interacts_with DB01409?
Statin Modulation of Human T-Cell Proliferation , IL-1β and Q16552 Production , and IFN-γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune-mediated disease and in experimental models . The aim of this study was to compare statin-mediated immunosuppressive effects on human T-cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T-cell proliferation . At concentrations that inhibited anti-CD3/28-stimulated T-cell proliferation ( P < 0.01 ) , simvastatin significantly decreased intracellular P01730 (+) T-cell expression of IFN-γ ( P < 0.01 ) to levels similar to those induced by conventional immunosuppressives . DB01076 and lovastatin also decreased IFN-γ expression , although to a lesser degree ( P < 0.05 ) . All three statins reduced levels of Q16552 production ( P < 0.01 ) . However , in response to anti-CD3/28 stimulation , simvastatin significantly upregulated IL-1β production ( P < 0.05 ) . The profile of cytokines produced in response to anti-CD3/28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin-mediated immunomodulatory effects on human immune cells . Small and colorful stones make beautiful mosaics : fragment-based chemogenomics . Smaller stones with a wide variety of colors make a higher resolution mosaic . In much the same way , smaller chemical entities that are structurally diverse are better able to interrogate protein binding sites . This feature article describes the construction of a diverse fragment library and an analysis of the screening of six representative protein targets belonging to three diverse target classes ( G protein-coupled receptors P07550 , P35367 , Q9Y5N1 , and Q9H3N8 , the ligand-gated ion channel P46098 , and the kinase PKA ) using chemogenomics approaches . The integration of experimentally determined bioaffinity profiles across related and unrelated protein targets and chemogenomics analysis of fragment binding and protein structure allow the identification of : ( i ) unexpected similarities and differences in ligand binding properties , and ( ii ) subtle ligand affinity and selectivity cliffs . With a wealth of fragment screening data being generated in industry and academia , such approaches will contribute to a more detailed structural understanding of ligand-protein interactions . Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis/metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long-term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 *4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P=0.003 and P=0.007 ) and were 2.2- and 2.5-fold more likely to develop P42126 and CND ( P=0.039 and P=0.041 ) , respectively . P34913 55Arg , P51589 *7 , P10632 *1B , and P10632 g.36785A allele carriers had lower EET and DHET P04141 levels . P10632 g.25369T and P10632 g.36755A allele carriers had higher EET levels . Patients with P10632 *2C and P34913 404del variants had worse long-term outcomes while those with P34913 287Gln , P51589 *7 , and P11712 g.816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3-month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis/metabolic pathway and the pathophysiology of aSAH . Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time-averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . DB04844 almost abolished phasic dopamine release but increased extracellular dopamine to ∼500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20-30 nM ) and largely arises from phasic dopamine transients . Genotype frequencies of 50 polymorphisms for 241 Japanese non-cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL-1A , IL-1B , IL-1RN , IL-1R1 , P05231 , P10145 , P22301 , P41159 , Le , L-myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF-B , P01375 -A , P01375 -B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non-cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C/T at intron 2 and G2502T , IL-1A 46-bp VNTR , IL-1R1 C-116T , P05231 Ins/Del 17C , P10145 A-278T and C74T , IL- 10 T-819C , P41159 A-2548G , P31213 2-bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL-1B C-31T and IL-1A C-889T , IL-1B C-31T and IL-1RN 86-bp VNTR , IL-1B C-31T and IL-1R1 C-116T , P01375 -A G-308A and P01375 -B A252G , P31213 Val89Leu and 2-bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype/allele frequencies among Japanese for an archival purpose . DB00227 , a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3-Hydroxy-3-methylglutaryl coenzyme A ( HMG- DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization/flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3-dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer . Genetic polymorphisms of beta2- and beta3-adrenergic receptor genes associated with characteristics of the metabolic syndrome in black South African women . BACKGROUND : Genetic variation in the beta2 ( P07550 ) and beta3 ( P13945 ) adrenergic receptor genes are associated with obesity and insulin resistance . To further elucidate the role of these genes in the pathophysiology of obesity the present study investigated associations between certain polymorphisms in P07550 and P13945 and parameters of carbohydrate and lipid metabolism in a population of African origin . MATERIAL AND METHODS : Data of 102 black South African women obtained in the POWIRS ( Profile of Obese Women with the P01308 Resistance Syndrome ) study were used . Endpoint measurements included several anthropometric variables , resting blood pressure , plasma glucose , insulin , free fatty acids ( FFA ) , ghrelin , leptin and lipids , and insulin resistance as estimated by the homeostasis model assessment ( HOMA-IR ) index . Polymorphisms were analyzed via PCR based methods . RESULTS : The percentage body fat was significantly lower ( p < or =0.05 ) and the FFA significantly higher ( p < or =0.05 ) in lean subjects ( BMI < or =25 kg/m2 ) with the Glu27 variant allele compared to subjects with the Gln27 wildtype allele of the P07550 gene . In contrast , the variant allele of the P07550 gene was significantly positive associated ( p < or =0.05 ) with the HOMA-IR-index in overweight black African women ( BMI > 25 kg/m2 ) . No significant differences in parameters of the metabolic syndrome were apparent between subjects with the wildtype and variant alleles in the P13945 gene . CONCLUSION : The presence of the Glu27 and Arg64 polymorphisms of the P07550 and P13945 genes are not directly related to indices of the metabolic syndrome . 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 . [ Obesity studies in candidate genes ] . There are more than 430 chromosomic regions with gene variants involved in body weight regulation and obesity development . Polymorphisms in genes related to energy expenditure -- uncoupling proteins ( UCPs ) , related to adipogenesis and insulin resistance -- hormone-sensitive lipase ( Q96M11 ) , peroxisome proliferator-activated receptor gamma ( Q07869 gamma ) , beta adrenergic receptors ( P07550 ,3 ) , and alfa tumor necrosis factor ( P01375 ) , and related to food intake -- ghrelin ( Q9UBU3 ) -- appear to be associated with obesity phenotypes . Obesity risk depends on two factors : a ) genetic variants in candidate genes , and b ) biographical exposure to environmental risk factors . It is necessary to perform new studies , with appropriate control groups and designs , in order to reach relevant conclusions with regard to gene/environmental ( diet , lifestyle ) interactions . P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1. P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] -doxepin . 2 . (+)- DB01114 , a selective and classical antihistamine , occupied 76.8 +/- 4.2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)-chlorpheniramine almost completely abolished the binding of [ 11C ] -doxepin to H1 receptors ( H1 receptor occupancy : 98.2 +/- 1.2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17.2 +/- 14.2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea-pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea-pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second-generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively . New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β-cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among-species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double-label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 -immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 -IR did not exist in insulin ( P01308 ) -IR cells but was abundantly present in glucagon ( GLU ) -IR and pancreatic polypeptide ( PP ) -IR cells in monkey and human islets . Q05940 -IR had no colocalization with P01308 -IR in any part of the rat pancreas ( head , body , and tail ) . P01308 -IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 -IR cells and GLU-IR cells was observed . Furthermore , a strong colocalization of Q05940 -IR with GLU-IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass . 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 . Dual P00533 and P42345 targeting in squamous cell carcinoma models , and development of early markers of efficacy . The epidermal growth factor receptor ( P00533 ) is a validated target in squamous cell carcinoma ( SCC ) of the head and neck . Most patients , however , do not respond or develop resistance to this agent . P42345 ( P42345 ) is involved in the pathogenesis of SCC of the head and neck ( SCCHN ) . This study aimed to determine if targeting P42345 in combination with P00533 is effective in SCC , and to develop early pharmacodynamic markers of efficacy . Two SCC cell lines , one resistant ( HEP2 ) and one of intermediate susceptibility ( Detroit 562 ) to P00533 inhibitors , were xenografted in vivo and treated with an P42345 inhibitor ( temsirolimus ) , an P00533 inhibitor ( erlotinib ) or a combination of both . DB06287 exerted superior growth arrest in both cell lines than erlotinib . The combined treatment resulted in synergistic antitumor effects in the Detroit 562 cell line . Immunohistochemical assessment of pharmacodynamic effects in fine-needle aspiration ( FNA ) biopsies early after treatment using phospho MAPK , Phospho-P70 and Ki67 as end points demonstrated pathway abrogation in the Detroit 562 tumours treated with the combination , the only group where regressions were seen . In conclusion , an P42345 inhibitor showed antitumor activity in P00533 -resistant SCC cell lines . Marked antitumor effects were associated with dual pathway inhibition , which were detected by early FNA biopsies . Involvement of base excision repair in response to therapy targeted at thymidylate synthase . P04818 ( TS ) is an important target of several classes of chemotherapeutic agents . Although the precise mechanism of cytotoxicity in thymidylate deprivation remains obscure , uracil misincorporation and DNA strand breaks are recognized as important events during thymidylate deprivation . Base excision repair ( BER ) plays a primary role in removing damaged or modified bases from the genome , including uracil . Because of uracil misincorporation , BER is hypothesized to play a role in the cellular response to thymidylate deprivation . In this study , we used murine embryo fibroblasts wild-type or homozygous null for P06746 ( beta-pol ) , which plays a central role in BER . We found that , compared with wild-type , beta-pol null cells were resistant to the toxic effects of raltitrexed ( DB00293 , DB00293 ) , a folate inhibitor of TS . There was little difference in TS levels or in TS-ligand complex formation between the cell lines . Furthermore , cells deficient in P18887 , a scaffold protein for the final steps of BER , were also modestly resistant to raltitrexed compared with P18887 -proficient cells . Cell cycle analysis revealed that the responses of the wild-type and beta-pol null cells were similar during drug exposure . However , following drug removal , the beta-pol null cells appeared to resume cell cycle progression more rapidly than the wild-type cells . The results suggest that BER plays a role in modulating the toxic effects of TS inhibitors , and that this role occurs during recovery from TS inhibition . Additive role of tiotropium in severe asthmatics and Arg16Gly in P07550 as a potential marker to predict response . BACKGROUND : Recent findings have raised new interests about the use of anticholinergics , especially tiotropium , for the treatment of asthma . This study was performed to determine whether an additional improvement in lung function is obtained when tiotropium is administrated in addition to conventional therapies in severe asthmatics , and to identify factors capable of predicting the response to tiotropium , using a pharmacogenetic approach . METHODS : A total of 138 severe asthmatics on conventional medications and with decreased lung function were randomly recruited . DB01409 18 microg was added once a day and lung functions were measured every 4 weeks . Responders were defined as those with an improvement of > or = 15 % ( or 200 ml ) in the forced expiratory volume in 1 s ( FEV1 ) that was maintained for at least 8 successive weeks . Eleven single nucleotide polymorphisms ( SNPs ) in P11229 -3 ( coding muscarinic receptors one to three ) which were identified by re-sequencing , and Arg16Gly and Gln27Glu in P07550 ( coding beta(2) adrenoreceptor ) were scored in 80 of the 138 asthmatics . RESULTS : Forty-six of the 138 asthmatics ( 33.3 % ) responded to tiotropium treatment . Logistic regression analyses ( controlled for age , gender , and smoking status ) showed that Arg16Gly in P07550 [ P = 0.003 , OR ( 95 % CI ) = 0.21 ( 0.07-0.59 ) in a minor allele-dominant model ] was significantly associated with response to tiotropium . CONCLUSIONS : As many as 30 % of severe asthmatics on conventional medications with reduced lung function were found to respond to adjuvant tiotropium . The presence of Arg16Gly in P07550 may predict response to tiotropium . Monoamine oxidase A suppresses hepatocellular carcinoma metastasis by inhibiting the adrenergic system and its transactivation of P00533 signaling . BACKGROUND & AIMS : Monoamine oxidase A ( P21397 ) , a catecholamine neurotransmitter degrading enzyme , is closely associated with neurological and psychiatric disorders . However , its role in cancer progression remains unknown . METHODS : Hepatocellular carcinoma ( HCC ) tissue arrays ( n=254 ) were used to investigate the correlation between P21397 expression and clinicopathological findings . In vitro invasion and anoikis assays , and in vivo intrahepatic and lung metastasis models were used to determine the role of P21397 in HCC metastasis . Quantitative real-time PCR , western blotting , immunohistochemical staining and HPLC analysis were performed to uncover the mechanism of P21397 in HCC . RESULTS : We found that P21397 expression was significantly downregulated in 254 clinical HCC samples and was closely correlated with cancer vasoinvasion , metastasis , and poor prognoses . We then demonstrated that P21397 suppressed norepinephrine/epinephrine ( NE/E ) -induced HCC invasion and anoikis inhibition , and uncovered that the effects of NE/E on HCC behaviors were primarily mediated through alpha 1A ( ADRA1A ) and beta 2 adrenergic receptors ( P07550 ) . In addition to the canonical signaling pathway , which is mediated via adrenergic receptors ( ADRs ) , we found that ADR-mediated P00533 transactivation was also involved in NE-induced HCC invasion and anoikis inhibition . Notably , we found that P21397 could synergize with P00533 inhibitors or ADR antagonists to abrogate NE-induced HCC behaviors . CONCLUSIONS : Taken together , the results of our study may provide insights into the application of P21397 as a novel predictor of clinical outcomes and indicate that increasing P21397 expression or enzyme activity may be a new approach that can be used for HCC treatment . Risks of human limb deficiency anomalies associated with 29 SNPs of genes involved in homocysteine metabolism , coagulation , cell-cell interactions , inflammatory response , and blood pressure regulation . This study explored risks of limb deficiency anomalies associated with 29 single nucleotide polymorphisms ( SNPs ) of genes involved in homocysteine metabolism , coagulation , cell-cell interaction , inflammatory response , and blood pressure regulation . The authors genotyped 96 cases and 437 non-malformed controls from a California population-based case-control study ( 1987-1988 birth cohort ) . Increased risk of limb anomaly was observed for three SNPs : heterozygosity for P12259 Arg506Gln , with an odds ratio ( OR ) of 2.5 ( 95 % confidence interval ( CI ) , 1.0 , 6.5 ) ; heterozygosity for P01375 (-376)G > A , OR 2.1 ( 0.7 , 6.2 ) ; and homozygosity for P01160 2238T > C , OR 4.0 ( 1.1 , 15.4 ) . We hypothesized that effects of variant genotypes in the presence of maternal smoking , and/or in the absence of supplement intake , may exceed effects of any of these factors alone . In particular , findings for polymorphisms in P05121 , P17301 , P16581 , P01375 , P01374 , P01160 , P16520 , and P07550 supported the hypotheses , both for smoking and for supplement intake . These results suggest involvement of genetic variation of biologically relevant candidate genes , and gene-environment interaction , for some limb anomalies whose pathogenesis may be related to altered vascular tone or integrity . [ Relation between insulin secretion and action -- study of genetic determination ] . BACKGROUND : The disposition index represents insulin secretion related to the degree of insulin sensitivity , being constant for given degree of glucose tolerance . The aim of this study is to discern genetic determinants influencing the value of disposition index , e.g. predisposition to glucose intolerance . METHODS AND RESULTS : Two hundred and four non-diabetic subjects with varied glucose tolerance were divided into groups according to the values of disposition index . DB09341 and lipid metabolism , anthropometric parameters and family history of type 2 diabetes mellitus ( DM2 ) were examined . The genotype frequency of candidate genes was compared between the groups of individuals within the lowest ( Q1 ) and the highest ( Q4 ) quartiles of the disposition index values . Those groups were not different concerning