .