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Sample records for a1 a2a a2b

  1. A2 /A2 B to B Renal Transplantation: Past, Present, and Future Directions.

    Science.gov (United States)

    Bryan, C F; Cherikh, W S; Sesok-Pizzini, D A

    2016-01-01

    One component of the new national kidney allocation system (KAS) in the United States that was implemented on December 4, 2014, was the allocation of kidneys from A2 and A2 B (A, non-A1 and AB, non-A1 B) deceased donors into blood group B candidates (A2 /A2 B → B). In so far as this is an important component of the new KAS that has the potential to further increase the access to transplantation for blood group B candidates on the waiting list, most of whom are minority candidates, we will review the body of evidence and historical perspectives that led to its inclusion in the new KAS. This review will also describe prospects for more widespread use of A2 /A2 B → B transplantation and a novel mechanism of humoral immunosuppression in B patients before and after transplantation with an A2 or A2 B kidney. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

  2. First Report on the OPTN National Variance: Allocation of A2 /A2 B Deceased Donor Kidneys to Blood Group B Increases Minority Transplantation.

    Science.gov (United States)

    Williams, W W; Cherikh, W S; Young, C J; Fan, P Y; Cheng, Y; Distant, D A; Bryan, C F

    2015-12-01

    In 2002, the Organ Procurement and Transplantation Network (OPTN) Minority Affairs Committee (MAC) implemented a national, prospective, "variance of practice" to allow deceased donor, ABO blood group incompatible, A2 antigen, kidney transplantation into blood group B recipients; outcomes of this cohort were compared to ABO compatible recipients. The goal of the variance was to increase the number of transplants to B candidates without negatively impacting survival or compromising system equity. Only B recipients with low anti-A IgG titers (A2 /A2 B to B transplants through 12/31/11, of which the majority of the recipients (61%) were ethnic minorities. At 12, 24, and 36 months, Kaplan-Meier graft survival rates for the B recipients of A2 /A2 B kidneys were 95.0%, 90.6%, and 85.4%, respectively, comparable to outcomes for B recipients of B kidneys, 92.6%, 87.9%, and 82.5%, respectively (p-value = 0.48). Five DSAs increased the proportion of B transplants during 41 months postvariance, with a lesser proportional decrease in blood group A transplants. The data support the proposition that this allocation algorithm may provide a robust mechanism to increase access of blood group B minority candidates to kidney transplantation. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

  3. Successful unintentional ABO-incompatible renal transplantation: Blood group A1B donor into an A2B recipient.

    Science.gov (United States)

    Fadeyi, Emmanuel A; Stratta, Robert J; Farney, Alan C; Pomper, Gregory J

    2014-05-01

    To report a successful unintentional transplantation of a deceased donor kidney from an "incompatible" A1B donor into a recipient who was blood group A2B with unsuspected preformed anti-A1 antibodies. The donor and recipient were both typed for ABO antigens. The recipient was tested for ABO and non-ABO antibodies. The recipient was typed for HLA class I and class II antigens, including HLA antibody screen. The T-and B-flow cytometry crossmatch test was performed using standard protocol. The donor-recipient pair was a complete six-antigen human leukocyte antigen mismatch, but final T- and B-flow cytometry cross-match tests were compatible. The recipient was a 65-year-old woman with a medical history of end-stage renal disease secondary to diabetic nephropathy who underwent kidney transplantation from a 46-year-old brain-dead standard criteria donor. The recipient's RBCs were negative with A1 lectin, and the recipient was thus typed as an A2 subgroup. Anti-A1 could be demonstrated in the recipient's plasma. The donor's RBCs were positive with A1 lectin, thereby conferring an A1 blood type. It is safe to transplant across the A1/A2 blood group barrier provided that the preformed antibodies are not reactive at 37°C and with anti-human globulin.

  4. Successful ABO-Incompatible Renal Transplantation:  Blood Group A1B Donor Into A2B Recipient With Anti-A1 Isoagglutinins.

    Science.gov (United States)

    Fadeyi, Emmanuel A; Stratta, Robert J; Farney, Alan C; Pomper, Gregory J

    2016-08-01

    Transplantation of the blood group A2B in a recipient was successfully performed in the setting of receiving a deceased donor kidney from an "incompatible" A1B donor. The donor and recipient were both typed for ABO blood group, including ABO genotyping. The donor and recipient were tested for ABO, non-ABO, and human leukocyte antigen (HLA) antibodies. The donor and recipient were typed for HLA antigens, including T- and B-flow cytometry crossmatch tests. The recipient's RBCs were negative with A1 lectin, and immunoglobulin G anti-A1 was demonstrated in the recipient's plasma. The donor-recipient pair was a four-antigen HLA mismatch, but final T- and B-flow cytometry crossmatch tests were compatible. The transplant procedure was uneventful; the patient experienced immediate graft function with no episodes of rejection or readmissions more than 2 years later. It may be safe to transplant across the A1/A2 blood group AB mismatch barrier in the setting of low titer anti-A1 isoagglutinins without the need for pretransplant desensitization even if the antibody produced reacts with anti-human globulin. © American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  5. VpStyA1/VpStyA2B of Variovorax paradoxus EPS: An Aryl Alkyl Sulfoxidase Rather than a Styrene Epoxidizing Monooxygenase

    Directory of Open Access Journals (Sweden)

    Dirk Tischler

    2018-04-01

    Full Text Available Herein we describe the first representative of an E2-type two-component styrene monooxygenase of proteobacteria. It comprises a single epoxidase protein (VpStyA1 and a two domain protein (VpStyA2B harboring an epoxidase (A2 and a FAD-reductase (B domain. It was annotated as VpStyA1/VpStyA2B of Variovorax paradoxus EPS. VpStyA2B serves mainly as NADH:FAD-oxidoreductase. A Km of 33.6 ± 4.0 µM for FAD and a kcat of 22.3 ± 1.1 s−1 were determined and resulted in a catalytic efficiency (kcat Km−1 of 0.64 s−1 μM−1. To investigate its NADH:FAD-oxidoreductase function the linker between A2- and B-domain (AREAV was mutated. One mutant (AAAAA showed 18.7-fold higher affinity for FAD (kcat Km−1 of 5.21 s−1 μM−1 while keeping wildtype NADH-affinity and -oxidation activity. Both components, VpStyA2B and VpStyA1, showed monooxygenase activity on styrene of 0.14 U mg−1 and 0.46 U mg−1, as well as on benzyl methyl sulfide of 1.62 U mg−1 and 3.11 U mg−1, respectively. The high sulfoxidase activity was the reason to test several thioanisole-like substrates in biotransformations. VpStyA1 showed high substrate conversions (up to 95% in 2 h and produced dominantly (S-enantiomeric sulfoxides of all tested substrates. The AAAAA-mutant showed a 1.6-fold increased monooxygenase activity. In comparison, the GQWCSQY-mutant did neither show monooxygenase nor efficient FAD-reductase activity. Hence, the linker between the two domains of VpStyA2B has effects on the reductase as well as on the monooxygenase performance. Overall, this monooxygenase represents a promising candidate for biocatalyst development and studying natural fusion proteins.

  6. Isolation and total syntheses of cytotoxic cryptolactones A1, A2, B1, and B2: α,β-unsaturated δ-lactones from a Cryptomyzus sp. aphid.

    Science.gov (United States)

    Horikawa, Mitsuyo; Inai, Makoto; Oguri, Yuki; Kuroda, Eri; Tanaka, Masami; Suzuki, Shinya; Ito, Takuya; Takahashi, Shigeru; Kaku, Hiroto; Tsunoda, Tetsuto

    2014-11-26

    The cryptolactones A1, A2, B1, and B2, which are α,β-unsaturated δ-lactones, were isolated from a Cryptomyzus sp. aphid. The structures were established by 1-D and 2-D NMR spectra and CI-HRMS. Their absolute configurations were determined with the Kusumi-Mosher method, combined with asymmetric total syntheses. The syntheses were accomplished with the Mukaiyama aldol reaction and olefin metathesis, which utilized the second-generation Grubbs catalyst for the key steps. These compounds exhibited cytotoxic activity against human promyelocytic leukemia HL-60 cells with IC50 values of 0.97-5.3 μM.

  7. In vitro digestion of purified β-casein variants A(1), A(2), B, and I: effects on antioxidant and angiotensin-converting enzyme inhibitory capacity.

    Science.gov (United States)

    Petrat-Melin, B; Andersen, P; Rasmussen, J T; Poulsen, N A; Larsen, L B; Young, J F

    2015-01-01

    Genetic polymorphisms of bovine milk proteins affect the protein profile of the milk and, hence, certain technological properties, such as casein (CN) number and cheese yield. However, reports show that such polymorphisms may also affect the health-related properties of milk. Therefore, to gain insight into their digestion pattern and bioactive potential, β-CN was purified from bovine milk originating from cows homozygous for the variants A(1), A(2), B, and I by a combination of cold storage, ultracentrifugation, and acid precipitation. The purity of the isolated β-CN was determined by HPLC, variants were verified by mass spectrometry, and molar extinction coefficients at λ=280nm were determined. β-Casein from each of the variants was subjected to in vitro digestion using pepsin and pancreatic enzymes. Antioxidant and angiotensin-converting enzyme (ACE) inhibitory capacities of the hydrolysates were assessed at 3 stages of digestion and related to that of the undigested samples. Neither molar extinction coefficients nor overall digestibility varied significantly between these 4 variants; however, clear differences in digestion pattern were indicated by gel electrophoresis. In particular, after 60min of pepsin followed by 5min of pancreatic enzyme digestion, one ≈4kDa peptide with the N-terminal sequence (106)H-K-E-M-P-F-P-K- was absent from β-CN variant B. This is likely a result of the (122)Ser to (122)Arg substitution in variant B introducing a novel trypsin cleavage site, leading to the changed digestion pattern. All investigated β-CN variants exhibited a significant increase in antioxidant capacity upon digestion, as measured by the Trolox-equivalent antioxidant capacity assay. After 60min of pepsin + 120min of pancreatic enzyme digestion, the accumulated increase in antioxidant capacity was ≈1.7-fold for the 4 β-CN variants. The ACE inhibitory capacity was also significantly increased by digestion, with the B variant reaching the highest inhibitory

  8. Adenosine A1, A2a, A2B, and A3 receptors in hematopoiesis. 2. Expression of receptor mRNA in resting and lipopolysaccharide-activated mouse RAW 264.7 macrophages

    Czech Academy of Sciences Publication Activity Database

    Štreitová, Denisa; Hofer, Michal; Holá, Jiřina; Vacek, Antonín; Pospíšil, Milan

    2010-01-01

    Roč. 59, č. 1 (2010), s. 139-144 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GA305/06/0015; GA ČR(CZ) GA305/08/0158 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : adenosine receptors * macrophage * mRNA expression Subject RIV: BO - Biophysics Impact factor: 1.646, year: 2010

  9. Infectious genotype 1a, 1b, 2a, 2b, 3a, 5a, 6a and 7a hepatitis C virus lacking the hypervariable region 1 (HVR1)

    DEFF Research Database (Denmark)

    2014-01-01

    The present inventors used the previously developed H77/JFH 1.sub.T27OOC,A4O8OT (1a/2a), J4/JFH .sub.1T2996C,A4827T,.DELTA.HVRI (1b/2a), J6/JFH .sub.1.DELTA.HVRI (2a/2a), J8/JFH 1.sub..DELTA.HVRI (2b/2a), S52/JFH 1.sub.T27i8G,.tau.7i6oc (3a/2a), SA13/JFH 1.sub.C34O5G,A3696G (5a/2a) and HK6a/JFH 1T...... of the viruses identified mutations adapting H77/JFH 1.sub.T27OOC,A4O8OT,.DELTA.HVR1 (1a/2a), J8/JFH .sub.1.DELTA.HVR1 (2b/2a), S52/JFH 1.sub.T2718G,T716OC,.DELTA.HVR1 (3a/2a) and J4/JFH 1.sub.T2996C,A4827T,.DELTA.HVR1 (1b/2a) to the HVR1 deletion........sub.1389c,A1590G (6a/2a) constructs for the deletion of Hypervariable Region 1 (HVR1) to construct viable, JFH 1 (genotype 2a) based, genomes. The present inventors serially passaged the viruses in cell culture obtaining relatively high HCV RNA titers and infectivity titers. Sequence analysis...

  10. Infectious genotype 1a, 1b, 2a, 2b, 3a, 5a, 6a and 7a hepatitis C virus lacking the hypervariable region 1 (HVR1)

    DEFF Research Database (Denmark)

    2014-01-01

    .sub.1389c,A1590G (6a/2a) constructs for the deletion of Hypervariable Region 1 (HVR1) to construct viable, JFH 1 (genotype 2a) based, genomes. The present inventors serially passaged the viruses in cell culture obtaining relatively high HCV RNA titers and infectivity titers. Sequence analysis...... of the viruses identified mutations adapting H77/JFH 1.sub.T27OOC,A4O8OT,.DELTA.HVR1 (1a/2a), J8/JFH .sub.1.DELTA.HVR1 (2b/2a), S52/JFH 1.sub.T2718G,T716OC,.DELTA.HVR1 (3a/2a) and J4/JFH 1.sub.T2996C,A4827T,.DELTA.HVR1 (1b/2a) to the HVR1 deletion....

  11. Adenosine A(1) and A(2A) receptors in mouse prefrontal cortex modulate acetylcholine release and behavioral arousal.

    Science.gov (United States)

    Van Dort, Christa J; Baghdoyan, Helen A; Lydic, Ralph

    2009-01-21

    During prolonged intervals of wakefulness, brain adenosine levels rise within the basal forebrain and cortex. The view that adenosine promotes sleep is supported by the corollary that N-methylated xanthines such as caffeine increase brain and behavioral arousal by blocking adenosine receptors. The four subtypes of adenosine receptors are distributed heterogeneously throughout the brain, yet the neurotransmitter systems and brain regions through which adenosine receptor blockade causes arousal are incompletely understood. This study tested the hypothesis that adenosine A(1) and A(2A) receptors in the prefrontal cortex contribute to the regulation of behavioral and cortical arousal. Dependent measures included acetylcholine (ACh) release in the prefrontal cortex, cortical electroencephalographic (EEG) power, and time to waking after anesthesia. Sleep and wakefulness were also quantified after microinjecting an adenosine A(1) receptor antagonist into the prefrontal cortex. The results showed that adenosine A(1) and A(2A) receptors in the prefrontal cortex modulate cortical ACh release, behavioral arousal, EEG delta power, and sleep. Additional dual microdialysis studies revealed that ACh release in the pontine reticular formation is significantly altered by dialysis delivery of adenosine receptor agonists and antagonists to the prefrontal cortex. These data, and early brain transection studies demonstrating that the forebrain is not needed for sleep cycle generation, suggest that the prefrontal cortex modulates EEG and behavioral arousal via descending input to the pontine brainstem. The results provide novel evidence that adenosine A(1) receptors within the prefrontal cortex comprise part of a descending system that inhibits wakefulness.

  12. Imbalance in A2 and A2B phenotype frequency of ABO group in South India

    Science.gov (United States)

    Shastry, Shamee; Bhat, Sudha

    2010-01-01

    Background The heterogeneity of A and B alleles results in weak variants of these antigens. Subgroups of A differ from each other quantitatively and qualitatively. The expected frequencies of A1 and A2 subtypes will be in Hardy-Weinberg equilibrium for the Mendelian inheritance of the allelic A1 and A2 genes. The frequency of A subgroups in the population from south India is not known. The aim of our study was to study the frequency of A subtypes and the prevalence of anti-A1 antibody among this population. Methods Over a period of 3 years, patients’ blood group was typed using a standard tube technique. Anti-A1 lectin studies were done for all patients with groups A and AB. Based on serological reactivity the samples were classified into A1/A1B, A2/A2B and weak A subgroups. The prevalence of A subgroups was determined. The significance of differences in proportions was analysed using the chi-square test. Results A total of 40,113 patients’ samples were typed for ABO, Rh group and A subgroups in our blood bank attached to a tertiary care hospital. Among 10,325 group A samples, 98.14% classified as A1, 1.07% as A2, and 0.01% as weak A; the remaining group A samples were from neonates and reacted poorly with anti A1-lectin. The majority of AB samples (n=2,667) were of A1B type (89.28%). However, the proportion of A2B (8.99%) among AB samples was significantly higher than that of A2 in group A samples (p A1 antibodies among A2 and A2B samples was 1.8% and 3.75%, respectively, and none of them showed reactivity at 37°C. Conclusion The results of our study show a significantly higher proportion of A2B subtypes than A2 subgroups. A similar imbalance is seen in blacks and Japanese. The incidence of anti-A1 antibodies is also higher among A2B patients. PMID:20967168

  13. Ephrin receptor (Eph) -A1, -A2, -A4 and -A7 expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients survival.

    Science.gov (United States)

    Theocharis, Stamatios; Klijanienko, Jerzy; Giaginis, Constantinos; Alexandrou, Paraskevi; Patsouris, Efstratios; Sastre-Garau, Xavier

    2014-04-01

    Ephrin receptors (Ephs) are frequently overexpressed in a wide variety of human malignant tumors, being associated with tumor growth, invasion, metastasis and angiogenesis. The present study aimed to evaluate the clinical significance of Eph-A1, -A2, -A4 and -A7 protein expression in mobile tongue squamous cell carcinoma (SCC). Eph-A1, -A2, -A4 and -A7 protein expression was assessed immunohistochemically on 37 mobile tongue SCC tissue samples and was analyzed in relation with clinicopathological characteristics, overall and disease-free patients' survival. All the examined mobile tongue SCC cases were found positive for Eph-A1, -A2, -A4 and -A7. Significant associations were noted between high Eph-A1, -A4 and -A7 expression and absence of lymph node metastases (p = 0.0263, p = 0.0461 and p = 0.0461, respectively). High Eph-A1, -A2 and -A7 expression was significantly more frequently observed in patients presenting absence of vascular invasion (p = 0.0444), dense stromal inflammatory reaction (p = 0.0063) and female gender (p = 0.0327), respectively. Mobile tongue SCC patients with high Eph-A7 expression presented longer overall and disease-free survival compared to those with low Eph-A7 expression (log-rank test, p = 0.0093 and p = 0.0164, respectively). In multivariate analysis, Eph-A7 expression was identified as independent prognostic factor of overall survival (Cox-regression analysis, p = 0.0426). The present study supported evidence that Ephs may participate in the malignant transformation of mobile tongue SCC, reinforcing their utility as clinical markers for patients' management and prognosis, as also as targets for potential therapeutic intervention in tongue chemoprevention.

  14. Pharmacological Blockade of Adenosine A2A but Not A1 Receptors Enhances Goal-Directed Valuation in Satiety-Based Instrumental Behavior

    Directory of Open Access Journals (Sweden)

    Yan Li

    2018-04-01

    Full Text Available The balance and smooth shift between flexible, goal-directed behaviors and repetitive, habitual actions are critical to optimal performance of behavioral tasks. The striatum plays an essential role in control of goal-directed versus habitual behaviors through a rich interplay of the numerous neurotransmitters and neuromodulators to modify the input, processing and output functions of the striatum. The adenosine receptors (namely A2AR and A1R, with their high expression pattern in the striatum and abilities to interact and integrate dopamine, glutamate and cannabinoid signals in the striatum, may represent novel therapeutic targets for modulating instrumental behavior. In this study, we examined the effects of pharmacological blockade of the A2ARs and A1Rs on goal-directed versus habitual behaviors in different information processing phases of instrumental learning using a satiety-based instrumental behavior procedure. We found that A2AR antagonist acts at the coding, consolidation and expression phases of instrumental learning to modulate animals’ sensitivity to goal-directed valuation without modifying action-outcome contingency. However, pharmacological blockade and genetic knockout of A1Rs did not affect acquisition or sensitivity to goal-valuation of instrumental behavior. These findings provide pharmacological evidence for a potential therapeutic strategy to control abnormal instrumental behaviors associated with drug addiction and obsessive-compulsive disorder by targeting the A2AR.

  15. Nuovo Espresso 1, 2, 3 (za ravni A1, A2, B1

    Directory of Open Access Journals (Sweden)

    Darja Mertelj

    2015-12-01

    Full Text Available Delovni učbeniki Nuovo Espresso 1, 2, in 3 so na slovenskem tržišču ponovno na voljo, tokrat v veliki meri prenovljeni in vendarle z ohranjenim konceptom, zaradi katerega so ga v preteklih 15 letih množično uporabljali številni slovenski učitelji italijanščine kot tujega jezika. Niti v predhodnih verzijah niti sedaj učbenik s strani avtorjev in založbe ni namenjen gimnazijcem in ostalim srednješolcem, vendar ga prav tej ciljni skupini pričujoča prenovljena izdaja najmočneje približa, predvsem zaradi video posnetkov v vsaki lekciji, kjer gre za krajše, humorne prigode in nezgode mladih ljudi v njihovem vsakdanu.

  16. Downregulation of the Adenosine A2b Receptor by RNA Interference Inhibits Hepatocellular Carcinoma Cell Growth

    OpenAIRE

    Xiang, Hong-Jun; Chai, Fu-Lu; Wang, De-Sheng; Dou, Ke-Feng

    2011-01-01

    To investigate the biological effect of adenosine A2b receptor (A2bR) on the human hepatocellular carcinoma cell line HepG2, three A2bR siRNA constructs were transiently transfected into HepG2 cells. The results showed that A2bR siRNA reduced the levels of A2bR mRNA and protein. In order to further detect the function of A2bR, we established a stable hepatocellular carcinoma cell line (HepG2) expressing siRNA targeting the adenosine A2b receptor. Targeted RNAi significantly inhibited tumor ce...

  17. The macrophage A2B adenosine receptor regulates tissue insulin sensitivity.

    Directory of Open Access Journals (Sweden)

    Hillary Johnston-Cox

    Full Text Available High fat diet (HFD-induced type 2 diabetes continues to be an epidemic with significant risk for various pathologies. Previously, we identified the A2b adenosine receptor (A2bAR, an established regulator of inflammation, as a regulator of HFD-induced insulin resistance. In particular, HFD was associated with vast upregulation of liver A2bAR in control mice, and while mice lacking this receptor showed augmented liver inflammation and tissue insulin resistance. As the A2bAR is expressed in different tissues, here, we provide the first lead to cellular mechanism by demonstrating that the receptor's influence on tissue insulin sensitivity is mediated via its expression in macrophages. This was shown using a newly generated transgenic mouse model expressing the A2bAR gene in the macrophage lineage on an otherwise A2bAR null background. Reinstatement of macrophage A2bAR expression in A2bAR null mice fed HFD restored insulin tolerance and tissue insulin signaling to the level of control mice. The molecular mechanism for this effect involves A2bAR-mediated changes in cyclic adenosine monophosphate in macrophages, reducing the expression and release of inflammatory cytokines, which downregulate insulin receptor-2. Thus, our results illustrate that macrophage A2bAR signaling is needed and sufficient for relaying the protective effect of the A2bAR against HFD-induced tissue inflammation and insulin resistance in mice.

  18. Power Generation Unit of Nano-Satellites STUDSAT 2A/2B

    Science.gov (United States)

    Velayudhan, Sneha; Bhavana, K. H.; Ravi Kumar, H. M.; Ranjith, H. G.; Ghosh, Sujay

    2014-08-01

    STUDSAT 2A/2B [8] are the twin nano-satellites. Electrical power system is one of the most important subsystems of STUDSAT 2A/2B which provides conditioned power to all the subsystem. Power generating unit is one of the most important units in Electrical Power system. The power generation unit of STUDSAT-2A/2B consists of 3 solar panels out of which 2 are deployable and 1 is body mounted and a maximum Power point Tracker(MPPT).The total orbital period of STUDSAT-2A/2B is 98min.The sunlit period is about 63.8min.The power can be generated by the solar panels only during this period. Since the power generated by the solar panel is affected by the solar irradiation, temperature etc. It's difficult to generate the maximum power at all the point in an orbit, hence maximum power point trackers are used. These maximum power point trackers track the maximum power point on the solar panel using perturb and observe algorithm and hence maximum power is generated at all the points in an orbit.This paper presents the power profile for both body mounted and deployable solar panels. It gives a brief description of how the power generated by the solar cells is conditioned and the power protection unit with simulation results and testing results for the solar panel used in STUDSAT-2A/2B.

  19. Immunodiagnosis of tumors in vivo using radiolabeled monoclonal antibody A2B5

    Energy Technology Data Exchange (ETDEWEB)

    Reintgen, D.S.; Shimizu, K.; Coleman, E.; Briner, W.; Kitzmiller, J.; Eisenbarth, G.; Seigler, H.F.

    1983-07-01

    Recently a murine monoclonal antibody (A2B5) has been described that reacts with a membrane associated GQ ganglioside common to peptide secreting normal cells and tumors. In vitro binding data demonstrated the presence of this ganglioside on neurons, adrenal medulla, and pancreatic islets, along with neuroendocrine tumors such as insulinomas, pheochromocytomas, melanomas and neuroblastomas. Negative binding has previously been shown for tissue sections from liver, kidney, colon, lung, stomach, and tumors not derived from the neural crest. Because of the specificity at A2B5 in vitro, this monoclonal antibody was labeled with /sup 131/I for in vivo tumor localization studies. Daily radionuclear scans were obtained in 5 KX rats bearing the radiation induced rat insulinoma with disappearance of the label from the blood pool and concentration in the tumor so that by the fourth day, the only activity present by scan was in the insulinoma. In addition A2B5 also localized to five different human melanoma cells lines grown in nude mice with high tumor/blood levels compared to normal tissues, while no localization is seen in nudes carrying osteosarcomas, colon, bladder, and renal cell carcinomas. In addition antibody A2B5 did not concentrate in any normal tissue though the antigen is present on several. The finding that A2B5 reacts across species lines (mouse, rat, man) lends itself to obvious diagnostic and therapeutic possibilities.

  20. Presynaptic muscarinic acetylcholine autoreceptors (M1, M2 and M4 subtypes), adenosine receptors (A1 and A2A) and tropomyosin-related kinase B receptor (TrkB) modulate the developmental synapse elimination process at the neuromuscular junction.

    Science.gov (United States)

    Nadal, Laura; Garcia, Neus; Hurtado, Erica; Simó, Anna; Tomàs, Marta; Lanuza, Maria A; Santafé, Manel; Tomàs, Josep

    2016-06-23

    The development of the nervous system involves an initially exuberant production of neurons that make an excessive number of synaptic contacts. The initial overproduction of synapses promotes connectivity. Hebbian competition between axons with different activities (the least active are punished) leads to the loss of roughly half of the overproduced elements and this refines connectivity and increases specificity. The neuromuscular junction is innervated by a single axon at the end of the synapse elimination process and, because of its relative simplicity, has long been used as a model for studying the general principles of synapse development. The involvement of the presynaptic muscarinic ACh autoreceptors may allow for the direct competitive interaction between nerve endings through differential activity-dependent acetylcholine release in the synaptic cleft. Then, the most active ending may directly punish the less active ones. Our previous results indicate the existence in the weakest axons on the polyinnervated neonatal NMJ of an ACh release inhibition mechanism based on mAChR coupled to protein kinase C and voltage-dependent calcium channels. We suggest that this mechanism plays a role in the elimination of redundant neonatal synapses. Here we used confocal microscopy and quantitative morphological analysis to count the number of brightly fluorescent axons per endplate in P7, P9 and P15 transgenic B6.Cg-Tg (Thy1-YFP)16 Jrs/J mice. We investigate the involvement of individual mAChR M1-, M2- and M4-subtypes in the control of axonal elimination after the Levator auris longus muscle had been exposed to agonist and antagonist in vivo. We also analysed the role of adenosine receptor subtypes (A1 and A2A) and the tropomyosin-related kinase B receptor. The data show that postnatal axonal elimination is a regulated multireceptor mechanism that guaranteed the monoinnervation of the neuromuscular synapses. The three receptor sets considered (mAChR, AR and TrkB receptors

  1. Adenosine A(2A) receptor dynamics studied with the novel fluorescent agonist Alexa488-APEC.

    Science.gov (United States)

    Brand, Frank; Klutz, Athena M; Jacobson, Kenneth A; Fredholm, Bertil B; Schulte, Gunnar

    2008-08-20

    G protein-coupled receptors, such as the adenosine A(2A) receptor, are dynamic proteins, which undergo agonist-dependent redistribution from the cell surface to intracellular membranous compartments, such as endosomes. In order to study the kinetics of adenosine A(2A) receptor redistribution in living cells, we synthesized a novel fluorescent agonist, Alexa488-APEC. Alexa488-APEC binds to adenosine A(2A) (K(i)=149+/-27 nM) as well as A(3) receptors (K(i)=240+/-160 nM) but not to adenosine A(1) receptors. Further, we characterized the dose-dependent increase in Alexa488-APEC-induced cAMP production as well as cAMP response element binding (CREB) protein phosphorylation, verifying the ligand's functionality at adenosine A(2A) but not A(2B) receptors. In live-cell imaging studies, Alexa488-APEC-induced adenosine A(2A) receptor internalization, which was blocked by the competitive reversible antagonist ZM 241385 and hyperosmolaric sucrose. Further, internalized adenosine A(2A) receptors co-localized with clathrin and Rab5, indicating that agonist stimulation promotes adenosine A(2A) receptor uptake through a clathrin-dependent mechanism to Rab5-positive endosomes. The basic characterization of Alexa488-APEC described here showed that it provides a useful tool for tracing adenosine A(2A) receptors in vitro.

  2. Pressure induced phase transition behavior in selected A2B3 type topological insulator minerals

    Science.gov (United States)

    Liu, H.; Liu, L. L.

    2013-12-01

    In this presentation, the recently projects from HIT Overseas Collaborative Base at Argonne, including phase transitions of selected A2B3 type topological insulator minerals upon compression at room and low temperature, studies on amorphous and melt samples under high pressure conditions using synchrotron x-ray 3D imaging techniques in diamond anvil cell and large volume press, etc, will be introduced. The advance of synchrotron greatly improved our knowledge of the minerals under pressure, which is critical for understanding the evolution of Earth.

  3. Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia.

    Science.gov (United States)

    Huang, Aji; Wu, Hongyu; Iriyama, Takayuki; Zhang, Yujin; Sun, Kaiqi; Song, Anren; Liu, Hong; Peng, Zhangzhe; Tang, Lili; Lee, Minjung; Huang, Yun; Ni, Xin; Kellems, Rodney E; Xia, Yang

    2017-07-01

    Preeclampsia is a prevalent pregnancy hypertensive disease with both maternal and fetal morbidity and mortality. Emerging evidence indicates that global placental DNA hypomethylation is observed in patients with preeclampsia and is linked to altered gene expression and disease development. However, the molecular basis underlying placental epigenetic changes in preeclampsia remains unclear. Using 2 independent experimental models of preeclampsia, adenosine deaminase-deficient mice and a pathogenic autoantibody-induced mouse model of preeclampsia, we demonstrate that elevated placental adenosine not only induces hallmark features of preeclampsia but also causes placental DNA hypomethylation. The use of genetic approaches to express an adenosine deaminase minigene specifically in placentas, or adenosine deaminase enzyme replacement therapy, restored placental adenosine to normal levels, attenuated preeclampsia features, and abolished placental DNA hypomethylation in adenosine deaminase-deficient mice. Genetic deletion of CD73 (an ectonucleotidase that converts AMP to adenosine) prevented the elevation of placental adenosine in the autoantibody-induced preeclampsia mouse model and ameliorated preeclampsia features and placental DNA hypomethylation. Immunohistochemical studies revealed that elevated placental adenosine-mediated DNA hypomethylation predominantly occurs in spongiotrophoblasts and labyrinthine trophoblasts and that this effect is independent of A2B adenosine receptor activation in both preeclampsia models. Extending our mouse findings to humans, we used cultured human trophoblasts to demonstrate that adenosine functions intracellularly and induces DNA hypomethylation without A2B adenosine receptor activation. Altogether, both mouse and human studies reveal novel mechanisms underlying placental DNA hypomethylation and potential therapeutic approaches for preeclampsia. © 2017 American Heart Association, Inc.

  4. Textbook Evaluation: An Analysis of Listening Comprehension Parts in Top Notch 2A & 2B

    Directory of Open Access Journals (Sweden)

    Afshin Soori

    2015-10-01

    Full Text Available Textbooks are the instruments that assist both teachers and learners in process of second language learning. With respect to the importance of textbooks in a language course, evaluation of course books is a significant issue for most researchers. The present study investigated and analyzed Listening Comprehension parts in Top Notch 2A & 2B 2nd edition. Top Notch 2A & 2B have 10 Units. The number of listening comprehension parts is in the range of 2 to 4 parts in each unit through the book. So the number of listening comprehension parts is not equally distributed. The participants of this study are 10 EFL teachers of two English language Institutes in Jahrom. Strong and weak aspects of Listening Comprehension parts have indicated in this research. The weaknesses involve the pictures and visuals are not clear enough to enhance students' motivation and interest, the audio is not completely suitable for students' English level, and Discussion parts are not stimulating students' talking. Furthermore this study revealed the crucial function of teachers in listening achievement of students. Keywords: textbook evaluation, listening comprehension, ELT

  5. 2′,3′-cAMP, 3′-AMP, and 2′-AMP inhibit human aortic and coronary vascular smooth muscle cell proliferation via A2B receptors

    Science.gov (United States)

    Ren, Jin; Gillespie, Delbert G.

    2011-01-01

    Rat vascular smooth muscle cells (VSMCs) from renal microvessels metabolize 2′,3′-cAMP to 2′-AMP and 3′-AMP, and these AMPs are converted to adenosine that inhibits microvascular VSMC proliferation via A2B receptors. The goal of this study was to test whether this mechanism also exists in VSMCs from conduit arteries and whether it is similarly expressed in human vs. rat VSMCs. Incubation of rat and human aortic VSMCs with 2′,3′-cAMP concentration-dependently increased levels of 2′-AMP and 3′-AMP in the medium, with a similar absolute increase in 2′-AMP vs. 3′-AMP. In contrast, in human coronary VSMCs, 2′,3′-cAMP increased 2′-AMP levels yet had little effect on 3′-AMP levels. In all cell types, 2′,3′-cAMP increased levels of adenosine, but not 5′-AMP, and 2′,3′-AMP inhibited cell proliferation. Antagonism of A2B receptors (MRS-1754), but not A1 (1,3-dipropyl-8-cyclopentylxanthine), A2A (SCH-58261), or A3 (VUF-5574) receptors, attenuated the antiproliferative effects of 2′,3′-cAMP. In all cell types, 2′-AMP, 3′-AMP, and 5′-AMP increased adenosine levels, and inhibition of ecto-5′-nucleotidase blocked this effect of 5′-AMP but not that of 2′-AMP nor 3′-AMP. Also, 2′-AMP, 3′-AMP, and 5′-AMP, like 2′,3′-cAMP, exerted antiproliferative effects that were abolished by antagonism of A2B receptors with MRS-1754. In conclusion, VSMCs from conduit arteries metabolize 2′,3′-cAMP to AMPs, which are metabolized to adenosine. In rat and human aortic VSMCs, both 2′-AMP and 3′-AMP are involved in this process, whereas, in human coronary VSMCs, 2′,3′-cAMP is mainly converted to 2′-AMP. Because adenosine inhibits VSMC proliferation via A2B receptors, local vascular production of 2′,3′-cAMP may protect conduit arteries from atherosclerosis. PMID:21622827

  6. Adenosine A2A receptor binding profile of two antagonists, ST1535 and KW6002: consideration on the presence of atypical adenosine A2A binding sites

    Directory of Open Access Journals (Sweden)

    Teresa Riccioni

    2010-08-01

    Full Text Available Adenosine A2A receptors seem to exist in typical (more in striatum and atypical (more in hippocampus and cortex subtypes. In the present study, we investigated the affinity of two adenosine A2A receptor antagonists, ST1535 [2 butyl -9-methyl-8-(2H-1,2,3-triazol 2-yl-9H-purin-6-xylamine] and KW6002 [(E-1,3-diethyl-8-(3,4-dimethoxystyryl-7-methyl-3,7-dihydro-1H-purine-2,6,dione] to the “typical” and “atypical” A2A binding sites. Affinity was determined by radioligand competition experiments in membranes from rat striatum and hippocampus. Displacement of the adenosine analog [3H]CGS21680 [2-p-(2-carboxyethylphenethyl-amino-5’-N-ethylcarbox-amidoadenosine] was evaluated in the absence or in the presence of either CSC [8-(3-chlorostyryl-caffeine], an adenosine A2A antagonist that pharmacologically isolates atypical binding sites, or DPCPX (8-cyclopentyl-1,3-dipropylxanthine, an adenosine A1 receptor antagonist that pharmacologically isolates typical binding site. ZM241385 [84-(2-[7-amino-2-(2-furyl [1,2,4]-triazol[2,3-a][1,3,5]triazin-5-yl amino]ethyl phenol] and SCH58261 [(5-amino-7-(β-phenylethyl-2-(8-furylpyrazolo(4,3-e-1,2,4-triazolo(1,5-c pyrimidine], two other adenosine A2A receptor antagonists, which were reported to differently bind to atypical and typical A2A receptors, were used as reference compounds. ST1535, KW6002, ZM241385 and SCH58261 displaced [3H]CGS21680 with higher affinity in striatum than in hippocampus. In hippocampus, no typical adenosine A2A binding was detected, and ST1535 was the only compound that occupied atypical A2A adenosine receptors. Present data are explained in terms of heteromeric association among adenosine A2A, A2B and A1 receptors, rather than with the presence of atypical A2A receptor subtype.

  7. Up-regulation and subcellular localization of hnRNP A2/B1 in the development of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Cui, Huaqing; Wu, Feng; Sun, Yanling; Fan, Guocai; Wang, Qingming

    2010-01-01

    Hepatocellular carcinoma (HCC) is one of the world's leading causes of death among cancer patients. It is important to find a new biomarker that diagnoses HCC and monitors its treatment. In our previous work, we screened a single-chain antibody (scFv) N14, which could specifically recognize human HepG2 HCC cells but not human non-cancerous liver LO2 cells. However, the antigen it recognized in the cells remained unknown. Recombinant scFv N14 antibody was expressed as an active antibody. Using this antibody with a combination of immunological and proteomic approaches, we identified the antigen of scFv N14 antibody as the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1). The expression of hnRNP A2/B1 in HCC cells was then investigated by semi-quantitative RT-PCR and immunohistochemistry. We found that the up-regulation of hnRNP A2/B1 was measured at both transcriptional and translational levels in rat HCC cells but not in rat hepatic cells. We also found that in various human hepatic tissues, hnRNP A2/B1 was highly expressed in both human hepatitis virus positive liver tissues and human HCC tissues but not in normal liver tissues. Interestingly, we observed that the localization of hnRNP A2/B1 in HCC cells was altered during the development of HCC. In human hepatitis virus infected tissues hnRNP A2/B1 resides exclusively in the nuclei of hepatocytes. However, when the HCC progressed from a well differentiated to a poorly differentiated stage, hnRNP A2/B1 was increasingly localized in the cytoplasm. In contrast, the HCC tissues with hnRNP A2/B1 highly expressed in the nucleus decreased. This work is the first to show that hnRNP A2/B1 is the antigen specifically recognized by the scFv N14 antibody in HCC cells. The over-expression of hnRNP A2/B1 was confirmed in cultured human and rat HCC cell lines, human virus related hepatitis liver tissues and human HCC tissues. The increased localization of hnRNP A2/B1 in the cytoplasm of HCC cells was revealed

  8. 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine and analogues as A2A adenosine receptor antagonists. Design, synthesis, and pharmacological characterization.

    Science.gov (United States)

    Minetti, Patrizia; Tinti, Maria Ornella; Carminati, Paolo; Castorina, Massimo; Di Cesare, Maria Assunta; Di Serio, Stefano; Gallo, Grazia; Ghirardi, Orlando; Giorgi, Fabrizio; Giorgi, Luca; Piersanti, Giovanni; Bartoccini, Francesca; Tarzia, Giorgio

    2005-11-03

    Two types of adenosine receptor ligands were designed, i.e., 9H-purine and 1H-imidazo[4,5-c]pyridines, to obtain selective A(2A) antagonists, and we report here their synthesis and binding affinities for the four adenosine receptor subtypes A(1), A(2A), A(2B) and A(3). The design was carried out on the basis of the molecular modeling of a number of potent adenosine receptor antagonists described in the literature. Three compounds (25b-d) showed an interesting affinity and selectivity for the A(2A) subtype. One of them, i.e., ST1535 (2-n-butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine, 25b) (K(i) A(2A) = 6.6 nM, K(i) A(1)/A(2A) = 12; K(i) A(2B)/A(2A) = 58; K(i) A(3)/A(2A) > 160), was selected for in vivo study and shown to induce a dose-related increase in locomotor activity, suggestive of an A(2A) antagonist type of activity.

  9. Degradation mechanisms of high-energy bipolar nickel metal hydride battery with AB5 and A2B7 alloys

    International Nuclear Information System (INIS)

    Zhou, X.; Young, K.; West, J.; Regalado, J.; Cherisol, K.

    2013-01-01

    Highlights: •Failure modes of NiMH battery with AB 5 and A 2 B 7 alloys were reported. •Stable gamma-NiOOH was formed with the incorporation of Al from negative electrode. •The formation of gamma-NiOOH caused capacity degradation in AB 5 -containing battery. •Pulverization of the main A 2 B 7 phase is the main failure mode for A 2 B 7 -containing battery. -- Abstract: The failure modes of nickel/metal hydride batteries made from conventional AB 5 and La-only Mg-containing A 2 B 7 metal hydride alloys were studied at the end of 70% state-of-charge cycle life testing (reaching below 3.1 Ah capacity in a 5.5 Ah design cell) by the combination of inductively coupled plasma, scanning electron microscope, X-ray energy dispersive spectroscopy and composition mapping, and X-ray diffraction analysis. The capacity degradation of cell with AB 5 alloy was found to have been caused by the combination of metal hydride alloy oxidation and non-reversible γ-NiOOH phase formation, which was promoted by the incorporation of Al leached out from the oxidation product of the Al-containing negative electrode. In the cell with Al-free A 2 B 7 alloy, the end of cycle life was the result of pulverization in the main A 2 B 7 phase

  10. Expression of Receptors for Tetanus Toxin and Monoclonal Antibody A2B5 by Pancreatic Islet Cells

    Science.gov (United States)

    Eisenbarth, G. S.; Shimizu, K.; Bowring, M. A.; Wells, S.

    1982-08-01

    Studies of the reaction of antibody A2B5 and tetanus toxin with pancreatic islet cells, islet cell tumors, and other human amine precursor uptake and decarboxylation (APUD) tumors are described. By indirect immunofluorescence, antibody A2B5 and tetanus toxin were shown to specifically bind to the plasma membrane of human, rat, chicken, and mouse islet cells. The binding of antibody A2B5 to the cell surface of living islet cells has allowed isolation of these cells from a suspension of pancreatic cells by using a fluorescence-activated cell sorter. In studies designed to determine whether tetanus toxin and antibody A2B5 bound to the same surface antigen, A2B5 and tetanus toxin did not compete for binding to normal islet cells, a human islet cell tumor, or a rat islet cell tumor. In addition to binding to islet cell tumors, antibody A2B5 reacts with frozen sections, isolated cells, and cell lines of neural, neural crest, and APUD origin.

  11. Adenosine A2A receptor hyperexpression in patients with severe SIRS after cardiopulmonary bypass.

    Science.gov (United States)

    Kerbaul, François; Bénard, Frédéric; Giorgi, Roch; Youlet, By; Carrega, Louis; Zouher, Ibrahim; Mercier, Laurence; Gérolami, Victoria; Bénas, Vincent; Blayac, Dorothée; Gariboldi, Vlad; Collart, Frédéric; Guieu, Régis

    2008-08-01

    Adenosine (ADO) is an endogenous nucleoside, which has been involved in blood pressure failure during severe systemic inflammatory response syndrome (severe SIRS) after cardiac surgery with cardiopulmonary bypass (CPB). Adenosine acts via its receptor subtypes, namely A1, A2A, A2B, or A3. Because A2A receptors are implicated in vascular tone, their expression might contribute to severe SIRS. We compared adenosine plasma levels (APLs) and A2A ADO receptor expression (ie, B, K, and mRNA amount) in patients with or without postoperative SIRS. : This was a prospective comparative observational study. Forty-four patients who underwent cardiac surgery involving CPB. Ten healthy subjects served as controls. Among the patients, 11 presented operative vasoplegia and postoperative SIRS (named complicated patients) and 33 were without vasoplegia or SIRS (named uncomplicated patients). Adenosine plasma levels, K, B, and mRNA amount (mean +/- SD) were measured on peripheral blood mononuclear cells. Adenosine plasma levels, B, and K were significantly higher in complicated patients than in uncomplicated patients (APLs: 2.7 +/- 1.0 vs 1.0 +/- 0.5 micromol l, P SIRS after CPB.

  12. Adenosine A2B Receptors: An Optional Target for the Management of Irritable Bowel Syndrome with Diarrhea?

    Directory of Open Access Journals (Sweden)

    Teita Asano

    2017-11-01

    Full Text Available Irritable bowel syndrome (IBS is a functional gastrointestinal disorder, with the characteristic symptoms of chronic abdominal pain and altered bowel habits (diarrhea, constipation, or both. IBS is a highly prevalent condition, which negatively affects quality of life and is a significant burden on global healthcare costs. Although many pharmacological medicines have been proposed to treat IBS, including those targeting receptors, channels, and chemical mediators related to visceral hypersensitivity, successful pharmacotherapy for the disease has not been established. Visceral hypersensitivity plays an important role in IBS pathogenesis. Immune activation is observed in diarrhea-predominant patients with IBS and contributes to the development of visceral hypersensitivity. Adenosine is a chemical mediator that regulates many physiological processes, including inflammation and nociception. Among its receptors, the adenosine A2B receptor regulates intestinal secretion, motor function, and the immune response. We recently demonstrated that the adenosine A2B receptor is involved in visceral hypersensitivity in animal models of IBS. In this review, we discuss the possibility of the adenosine A2B receptor as a novel therapeutic target for IBS.

  13. Adenosine inhibits neutrophil vascular endothelial growth factor release and transendothelial migration via A2B receptor activation.

    LENUS (Irish Health Repository)

    Wakai, A

    2012-02-03

    The effects of adenosine on neutrophil (polymorphonuclear neutrophils; PMN)-directed changes in vascular permeability are poorly characterized. This study investigated whether adenosine modulates activated PMN vascular endothelial growth factor (vascular permeability factor; VEGF) release and transendothelial migration. PMN activated with tumour necrosis factor-alpha (TNF-alpha, 10 ng\\/mL) were incubated with adenosine and its receptor-specific analogues. Culture supernatants were assayed for VEGF. PMN transendothelial migration across human umbilical vein endothelial cell (HUVEC) monolayers was assessed in vitro. Adhesion molecule receptor expression was assessed flow cytometrically. Adenosine and some of its receptor-specific analogues dose-dependently inhibited activated PMN VEGF release. The rank order of potency was consistent with the affinity profile of human A2B receptors. The inhibitory effect of adenosine was reversed by 3,7-dimethyl-1-propargylxanthine, an A2 receptor antagonist. Adenosine (100 microM) or the A2B receptor agonist 5\\'-N-ethylcarboxamidoadenosine (NECA, 100 microM) significantly reduced PMN transendothelial migration. However, expression of activated PMN beta2 integrins and HUVEC ICAM-1 were not significantly altered by adenosine or NECA. Adenosine attenuates human PMN VEGF release and transendothelial migration via the A2B receptor. This provides a novel target for the modulation of PMN-directed vascular hyperpermeability in conditions such as the capillary leak syndrome.

  14. Ab initio calculations on the X (2)B1 and A (2)A1 states of AsH2, and Franck-Condon simulation, including anharmonicity, of the A(0,0,0)-X single vibronic level emission spectrum of AsH2.

    Science.gov (United States)

    Lee, Edmond P F; Mok, Daniel K W; Chau, Foo-Tim; Dyke, John M

    2010-06-21

    Restricted-spin coupled-cluster single-double plus perturbative triple excitation {RCCSD(T)} calculations were carried out on the X (2)B(1) and A (2)A(1) states of AsH(2) employing the fully relativistic small-core effective core potential (ECP10MDF) for As and basis sets of up to the augmented correlation-consistent polarized valence quintuple-zeta (aug-cc-pV5Z) quality. Minimum-energy geometrical parameters and relative electronic energies were evaluated, including contributions from extrapolation to the complete basis set limit and from outer core correlation of the As 3d(10) electrons employing additional tight 4d3f2g2h functions designed for As. In addition, simplified, explicitly correlated CCSD(T)-F12 calculations were also performed employing different atomic orbital basis sets of up to aug-cc-pVQZ quality, and associated complementary auxiliary and density-fitting basis sets. The best theoretical estimate of the relative electronic energy of the A (2)A(1) state of AsH(2) relative to the X (2)B(1) state including zero-point energy correction (T(0)) is 19,954(32) cm(-1), which agrees very well with available experimental T(0) values of 19,909.4531(18) and 19,909.4910(17) cm(-1) obtained from recent laser induced fluorescence and cavity ringdown absorption spectroscopic studies. In addition, potential energy functions (PEFs) of the X (2)B(1) and A (2)A(1) states of AsH(2) were computed at different RCCSD(T) and CCSD(T)-F12 levels. These PEFs were used in variational calculations of anharmonic vibrational wave functions, which were then utilized to calculate Franck-Condon factors (FCFs) between these two states, using a method which includes allowance for anharmonicity and Duschinsky rotation. The A(0,0,0)-X single vibronic level (SVL) emission spectrum of AsH(2) was simulated using these computed FCFs. Comparison between simulated and available experimental vibrationally resolved spectra of the A(0,0,0)-X SVL emission of AsH(2), which consist essentially of

  15. Purification and characterization of Yersinia enterocolitica and Yersinia pestis LcrV-cholera toxin A(2)/B chimeras.

    Science.gov (United States)

    Tinker, Juliette K; Davis, Chadwick T; Arlian, Britni M

    2010-11-01

    Yersinia pestis is a virulent human pathogen and potential biological weapon. Despite a long history of research on this organism, there is no licensed vaccine to protect against pneumonic forms of Y. pestis disease. In the present study, plasmids were constructed to express cholera toxin A(2)/B chimeric molecules containing the LcrV protective antigen from Yersinia enterocolitica and Y. pestis. These chimeras were expressed and purified to high yields from the supernatant of transformed Escherichia coli. Western and GM(1) ELISA assays were used to characterize the composition, receptor-binding and relative stability of the LcrV-CTA(2)/B chimera in comparison to cholera toxin. In addition, we investigated the ability of the Y. pestis LcrV-CTA(2)/B chimera to bind to and internalize into cultured epithelial cells and macrophages by confocal microscopy. These studies indicate that the uptake and trafficking of the LcrV antigen from the chimera is comparable to the trafficking of native toxin. Together these findings report that stable, receptor-binding, non-toxic LcrV-cholera toxin A(2)/B chimeras can be expressed at high levels in E. coli and purified from the supernatant. In addition, the internalization of antigen in vitro reported here supports the development of these molecules as novel mucosal vaccine candidates. Copyright 2010 Elsevier Inc. All rights reserved.

  16. Breadth of neutralization and synergy of clinically relevant human monoclonal antibodies against HCV genotypes 1a, 1b, 2a, 2b, 2c, and 3a

    DEFF Research Database (Denmark)

    Carlsen, Thomas H R; Pedersen, Jannie; Prentoe, Jannick C

    2014-01-01

    UNLABELLED: Human monoclonal antibodies (HMAbs) with neutralizing capabilities constitute potential immune-based treatments or prophylaxis against hepatitis C virus (HCV). However, lack of cell culture-derived HCV (HCVcc) harboring authentic envelope proteins (E1/E2) has hindered neutralization...... synergism obtained when pooling the most potent HMAbs could have significant implications for developing novel strategies to treat and control HCV....

  17. Human Adenosine A2A Receptor: Molecular Mechanism of Ligand Binding and Activation

    Directory of Open Access Journals (Sweden)

    Byron Carpenter

    2017-12-01

    Full Text Available Adenosine receptors (ARs comprise the P1 class of purinergic receptors and belong to the largest family of integral membrane proteins in the human genome, the G protein-coupled receptors (GPCRs. ARs are classified into four subtypes, A1, A2A, A2B, and A3, which are all activated by extracellular adenosine, and play central roles in a broad range of physiological processes, including sleep regulation, angiogenesis and modulation of the immune system. ARs are potential therapeutic targets in a variety of pathophysiological conditions, including sleep disorders, cancer, and dementia, which has made them important targets for structural biology. Over a decade of research and innovation has culminated with the publication of more than 30 crystal structures of the human adenosine A2A receptor (A2AR, making it one of the best structurally characterized GPCRs at the atomic level. In this review we analyze the structural data reported for A2AR that described for the first time the binding of mode of antagonists, including newly developed drug candidates, synthetic and endogenous agonists, sodium ions and an engineered G protein. These structures have revealed the key conformational changes induced upon agonist and G protein binding that are central to signal transduction by A2AR, and have highlighted both similarities and differences in the activation mechanism of this receptor compared to other class A GPCRs. Finally, comparison of A2AR with the recently solved structures of A1R has provided the first structural insight into the molecular determinants of ligand binding specificity in different AR subtypes.

  18. Imidazo[2,1-i]purin-5-ones and related tricyclic water-soluble purine derivatives: potent A(2A)- and A(3)-adenosine receptor antagonists.

    Science.gov (United States)

    Müller, Christa E; Thorand, Mark; Qurishi, Ramatullah; Diekmann, Martina; Jacobson, Kenneth A; Padgett, William L; Daly, John W

    2002-08-01

    A series of tricyclic imidazo[2,1-i]purinones and ring-enlarged analogues derived from xanthine derivatives have been prepared as adenosine receptor (AR) antagonists. In comparison with xanthines, the tricyclic compounds exhibit increased water solubility due to a basic nitrogen atom, which can be protonated under physiological conditions. Substituents were introduced that confer high affinity for A(2A) or A(3) ARs, respectively. A new capillary electrophoresis method was developed for the determination of the enantiomeric purity of selected chiral products using native and modified beta-cyclodextrins as chiral discriminators. The compounds were investigated in radioligand binding assays at rat brain A(1) and A(2A) ARs. Selected compounds were additionally investigated in radioligand binding assays at human recombinant A(3) ARs and in functional studies (adenylate cyclase assays) at A(1) ARs of rat fat cell membranes, A(2A) ARs of rat PC 12 cell membranes, and mouse A(2B) ARs of NIH 3T3 cell membranes. Structure-activity relationships were similar to those of corresponding xanthine derivatives. The 2-styrylimidazopurinones were less potent at A(2A) ARs as compared to 8-styrylxanthine derivatives. The most potent compound at A(2A) ARs was (S)-1,4-dimethyl-8-ethyl-2-styryl-imidazo[2,1-i]purinone (S-25) exhibiting a K(i) value of 424 nM at rat A(2A) ARs. The compound was highly selective for A(2A) receptors vs A(1) and A(3) ARs. Selectivity vs A(2B) ARs, however, was low. Among the 1-unsubstituted 2-phenyl-imidazo[2,1-i]purin-5-one derivatives, very potent and highly selective antagonists for human A(3) ARs were identified. The most potent A(3) antagonist of the present series was (R)-4-methyl-8-ethyl-2-phenyl-imidazo[2,1-i]purin-5-one (R-24) exhibiting a K(i) value of 2.3 nM and high selectivity for A(3) receptors vs all other AR subtypes.

  19. Combined interferon a2b and cyclosporin A in the treatment of chronic hepatitis C: controlled trial - Reply

    Directory of Open Access Journals (Sweden)

    M. Galeazzi

    2011-09-01

    Full Text Available Solo il 15-20% dei pazienti con epatite C cronica presenta una risposta virologica protratta dopo terapia con solo interferon (IFN. Lo scopo di questo studio è di confrontare l’efficacia e la sicurezza dell’IFN in combinazione con ciclosporina A (CsA orale con l’IFN in monoterapia nel trattamento dell’epatite C cronica. 120 pazienti affetti da epatite C cronica hanno ricevuto la dose standard Giapponese di IFN a2b da solo per 24 settimane o questa dose di IFN a2b in combinazione con CsA, alla dose di 200 mg/die per le prime 4 settimane e poi di 100 mg/die per altre 20 settimane. In tutti i pazienti sono stati valutati la sicurezza, l’efficacia e la tolleranza alla fine delle settimane 4, 12, 24 e 48. L’efficacia è stata valutata mediante la scomparsa dei livelli sierici del genoma di HCV (RNA-HCV ricercato con reazione polimerasica a catena (PCR, e la normalizzazione delle transaminasi. L’end point primario era il mantenimento della risposta virologica; cioè il mantenimento di RNA-HCV a livelli sierici indosabili fino alla 48esima settimana. Il grado di mantenimento della risposta virologica è stata significativamente più alto nel gruppo con terapia combinata, IFN-CsA, rispetto al gruppo con IFN in monoterapia (p = 0.01. Il grado di mantenimento della risposta biochimica era più alto nel gruppo con terapia combinata rispetto a quello con monoterapia (p = 0.017. Nei pazienti con genotipo virale 1 di HCV ed alta carica virale, il grado di mantenimento della risposta virologica era marcatamente più alto nel gruppo con terapia combinata rispetto al gruppo con IFN in monoterapia (p = 0.006. Il profilo di effetti collaterali era simile nei due gruppi. In pazienti con epatite C cronica il trattamento combinato IFNCsA è più efficace rispetto alla monoterapia con IFN, soprattutto nei pazienti con genotipo virale 1 di HCV ed alta viremia. Altri studi in vitro hanno recentemente dimostrato che la CsA, a differenza di altri

  20. LASSBio-897 Reduces Lung Injury Induced by Silica Particles in Mice: Potential Interaction with the A2A Receptor

    Science.gov (United States)

    Carvalho, Vinicius F.; Ferreira, Tatiana P. T.; de Arantes, Ana C. S.; Noël, François; Tesch, Roberta; Sant’Anna, Carlos M. R.; Barreiro, Eliezer J. L.; Fraga, Carlos A. M.; Rodrigues e Silva, Patrícia M.; Martins, Marco A.

    2017-01-01

    Silicosis is a lethal fibro-granulomatous pulmonary disease highly prevalent in developing countries, for which no proper therapy is available. Among a small series of N-acylhydrazones, the safrole-derived compound LASSBio-897 (3-thienylidene-3, 4-methylenedioxybenzoylhydrazide) raised interest due to its ability to bind to the adenosine A2A receptor. Here, we evaluated the anti-inflammatory and anti-fibrotic potential of LASSBio-897, exploring translation to a mouse model of silicosis and the A2A receptor as a site of action. Pulmonary mechanics, inflammatory, and fibrotic changes were assessed 28 days after intranasal instillation of silica particles in Swiss–Webster mice. Glosensor cAMP HEK293G cells, CHO cells stably expressing human adenosine receptors and ligand binding assay were used to evaluate the pharmacological properties of LASSBio-897 in vitro. Molecular docking studies of LASSBio-897 were performed using the genetic algorithm software GOLD 5.2. We found that the interventional treatment with the A2A receptor agonist CGS 21680 reversed silica particle-induced airway hyper-reactivity as revealed by increased responses of airway resistance and lung elastance following aerosolized methacholine. LASSBio-897 (2 and 5 mg/kg, oral) similarly reversed pivotal lung pathological features of silicosis in this model, reducing levels of airway resistance and lung elastance, granuloma formation and collagen deposition. In competition assays, LASSBio-897 decreased the binding of the selective A2A receptor agonist [3H]-CGS21680 (IC50 = 9.3 μM). LASSBio-897 (50 μM) induced modest cAMP production in HEK293G cells, but it clearly synergized the cAMP production by adenosine in a mechanism sensitive to the A2A antagonist SCH 58261. This synergism was also seen in CHO cells expressing the A2A, but not those expressing A2B, A1 or A3 receptors. Based on the evidence that LASSBio-897 binds to A2A receptor, molecular docking studies were performed using the A2A receptor

  1. LASSBio-897 Reduces Lung Injury Induced by Silica Particles in Mice: Potential Interaction with the A2A Receptor

    Directory of Open Access Journals (Sweden)

    Vinicius F. Carvalho

    2017-10-01

    Full Text Available Silicosis is a lethal fibro-granulomatous pulmonary disease highly prevalent in developing countries, for which no proper therapy is available. Among a small series of N-acylhydrazones, the safrole-derived compound LASSBio-897 (3-thienylidene-3, 4-methylenedioxybenzoylhydrazide raised interest due to its ability to bind to the adenosine A2A receptor. Here, we evaluated the anti-inflammatory and anti-fibrotic potential of LASSBio-897, exploring translation to a mouse model of silicosis and the A2A receptor as a site of action. Pulmonary mechanics, inflammatory, and fibrotic changes were assessed 28 days after intranasal instillation of silica particles in Swiss–Webster mice. Glosensor cAMP HEK293G cells, CHO cells stably expressing human adenosine receptors and ligand binding assay were used to evaluate the pharmacological properties of LASSBio-897 in vitro. Molecular docking studies of LASSBio-897 were performed using the genetic algorithm software GOLD 5.2. We found that the interventional treatment with the A2A receptor agonist CGS 21680 reversed silica particle-induced airway hyper-reactivity as revealed by increased responses of airway resistance and lung elastance following aerosolized methacholine. LASSBio-897 (2 and 5 mg/kg, oral similarly reversed pivotal lung pathological features of silicosis in this model, reducing levels of airway resistance and lung elastance, granuloma formation and collagen deposition. In competition assays, LASSBio-897 decreased the binding of the selective A2A receptor agonist [3H]-CGS21680 (IC50 = 9.3 μM. LASSBio-897 (50 μM induced modest cAMP production in HEK293G cells, but it clearly synergized the cAMP production by adenosine in a mechanism sensitive to the A2A antagonist SCH 58261. This synergism was also seen in CHO cells expressing the A2A, but not those expressing A2B, A1 or A3 receptors. Based on the evidence that LASSBio-897 binds to A2A receptor, molecular docking studies were performed using the

  2. Anesthesia for coronary artery bypass grafting with hypothermic cardiopulmonary bypass in a patient with a A2B negative Blood Group

    Directory of Open Access Journals (Sweden)

    M Toufan

    2008-03-01

    Full Text Available A2B negative is one of rare subgroups of ABO blood group system. Herein, we report a 59-year-old male patientwho was candidate for coronary artery bypass grafting surgery (CABG due to coronary artery stenosis. The patient`s blood group was reported as AB negative in routine laboratory, and because of doubtful result, a complementary test confirmed his blood group as A2B negative. The consultant hematologist recommended reserving either negative A2B packed red blood cell (PRBC or if unavailable O- blood group. After induction of anesthesia three units of patient’s own blood were collected and replaced by colloid solution. The patient underwentCABG with hypothermic cardiopulmonary bypass. The collected autologous blood units were transfused at the end of operation. The patient received one unit of A2B- homologous PRBC in the postoperative period, and was discharged without any reaction to transfusion.

  3. Fluorescence and FTIR Spectra Analysis of Trans-A2B2-Substituted Di- and Tetra-Phenyl Porphyrins

    Directory of Open Access Journals (Sweden)

    Chantal Andraud

    2010-08-01

    Full Text Available A series of asymmetrically substituted free-base di- and tetra-phenylporphyrins and the associated Zn-phenylporphyrins were synthesized and studied by X-ray diffraction, NMR, infrared, electronic absorption spectra, as well as fluorescence emission spectroscopy, along with theoretical simulations of the electronic and vibration structures. The synthesis selectively afforded trans-A2B2 porphyrins, without scrambling observed, where the AA and BB were taken as donor- and acceptor-substituted phenyl groups. The combined results point to similar properties to symmetrically substituted porphyrins reported in the literature. The differences in FTIR and fluorescence were analyzed by means of detailed density functional theory (DFT calculations. The X-ray diffraction analysis for single crystals of zinc-containing porphyrins revealed small deviations from planarity for the porphyrin core in perfect agreement with the DFT optimized structures. All calculated vibrational modes (2162 modes for all six compounds studied were found and fully characterized and assigned to the observed FTIR spectra. The most intense IR bands are discussed in connection with the generic similarity and differences of calculated normal modes. Absorption spectra of all compounds in the UV and visible regions show the typical ethio type feature of meso-tetraarylporphyrins with a very intense Soret band and weak Q bands of decreasing intensity. In diphenyl derivatives, the presence of only two phenyl rings causes a pronounced hypsochromic shift of all bands in the absorption spectra. Time-dependent DFT calculations revealed some peculiarities in the electronic excited states structure and connected them with vibronic bands in the absorption and fluorescence spectra from associated vibrational sublevels.

  4. Draft genome sequence of Bacillus velezensis 2A-2B strain: a rhizospheric inhabitant of Sporobolus airoides (Torr.) Torr., with antifungal activity against root rot causing phytopathogens.

    Science.gov (United States)

    Martínez-Raudales, Inés; De La Cruz-Rodríguez, Yumiko; Alvarado-Gutiérrez, Alejandro; Vega-Arreguín, Julio; Fraire-Mayorga, Ahuitz; Alvarado-Rodríguez, Miguel; Balderas-Hernández, Victor; Fraire-Velázquez, Saúl

    2017-01-01

    A Bacillus velezensis strain from the rhizosphere of Sporobolus airoides (Torr.) Torr . , a grass in central-north México, was isolated during a biocontrol of phytopathogens scrutiny study. The 2A-2B strain exhibited at least 60% of growth inhibition of virulent isolates of phytopathogens causing root rot. These phytopathogens include Phytophthora capsici , Fusarium solani , Fusarium oxysporum and Rhizoctonia solani . Furthermore, the 2A-2B strain is an indolacetic acid producer, and a plant inducer of PR1, which is an induced systemic resistance related gene in chili pepper plantlets. Whole genome sequencing was performed to generate a draft genome assembly of 3.953 MB with 46.36% of GC content, and a N50 of 294,737. The genome contains 3713 protein coding genes and 89 RNA genes. Moreover, comparative genome analysis revealed that the 2A-2B strain had the greatest identity (98.4%) with Bacillus velezensis.

  5. Novel Alexa Fluor-488 labeled antagonist of the A(2A) adenosine receptor: Application to a fluorescence polarization-based receptor binding assay.

    Science.gov (United States)

    Kecskés, Miklós; Kumar, T Santhosh; Yoo, Lena; Gao, Zhan-Guo; Jacobson, Kenneth A

    2010-08-15

    Fluorescence polarization (FP) assay has many advantages over the traditional radioreceptor binding studies. We developed an A(2A) adenosine receptor (AR) FP assay using a newly synthesized fluorescent antagonist of the A(2A)AR (MRS5346), a pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine derivative conjugated to the fluorescent dye Alexa Fluor-488. MRS5346 displayed a K(i) value of 111+/-16nM in radioligand binding using [(3)H]CGS21680 and membranes prepared from HEK293 cells stably expressing the human A(2A)AR. In a cyclic AMP functional assay, MRS5346 was shown to be an A(2A)AR antagonist. MRS5346 did not show any effect on A(1) and A(3) ARs in binding or the A(2B)AR in a cyclic AMP assay at 10microM. Its suitability as a fluorescent tracer was indicated in an initial observation of an FP signal following A(2A)AR binding. The FP signal was optimal with 20nM MRS5346 and 150microg protein/mL HEK293 membranes. The association and dissociation kinetic parameters were readily determined using this FP assay. The K(d) value of MRS5346 calculated from kinetic parameters was 16.5+/-4.7nM. In FP competition binding experiments using MRS5346 as a tracer, K(i) values of known AR agonists and antagonists consistently agreed with K(i) values from radioligand binding. Thus, this FP assay, which eliminates using radioisotopes, appears to be appropriate for both routine receptor binding and high-throughput screening with respect to speed of analysis, displaceable signal and precision. The approach used in the present study could be generally applicable to other GPCRs. Published by Elsevier Inc.

  6. MicroRNA-128b suppresses tumor growth and promotes apoptosis by targeting A2bR in gastric cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ping; Guo, Xueyan; Zong, Wei [Department of Gastroenterology, The Third Affiliated Hospital, College of Medicine, Xi' an Jiaotong University, Xi' an 710068 (China); Song, Bin [Department of General Surgery, The Third Affiliated Hospital, College of Medicine, Xi' an Jiaotong University, Xi' an 710068 (China); Liu, Guisheng [Department of Gastroenterology, The Third Affiliated Hospital, College of Medicine, Xi' an Jiaotong University, Xi' an 710068 (China); He, Shuixiang, E-mail: fisrstsxianghe@163.com [Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Xi' an Jiaotong University, Xi' an 710061 (China)

    2015-11-27

    MicroRNAs (miRNAs) play crucial roles in the development and progression of human cancers, including gastric cancer (GC). The discovery of miRNAs may provide a new and powerful tool for studying the mechanism, diagnosis, and treatment of GC. In this study, we aimed to investigate the role and mechanism of miR-128b in the development and progression of GC. Quantitative real-time PCR (qRT-PCR) was used to measure the expression level of miR-128b in GC tissues and cell lines. We found that miR-128b was significantly down-regulated in GC tissues and cell lines. In addition, over-expression of miR-128b inhibited GC cell proliferation, migration and invasion of GC cells in vitro. Gain-of-function in vitro experiments further showed that the miR-128b mimic significantly promoted GC cell apoptosis. Subsequent dual-luciferase reporter assay identified one of the proto-oncogene A2bR as direct target of miR-128b. Therefore, our results indicate that miR-128b is a proto-oncogene miRNA that can suppresses GC proliferation and migration through down-regulation of the oncogene gene A2bR. Taken together, our results indicate that miR-128b could serve as a potential diagnostic biomarker and therapeutic option for human GC in the near future. - Highlights: • The expression of MiR-128b is significantly down-regulated in GC tissues and cell lines. • Ectopic expression of miR-128b directly affects cell proliferation, migration and invasion in vitro. • Overexpression of miR-128b increases apoptosis in GC cells. • A2bR is a candidate target gene of miR-128b. • MiR-128b represses cell proliferation, migration and invasion and promotes apoptosis by targeting A2bR in GC.

  7. VHL Genetic Alteration in CCRCC Does Not Determine De-Regulation of HIF, CAIX, hnRNP A2/B1 and Osteopontin

    Directory of Open Access Journals (Sweden)

    Michelle J. Nyhan

    2010-01-01

    Full Text Available Background: von Hippel–Lindau (VHL tumour suppressor gene inactivation is associated with clear cell renal cell carcinoma (CCRCC development. The VHL protein (pVHL has been proposed to regulate the expression of several proteins including Hypoxia Inducible Factor-α (HIF-α, carbonic anhydrase (CAIX, heterogeneous nuclear ribonucleoprotein (hnRNP A2/B1 and osteopontin. pVHL has been characterized in vitro, however, clinical studies are limited. We evaluated the impact of VHL genetic alterations on the expression of several pVHL protein targets in paired normal and tumor tissue.

  8. DFT Predictions of Electronic, Transport, and Bulk Properties of Cubic Antifluorite A2B Compounds (A = Li, Na, B = O,S,Se)

    Science.gov (United States)

    Malozovsky, Yuriy; Franklin, Lashounda; Bagayoko, Diola

    We present results from ab-initio,self-consistent calculations of electronic, transport, and bulk properties of cubic antifluorite (anti-CaF2) compounds A2B (A = Li, Na, B = O, S, Se). Our computations employed the local density approximation (LDA) potential of Ceperley and Alder and the linear combination of atomic orbital (LCAO) formalism. The implementation of the LCAO formalism followed the Bagayoko, Zhao, and Williams method, as enhanced by Ekuma and Franklin (BZW-EF). Consequently, our calculations search for and attained the ground states of the systems under study, as required by DFT; our results therefore possess the full, physical content of DFT. We discuss band structures, band gaps, and related properties of these materials, including calculated, total and partial densities of states (DOS and PDOS), effective masses of charge carriers, equilibrium lattice constants, and the bulk moduli of cubic antifluorite compounds A2B (A = Li, Na, B = O, S, Se). Our results are predictions in some cases, due to the lack of experimental data. Work funded in part by the US Department of Energy (DOE), National Nuclear Security Administration (NNSA) (Award No.DE-NA0002630), the National Science Foundation (NSF) (Award No, 1503226), LaSPACE, and LONI-SUBR.

  9. VHL genetic alteration in CCRCC does not determine de-regulation of HIF, CAIX, hnRNP A2/B1 and osteopontin.

    LENUS (Irish Health Repository)

    Nyhan, Michelle J

    2012-01-31

    BACKGROUND: von Hippel-Lindau (VHL) tumour suppressor gene inactivation is associated with clear cell renal cell carcinoma (CCRCC) development. The VHL protein (pVHL) has been proposed to regulate the expression of several proteins including Hypoxia Inducible Factor-alpha (HIF-alpha), carbonic anhydrase (CA)IX, heterogeneous nuclear ribonucleoprotein (hnRNP) A2\\/B1 and osteopontin. pVHL has been characterized in vitro, however, clinical studies are limited. We evaluated the impact of VHL genetic alterations on the expression of several pVHL protein targets in paired normal and tumor tissue. METHODS: The VHL gene was sequenced in 23 CCRCC patients and VHL transcript levels were evaluated by real-time RT-PCR. Expression of pVHL\\'s protein targets were determined by Western blotting in 17 paired patient samples. RESULTS: VHL genetic alterations were identified in 43.5% (10\\/23) of CCRCCs. HIF-1alpha, HIF-2alpha and CAIX were up-regulated in 88.2% (15\\/17), 100% (17\\/17) and 88.2% (15\\/17) of tumors respectively and their expression is independent of VHL status. hnRNP A2\\/B1 and osteopontin expression was variable in CCRCCs and had no association with VHL genetic status. CONCLUSION: As expression of these proposed pVHL targets can be achieved independently of VHL mutation (and possibly by hypoxia alone), these data suggests that other pVHL targets may be more crucial in renal carcinogenesis.

  10. Role of adenosine A2A receptor signaling in the nicotine-evoked attenuation of reflex cardiac sympathetic control

    International Nuclear Information System (INIS)

    El-Mas, Mahmoud M.; El-gowilly, Sahar M.; Fouda, Mohamed A.; Saad, Evan I.

    2011-01-01

    Baroreflex dysfunction contributes to increased cardiovascular risk in cigarette smokers. Given the importance of adenosinergic pathways in baroreflex control, the hypothesis was tested that defective central adenosinergic modulation of cardiac autonomic activity mediates the nicotine-baroreflex interaction. Baroreflex curves relating changes in heart rate (HR) to increases or decreases in blood pressure (BP) evoked by i.v. doses (1-16 μg/kg) of phenylephrine (PE) and sodium nitroprusside (SNP), respectively, were constructed in conscious rats; slopes of the curves were taken as measures of baroreflex sensitivity (BRS). Nicotine (25 and 100 μg/kg i.v.) dose-dependently reduced BRS SNP in contrast to no effect on BRS PE . BRS SNP was also attenuated after intracisternal (i.c.) administration of nicotine. Similar reductions in BRS SNP were observed in rats pretreated with atropine or propranolol. The combined treatment with nicotine and atropine produced additive inhibitory effects on BRS, an effect that was not demonstrated upon concurrent exposure to nicotine and propranolol. BRS SNP was reduced in preparations treated with i.c. 8-phenyltheophylline (8-PT, nonselective adenosine receptor antagonist), 8-(3-Chlorostyryl) caffeine (CSC, A 2A antagonist), or VUF5574 (A 3 antagonist). In contrast, BRS SNP was preserved after blockade of A 1 (DPCPX) or A 2B (alloxazine) receptors or inhibition of adenosine uptake by dipyridamole. CSC or 8-PT abrogated the BRS SNP depressant effect of nicotine whereas other adenosinergic antagonists were without effect. Together, nicotine preferentially impairs reflex tachycardia via disruption of adenosine A 2A receptor-mediated facilitation of reflex cardiac sympathoexcitation. Clinically, the attenuation by nicotine of compensatory sympathoexcitation may be detrimental in conditions such as hypothalamic defense response, posture changes, and ventricular rhythms. - Research highlights: → The role of central adenosinergic sites in

  11. IL WEB E L’OFFERTA FORMATIVA PER L’AUTOAPPRENDIMENTO DELL’ITALIANO L2 PER STUDENTI DI LIVELLO A2/B1

    Directory of Open Access Journals (Sweden)

    Diego Santalucia

    2014-07-01

    Full Text Available Partendo dall’assunto che la competenza digitale e la frequentazione di ambienti virtuali siano in crescita costante, l’articolo si propone di esplorare e cercare di valutare l’offerta formativa on-line per quanto riguarda l’italiano LS e L2. Una ricerca con la pretesa di un’analisi definitiva su quanto la rete offre a tutti i livelli di competenza linguistica sarebbe stata poco coerente, con il rischio di apparire contraddittoria, considerando la “mobilità” del web e la vastità del campo; si è pensato, quindi, di restringere l’ambito di osservazione alle necessità di un’utenza target con un livello di competenza della lingua (A2/B1, presumibilmente quella maggiormente interessata a fruire dell’offerta formativa in auto-apprendimento. Sulla base dell’utenza presa in considerazione vengono analizzati alcuni siti ritenuti particolarmente significativi per la varietà, la quantità e la qualità della loro offerta e per la loro risonanza sui motori di ricerca. L’analisi diretta dei siti selezionati è preceduta da una tabella che ne sintetizza le caratteristiche principali: uno strumento d’indagine snello che analizza la struttura del sito, la modalità con cui sono offerti i materiali e le abilità linguistiche che possono essere sviluppate con l’ausilio dei percorsi didattici proposti. Tra gli obiettivi di questo lavoro, fondamentale è quello di fornire una traccia metodologica all’insegnate di italiano L2/LS  perché possa costruirsi una sitografia di riferimento utile per reperire materiali e attività integrative da usare in classe.  The web and educational opportunities for italian l2 self-learning for  a2/b1 level students  Silvia Bartolucci and Diego Santalucia   Starting from the assumption that digital competence and the popularity of virtual environments are in constant growth, the article explores and evaluates on-line education for Italian LS and L2. A study that aims to be a definitive

  12. EXPRESSÃO DO ANTÍGENO A1: frequência em recém-nascidos

    OpenAIRE

    Márcia Maria Vasconcellos Mikalauscas

    2011-01-01

    Dentro do sistema ABO existem diversos subgrupos sanguíneos: subgrupos A, subgrupos B e subgrupo H, sendo que os mais frequentemente encontrados na prática são os subgrupos A1, A2, A1B e A2B. As células de, aproximadamente, 80% da população adulta do grupo A são A1. Os 20% restantes são A2 ou subgrupos mais fracos. Porém, em recém-nascidos é muito escassa a literatura a respeito de dados quanto à frequência dos subgrupos de A. A maioria dos lactentes do grupo sanguíneo A parece apresentar-se ...