age and female to male ratio . Fasting and stimulated parameters of glucose metabolism and lipid profile were worse in group Q1 compared to group Q4 . Group Q1 is characterized with higher number of individuals with metabolic syndrome and family history of DM2 . The examination of candidate genes revealed the differences in genotype frequency of P07550 ( rs1042714 ) , Q07869 ( rs1800206 ) , Q14654 ( rs5219 ) , and Q8IWU4 ( rs13266634 ) between groups Q1 and Q4 . CONCLUSIONS : Low value of disposition index is related to the deterioration of glucose tolerance and other signs of metabolic syndrome . It is associated with genes affecting insulin secretion and genes related to energy metabolism and obesity . A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype-phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 *3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol-sensitive patient was found to possess , in addition to P11712 *3 allele , a P11712 *11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions DB01418 sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare *11 allele . Molecular mapping of uncharacteristically small 5q deletions in two patients with the 5q- syndrome : delineation of the critical region on 5q and identification of a 5q- breakpoint . Molecular mapping techniques have defined the region of gene loss in two patients with the 5q- syndrome and uncharacteristically small 5q deletions ( 5q31-q33 ) . The allelic loss of 10 genes localized to 5q23-qter ( centromere- P04141 - P18146 - P05230 -GRL- P07550 -CS F1R- P09486 - P42261 - P29459 - P35916 -telomere ) was investigated in peripheral blood cell fractions . Gene dosage experiments demonstrated that P04141 , P18146 , P29459 , and P35916 were retained on the 5q- chromosome in both patients and that P05230 was retained in one patient , thus placing these genes outside the critical region . GRL , P07550 , P07333 , P09486 , and P42261 were shown to be deleted in both patients . The proximal breakpoint is localized between P18146 and P05230 in one patient and between P05230 and P07550 in the other , and the distal breakpoint is localized between P42261 and P29459 in both patients . Pulsed-field gel electrophoresis was used to map the 5q deletion breakpoints , and breakpoint-specific fragments were detected with P05230 in the granulocyte but not the lymphocyte fraction of one patient . This study has established the critical region of gene loss of the 5q- chromosome in the 5q- syndrome , giving the location for a putative tumor-suppressor gene in the 5.6-Mb region between P05230 and P29459 . Effects of peroxisome proliferator-activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator-activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The DB01393 Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild-type mice and 3T3- Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha-deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha-RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes . Beta2-adrenergic receptor signaling in P01730 + Foxp3+ regulatory T cells enhances their suppressive function in a PKA-dependent manner . Beta2-adrenergic receptor ( P07550 ) signaling is known to impair Th1-cell differentiation and function in a DB02527 -dependent way , leading to inhibition of cell proliferation and decreased production of P60568 and IFN-γ . P01730 (+) Foxp3(+) Treg cells play a key role in the regulation of immune responses and are essential for maintenance of self-tolerance . Nevertheless , very little is known about adrenergic receptor expression in Treg cells or the influence of noradrenaline on their function . Here we show that Foxp3(+) Treg cells express functional P07550 . P07550 activation in Treg cells leads to increased intracellular DB02527 levels and to protein kinase A ( PKA ) -dependent CREB phosphorylation . We also found that signaling via P07550 enhances the in vitro suppressive activity of Treg cells . P07550 -mediated increase in Treg-cell suppressive function was associated with decreased P60568 mRNA levels in responder P01730 (+) T cells and improved Treg-cell-induced conversion of P01730 (+) Foxp3(-) cells into Foxp3(+) induced Treg cells . Moreover , P07550 signaling increased P16410 expression in Treg cells in a PKA-dependent way . Finally , we found that PKA inhibition totally prevented the P07550 -mediated increase in Treg-cell suppressive function . Our data suggest that sympathetic fibers are able to regulate Treg-cell suppressive activity in a positive manner through P07550 signaling .