  13. Possible involvement of CA1 5-HT1B/1D and 5-HT2A/2B/2C receptors in harmaline-induced amnesia.

    Science.gov (United States)

    Nasehi, Mohammad; Jamshidi-Mehr, Mehdi; Khakpai, Fatemeh; Zarrindast, Mohammad-Reza

    2014-10-01

    In the present study, effects of the serotonergic system of the dorsal hippocampus (CA1) on harmaline-induced amnesia were examined. A single-trial step-down passive avoidance task was used for the assessment of memory retention in adult male NMRI mice. Pre-training intra-peritoneal (i.p.) administration of harmaline (1mg/kg) induced impairment of memory retention. Moreover, intra-CA1 administration of 5-HT1B/1D receptor agonist, CP94253 (5 ng/mouse), 5-HT1B/1D receptor antagonist, GR127935 (0.05 and 0.5 ng/mouse), 5-HT2A/2B/2C receptor agonist, α-methyl 5-HT (0.5 ng/mouse) and 5-HT2 receptor antagonist, cinancerine (0.5 ng/mouse) impaired memory acquisition, but did not affect locomotor activity and tail flick. Furthermore, pre-training intra-CA1 injection of subthreshold dose of CP94253 (0.05 ng/mouse) or GR127935 (0.005 ng/mouse) reversed impairment of memory acquisition induced by harmaline (1 mg/kg, i.p.). However, pre-training intra-CA1 infusion of subthreshold dose of α-methyl 5-HT (0.005 ng/mouse) or cinancerine (0.005 ng/mouse) with the administration of harmaline (0.5 and 1 mg/kg, i.p.) heighten impairment of memory acquisition. These findings implicate the involvement of CA1 serotonergic mechanism in harmaline-induced impairment of memory acquisition. Copyright © 2014. Published by Elsevier Inc.

  14. Inhibition of A2A Adenosine Receptor Signaling in Cancer Cells Proliferation by the Novel Antagonist TP455

    Directory of Open Access Journals (Sweden)

    Stefania Gessi

    2017-12-01

    Full Text Available Several evidences indicate that the ubiquitous nucleoside adenosine, acting through A1, A2A, A2B, and A3 receptor (AR subtypes, plays crucial roles in tumor development. Adenosine has contrasting effects on cell proliferation depending on the engagement of different receptor subtypes in various tumors. The involvement of A2AARs in human A375 melanoma, as well as in human A549 lung and rat MRMT1 breast carcinoma proliferation has been evaluated in view of the availability of a novel A2AAR antagonist, with high affinity and selectivity, named as 2-(2-furanyl-N5-(2-methoxybenzyl[1,3]thiazolo[5,4-d]pyrimidine-5,7-diammine (TP455. Specifically, the signaling pathways triggered in the cancer cells of different origin and the antagonist effect of TP455 were investigated. The A2AAR protein expression was evaluated through receptor binding assays. Furthermore, the effect of A2AAR activation on cell proliferation at 24, 48 and 72 hours was studied. The selective A2AAR agonist 2-p-(2-carboxyethylphenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride (CGS21680, concentration-dependently induced cell proliferation in A375, A549, and MRMT1 cancer cells and the effect was potently antagonized by the A2AAR antagonist TP455, as well as by the reference A2AAR blocker 4-(2-[7-amino-2-(2-furyl[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethylphenol (ZM241385. As for the signaling pathway recruited in this response we demonstrated that, by using the specific inhibitors of signal transduction pathways, the effect of A2AAR stimulation was induced through phospholipase C (PLC and protein kinase C-delta (PKC-δ. In addition, we evaluated, through the AlphaScreen SureFire phospho(p protein assay, the kinases enrolled by A2AAR to stimulate cell proliferation and we found the involvement of protein kinase B (AKT, extracellular regulated kinases (ERK1/2, and c-Jun N-terminal kinases (JNKs. Indeed, we demonstrated that the CGS21680 stimulatory effect on kinases was

  15. Adenosine A2A receptors and A2A receptor heteromers as key players in striatal function

    Directory of Open Access Journals (Sweden)

    Sergi eFerre

    2011-06-01

    Full Text Available A very significant density of adenosine adenosine A2A receptors (A2ARs is present in the striatum, where they are preferentially localized postsynaptically in striatopallidal medium spiny neurons (MSNs. In this localization A2ARs establish reciprocal antagonistic interactions with dopamine D2 receptors (D2Rs. In one type of interaction, A2AR and D2R are forming heteromers and, by means of an allosteric interaction, A2AR counteracts D2R-mediated inhibitory modulation of the effects of NMDA receptor stimulation in the striato-pallidal neuron. This interaction is probably mostly responsible for the locomotor depressant and activating effects of A2AR agonist and antagonists, respectively. The second type of interaction involves A2AR and D2R that do not form heteromers and takes place at the level of adenylyl-cyclase (AC. Due to a strong tonic effect of endogenous dopamine on striatal D2R, this interaction keeps A2AR from signaling through AC. However, under conditions of dopamine depletion or with blockade of D2R, A2AR-mediated AC activation is unleashed with an increased gene expression and activity of the striato-pallidal neuron and with a consequent motor depression. This interaction is probably the main mechanism responsible for the locomotor depression induced by D2R antagonists. Finally, striatal A2ARs are also localized presynaptically, in cortico-striatal glutamatergic terminals that contact the striato-nigral MSN. These presynaptic A2ARs heteromerize with A1 receptors (A1Rs and their activation facilitates glutamate release. These three different types of A2ARs can be pharmacologically dissected by their ability to bind ligands with different affinity and can therefore provide selective targets for drug development in different basal ganglia disorders.

  16. No evidence for priming response in Galleria mellonella larvae exposed to toxin protein PirA2B2 from Photorhabdus luminescens TT01: An association with the inhibition of the host cellular immunity.

    Science.gov (United States)

    Wu, Gongqing; Yi, Yunhong; Sun, Jianyu; Li, Mei; Qiu, Lihong

    2015-11-17

    There is accumulating evidence that many invertebrates including insects can acquire enhanced immune protection against subsequently pathogens infection through immune priming. However, whether the toxin protein from pathogenic bacteria can induce such priming response remains unclear. Here we cloned, expressed and purified the toxin Photorhabdus insect-related proteins A2B2 (PirA2B2) from Photorhabdus luminescens TT01. We primed Galleria mellonella with sublethal dose of PirA2B2 and then challenged the larvae with viable P. luminescens TT01 at 48 h after priming. We found no evidence for immune priming in G. mellonella larvae exposed to PirA2B2. Priming the larvae with PirA2B2 did not improve their resistance in a subsequent challenge with P. luminescens TT01. Whereas a robust priming response was observed when the larvae exposed to lipopolysaccharide (LPS) extracted from P. luminescens TT01. Because the larvae primed with LPS showed significant higher resistance against P. luminescens TT01 infection than those of the PBS and BSA controls. Furthermore, we investigated the changes of the cellular immune parameters, such as hemocyte counts, phagocytic activity and encapsulation ability of the hemocytes, after priming. We found that the toxin PirA2B2 significantly decreased the cellular immunity of the larvae, whereas the LPS significantly increased them. These results indicated that the degree of priming response in G. mellonella correlated positively to the levels of cellular immune parameters, and the underlying mechanism in regulating the immune priming of invertebrates was not homologous to that of the immunological memory of vertebrates. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Předposlechová fáze ve výuce poslechu u dospělého žáka na úrovni A2 - B1.

    OpenAIRE

    Ždímalová, Hana

    2014-01-01

    The Pre-listening Stage in L2 Listening Instruction to A2 - B1 Adult Learners By Hana Ždímalová This dissertation deals with listening instruction to adult EFL learners in the Czech Republic and the phenomenon of pre-listening, which is currently under-researched. It examines adult EFL students' perspectives and perceptions of listening instruction and of the inclusion of different pre-listening techniques, particularly at CEFR A2-B1 proficiency levels. The theoretical part of the study focus...

  18. A2A Receptor Antagonism and Dyskinesia in Parkinson's Disease

    Science.gov (United States)

    Morelli, Micaela; Blandini, Fabio; Simola, Nicola; Hauser, Robert A.

    2012-01-01

    Dyskinesia, a major complication of treatment of Parkinson's disease (PD), involves two phases: induction, which is responsible for dyskinesia onset, and expression, which underlies its clinical manifestation. The unique cellular and regional distribution of adenosine A2A receptors in basal ganglia areas that are richly innervated by dopamine, and their antagonistic role towards dopamine receptor stimulation, have positioned A2A receptor antagonists as an attractive nondopaminergic target to improve the motor deficits that characterize PD. In this paper, we describe the biochemical characteristics of A2A receptors and the effects of adenosine A2A antagonists in rodent and primate models of PD on L-DOPA-induced dyskinesia, together with relevant biomarker studies. We also review clinical trials of A2A antagonists as adjuncts to L-DOPA in PD patients with motor fluctuations. These studies have generally demonstrated that the addition of an A2A antagonist to a stable L-DOPA regimen reduces OFF time and mildly increases dyskinesia. However, limited clinical data suggest that the addition of an A2A antagonist along with a reduction of L-DOPA might maintain anti-Parkinsonian benefit and reduce dyskinesia. Whether A2A antagonists might reduce the development of dyskinesia has not yet been tested clinically. PMID:22754707

  19. PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo

    DEFF Research Database (Denmark)

    Auvergne, R.; Wu, C.; Connell, A.

    2016-01-01

    Glioblastoma (GBM) remains the most common and lethal intracranial tumor. In a comparison of gene expression by A2B5-defined tumor-initiating progenitor cells (TPCs) to glial progenitor cells derived from normal adult human brain, we found that the F2R gene encoding PAR1 was differentially overex...

  20. Involvement of adenosine A2A receptors in depression and anxiety.

    Science.gov (United States)

    Yamada, Koji; Kobayashi, Minoru; Kanda, Tomoyuki

    2014-01-01

    When administered to normal healthy patients, a nonselective adenosine A1/A2A antagonist, caffeine, tended to improve anxiety and depression at low doses and to exacerbate anxiety at high doses. Caffeine also appears to enhance anxiety-related symptoms in patients with panic disorder, and A2A receptor-deficient mice have been reported to exhibit higher anxiety-like behaviors, as well as a lower incidence of depression-like behaviors. Some selective A2A antagonists were reported to ameliorate anxiety-like behaviors in rodents, while others did not affect these behaviors. In addition, most A2A antagonists showed inhibitory effects on depression-like behaviors. The mechanisms underlying the relationship between A2A receptor antagonists and anxiety and depression remain unclear at the present time, although many studies have produced hypotheses. Given that a selective A2A receptor antagonist has recently become available for use in humans, research on the role of A2A receptors in the treatment of mental illness should progress in the near future. © 2014 Elsevier Inc. All rights reserved.

  1. Gene trap mutagenesis of hnRNP A2/B1: a cryptic 3' splice site in the neomycin resistance gene allows continued expression of the disrupted cellular gene

    Directory of Open Access Journals (Sweden)

    DeGregori James V

    2003-01-01

    Full Text Available Abstract Background Tagged sequence mutagenesis is a process for constructing libraries of sequenced insertion mutations in embryonic stem cells that can be transmitted into the mouse germline. To better predict the functional consequences of gene entrapment on cellular gene expression, the present study characterized the effects of a U3Neo gene trap retrovirus inserted into an intron of the hnRNP A2/B1 gene. The mutation was selected for analysis because it occurred in a highly expressed gene and yet did not produce obvious phenotypes following germline transmission. Results Sequences flanking the integrated gene trap vector in 1B4 cells were used to isolate a full-length cDNA whose predicted amino acid sequence is identical to the human A2 protein at all but one of 341 amino acid residues. hnRNP A2/B1 transcripts extending into the provirus utilize a cryptic 3' splice site located 28 nucleotides downstream of the neomycin phosphotransferase start codon. The inserted Neo sequence and proviral poly(A site function as an 3' terminal exon that is utilized to produce hnRNP A2/B1-Neo fusion transcripts, or skipped to produce wild-type hnRNP A2/B1 transcripts. This results in only a modest disruption of hnRNPA2/B1 gene expression. Conclusions Expression of the occupied hnRNP A2/B1 gene and utilization of the viral poly(A site are consistent with an exon definition model of pre-mRNA splicing. These results reveal a mechanism by which U3 gene trap vectors can be expressed without disrupting cellular gene expression, thus suggesting ways to improve these vectors for gene trap mutagenesis.

  2. A2A receptor ligands: past, present and future trends.

    Science.gov (United States)

    Clementina, Manera; Giuseppe, Saccomanni

    2010-01-01

    The adenosine A(2A) receptor is a member of the G protein-coupled receptor family and mediates multiple physiological effects of adenosine, both at the central nervous system and at peripheral tissues. Increasing evidence relates the A(2A) receptor with several pathological conditions such as neurodegenerative disorders, inflammation, pharmacological stress, and wound healing renewing the interest in A(2A) receptor agonists and antagonists as promising leads for drugs. However some of them initially tested in clinical trials presented several side effects, short half-life, lower solubility, and in some cases a lack of effects, perhaps attributable to receptor desensitization or to low receptor density in the targeted tissue. For these reasons it is evident that additional rational chemical modifications of the existing A(2A) receptor ligands to improve their affinity/selectivity and bioavailability as well as further studies to get new template for A(2A)AR ligands are necessary. The purpose of this review is to analyze and summarize the past and the present aspects related to the medicinal chemistry of A(2A) receptor ligands. Moreover their current and possible therapeutic applications have been also highlighted.

  3. Leishmania infantum Parasites Subvert the Host Inflammatory Response through the Adenosine A2A Receptor to Promote the Establishment of Infection

    Directory of Open Access Journals (Sweden)

    Mikhael H. F. Lima

    2017-07-01

    Full Text Available Adenosine is an endogenously released purine nucleoside that signals through four widely expressed G protein-coupled receptors: A1, A2A, A2B, and A3. Of these, A2AR is recognized as mediating major adenosine anti-inflammatory activity. During cutaneous leishmaniasis, adenosine induces immunosuppression, which promotes the establishment of infection. Herein, we demonstrated that A2AR signaling is exploited by Leishmania infantum parasites, the etiologic agent that causes Visceral Leishmaniasis, to successfully colonize the vertebrate host. A2AR gene-deleted mice exhibited a well-developed cellular reaction with a strong Th1 immune response in the parasitized organs. An intense infiltration of activated neutrophils into the disease-target organs was observed in A2AR−/− mice. These cells were characterized by high expression of CXCR2 and CD69 on their cell surfaces and increased cxcl1 expression. Interestingly, this phenotype was mediated by IFN-γ on the basis that a neutralizing antibody specific to this cytokine prevented neutrophilic influx into parasitized organs. In evaluating the immunosuppressive effects, we identified a decreased number of CD4+ FOXP3+ T cells and reduced il10 expression in A2AR−/− infected mice. During ex vivo cell culture, A2AR−/− splenocytes produced smaller amounts of IL-10. In conclusion, we demonstrated that the A2AR signaling pathway is detrimental to development of Th1-type adaptive immunity and that this pathway could be associated with the regulatory process. In particular, it promotes parasite surveillance.

  4. Suppression of HPV-16 late L1 5′-splice site SD3632 by binding of hnRNP D proteins and hnRNP A2/B1 to upstream AUAGUA RNA motifs

    Science.gov (United States)

    Li, Xiaoze; Johansson, Cecilia; Glahder, Jacob; Mossberg, Ann-Kristin; Schwartz, Stefan

    2013-01-01

    Human papillomavirus type 16 (HPV-16) 5′-splice site SD3632 is used exclusively to produce late L1 mRNAs. We identified a 34-nt splicing inhibitory element located immediately upstream of HPV-16 late 5′-splice site SD3632. Two AUAGUA motifs located in these 34 nt inhibited SD3632. Two nucleotide substitutions in each of the HPV-16 specific AUAGUA motifs alleviated splicing inhibition and induced late L1 mRNA production from episomal forms of the HPV-16 genome in primary human keratinocytes. The AUAGUA motifs bind specifically not only to the heterogeneous nuclear RNP (hnRNP) D family of RNA-binding proteins including hnRNP D/AUF, hnRNP DL and hnRNP AB but also to hnRNP A2/B1. Knock-down of these proteins induced HPV-16 late L1 mRNA expression, and overexpression of hnRNP A2/B1, hnRNP AB, hnRNP DL and the two hnRNP D isoforms hnRNP D37 and hnRNP D40 further suppressed L1 mRNA expression. This inhibition may allow HPV-16 to hide from the immune system and establish long-term persistent infections with enhanced risk at progressing to cancer. There is an inverse correlation between expression of hnRNP D proteins and hnRNP A2/B1 and HPV-16 L1 production in the cervical epithelium, as well as in cervical cancer, supporting the conclusion that hnRNP D proteins and A2/B1 inhibit HPV-16 L1 mRNA production. PMID:24013563

  5. PET imaging of adenosine A2A receptors

    NARCIS (Netherlands)

    Zhou, Xiaoyun

    2017-01-01

    This thesis describes the development and evaluation of [11C]preladenant as a novel radioligand for in vivo imaging of adenosine A2A receptors in the brain with positron-emission tomography (PET). The 11C-labeled drug [11C]preladenant was produced with high radiochemical yield and specific activity.

  6. 5'-Carbamoyl derivatives of 2'-C-methyl-purine nucleosides as selective A1 adenosine receptor agonists: affinity, efficacy, and selectivity for A1 receptor from different species.

    Science.gov (United States)

    Cappellacci, Loredana; Franchetti, Palmarisa; Vita, Patrizia; Petrelli, Riccardo; Lavecchia, Antonio; Costa, Barbara; Spinetti, Francesca; Martini, Claudia; Klotz, Karl-Norbert; Grifantini, Mario

    2008-01-01

    A series of 5'-carbamoyl and 5'-thionocarbamoyl derivatives of 2'-C-methyl analogues of the A(1) adenosine receptor (A(1)AR) full agonists N(6)-cyclopentyladenosine (CPA), 2-chloro-N(6)-cyclopentyladenosine (CCPA), N(6)-[3-(R)-tetrahydrofuranyl]adenosine (tecadenoson), and 2-chloro analogue (2-Cl-tecadenoson) was synthesized and evaluated for their affinity for adenosine receptor subtypes from bovine, porcine, and human species. In the N(6)-cyclopentylamino series, the 5'-substituted derivatives showed a reduced affinity at the bovine A(1)AR compared to the parent compounds; however, the selectivity for A(1) versus A(2A) receptor was retained or increased. The corresponding N(6)-3-(R)-tetrahydrofuranylamino analogues displayed a very low affinity toward the bovine A(1)AR. The 5'-methylthionocarbamoyl derivative of 2'-Me-CCPA showed the best affinity at porcine A(1)AR with a K(i) value of 13 nM. At human AR subtypes tecadenoson derivatives showed 2.3- to 5-fold lower affinity at A(1)AR and very low affinity at the other subtypes (A(2A), A(2B), and A(3)) compared to the corresponding N(6)-cyclopentyl analogues. The 5'-carbamoyl and 5'-thionocarbamoyl derivatives of 2'-Me-CCPA 3, 4, 7 and tecadenoson derivative 12 were found to be partial A(1) agonists at the porcine receptor. Docking studies explained the lower affinity of N(6)-3-(R)-tetrahydrofuranyl-substituted compounds at bovine A(1)AR compared to that of N(6)-cyclopentyl analogues, showing that the oxygen of the tetrahydrofuranyl ring establishes unfavorable electrostatic interactions with the CO oxygen of Asn254. The low binding affinity of the 2'-C-methyl-N(6)-3-(R)-tetrahydrofuranyl adenosine analogues at human A(1)AR may be ascribed to the presence of unfavorable interactions between the hydrophilic tetrahydrofuranyl ring and the surrounding hydrophobic residues Leu250 (TM6) and Ile274 (TM7).

  7. Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience.

    Science.gov (United States)

    Pokorny, Thomas; Preller, Katrin H; Kraehenmann, Rainer; Vollenweider, Franz X

    2016-04-01

    The mixed serotonin (5-HT) 1A/2A/2B/2C/6/7 receptor agonist psilocybin dose-dependently induces an altered state of consciousness (ASC) that is characterized by changes in sensory perception, mood, thought, and the sense of self. The psychological effects of psilocybin are primarily mediated by 5-HT2A receptor activation. However, accumulating evidence suggests that 5-HT1A or an interaction between 5-HT1A and 5-HT2A receptors may contribute to the overall effects of psilocybin. Therefore, we used a double-blind, counterbalanced, within-subject design to investigate the modulatory effects of the partial 5-HT1A agonist buspirone (20mg p.o.) and the non-hallucinogenic 5-HT2A/1A agonist ergotamine (3mg p.o.) on psilocybin-induced (170 µg/kg p.o.) psychological effects in two groups (n=19, n=17) of healthy human subjects. Psychological effects were assessed using the Altered State of Consciousness (5D-ASC) rating scale. Buspirone significantly reduced the 5D-ASC main scale score for Visionary Restructuralization (VR) (pHT2A receptors, or both. The data suggest that the modulation of 5-HT1A receptor activity may be a useful target in the treatment of visual hallucinations in different psychiatric and neurological diseases. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  8. A1 not A2A adenosine receptors play a role in cortical epileptic afterdischarges in immature rats

    Czech Academy of Sciences Publication Activity Database

    Mareš, Pavel

    2014-01-01

    Roč. 121, č. 11 (2014), s. 1329-1336 ISSN 0300-9564 R&D Projects: GA MŠk(CZ) LH11015 Institutional support: RVO:67985823 Keywords : adenosine receptors * epileptic afterdischarges * cerebral cortex * ontogeny * rat Subject RIV: FH - Neurology Impact factor: 2.402, year: 2014

  9. Adenosine A(2A) receptors are necessary and sufficient to trigger memory impairment in adult mice.

    Science.gov (United States)

    Pagnussat, N; Almeida, A S; Marques, D M; Nunes, F; Chenet, G C; Botton, P H S; Mioranzza, S; Loss, C M; Cunha, R A; Porciúncula, L O

    2015-08-01

    Caffeine (a non-selective adenosine receptor antagonist) prevents memory deficits in aging and Alzheimer's disease, an effect mimicked by adenosine A2 A receptor, but not A1 receptor, antagonists. Hence, we investigated the effects of adenosine receptor agonists and antagonists on memory performance and scopolamine-induced memory impairment in mice. We determined whether A2 A receptors are necessary for the emergence of memory impairments induced by scopolamine and whether A2 A receptor activation triggers memory deficits in naïve mice, using three tests to assess short-term memory, namely the object recognition task, inhibitory avoidance and modified Y-maze. Scopolamine (1.0 mg·kg(-1) , i.p.) impaired short-term memory performance in all three tests and this scopolamine-induced amnesia was prevented by the A2 A receptor antagonist (SCH 58261, 0.1-1.0 mg·kg(-1) , i.p.) and by the A1 receptor antagonist (DPCPX, 0.2-5.0 mg·kg(-1) , i.p.), except in the modified Y-maze where only SCH58261 was effective. Both antagonists were devoid of effects on memory or locomotion in naïve rats. Notably, the activation of A2 A receptors with CGS 21680 (0.1-0.5 mg·kg(-1) , i.p.) before the training session was sufficient to trigger memory impairment in the three tests in naïve mice, and this effect was prevented by SCH 58261 (1.0 mg·kg(-1) , i.p.). Furthermore, i.c.v. administration of CGS 21680 (50 nmol) also impaired recognition memory in the object recognition task. These results show that A2 A receptors are necessary and sufficient to trigger memory impairment and further suggest that A1 receptors might also be selectively engaged to control the cholinergic-driven memory impairment. © 2015 The British Pharmacological Society.

  10. Adenosine A2A receptors are necessary and sufficient to trigger memory impairment in adult mice

    Science.gov (United States)

    Pagnussat, N; Almeida, A S; Marques, D M; Nunes, F; Chenet, G C; Botton, P H S; Mioranzza, S; Loss, C M; Cunha, R A; Porciúncula, L O

    2015-01-01

    Background and Purpose Caffeine (a non-selective adenosine receptor antagonist) prevents memory deficits in aging and Alzheimer’s disease, an effect mimicked by adenosine A2A receptor, but not A1 receptor, antagonists. Hence, we investigated the effects of adenosine receptor agonists and antagonists on memory performance and scopolamine-induced memory impairment in mice. Experimental Approach We determined whether A2A receptors are necessary for the emergence of memory impairments induced by scopolamine and whether A2A receptor activation triggers memory deficits in naïve mice, using three tests to assess short-term memory, namely the object recognition task, inhibitory avoidance and modified Y-maze. Key Results Scopolamine (1.0 mg·kg−1, i.p.) impaired short-term memory performance in all three tests and this scopolamine-induced amnesia was prevented by the A2A receptor antagonist (SCH 58261, 0.1–1.0 mg·kg−1, i.p.) and by the A1 receptor antagonist (DPCPX, 0.2–5.0 mg·kg−1, i.p.), except in the modified Y-maze where only SCH58261 was effective. Both antagonists were devoid of effects on memory or locomotion in naïve rats. Notably, the activation of A2A receptors with CGS 21680 (0.1–0.5 mg·kg−1, i.p.) before the training session was sufficient to trigger memory impairment in the three tests in naïve mice, and this effect was prevented by SCH 58261 (1.0 mg·kg−1, i.p.). Furthermore, i.c.v. administration of CGS 21680 (50 nmol) also impaired recognition memory in the object recognition task. Conclusions and Implications These results show that A2A receptors are necessary and sufficient to trigger memory impairment and further suggest that A1 receptors might also be selectively engaged to control the cholinergic-driven memory impairment. PMID:25939452

  11. The effects of clobazam treatment in rats on the expression of genes and proteins encoding glucronosyltransferase 1A/2B (UGT1A/2B) and multidrug resistance‐associated protein-2 (MRP2), and development of thyroid follicular cell hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Miyawaki, Izuru, E-mail: izuru-miyawaki@ds-pharma.co.jp; Tamura, Akitoshi; Matsumoto, Izumi; Inada, Hiroshi; Kunimatsu, Takeshi; Kimura, Juki; Funabashi, Hitoshi

    2012-12-15

    Clobazam (CLB) is known to increase hepatobiliary thyroxine (T4) clearance in Sprague–Dawley (SD) rats, which results in hypothyroidism followed by thyroid follicular cell hypertrophy. However, the mechanism of the acceleration of T4-clearance has not been fully investigated. In the present study, we tried to clarify the roles of hepatic UDP-glucronosyltransferase (UGT) isoenzymes (UGT1A and UGT2B) and efflux transporter (multidrug resistance–associated protein-2; MRP2) in the CLB-induced acceleration of T4-clearance using two mutant rat strains, UGT1A-deficient mutant (Gunn) and MRP2-deficient mutant (EHBR) rats, especially focusing on thyroid morphology, levels of circulating hormones (T4 and triiodothyronine (T3)) and thyroid-stimulating hormone (TSH), and mRNA or protein expressions of UGTs (Ugt1a1, Ugt1a6, and Ugt2b1/2) and MRP2 (Mrp). CLB induced thyroid morphological changes with increases in TSH in SD and Gunn rats, but not in EHBR rats. T4 was slightly decreased in SD and Gunn rats, and T3 was decreased in Gunn rats, whereas these hormones were maintained in EHBR rats. Hepatic Ugt1a1, Ugt1a6, Ugt2b1/2, and Mrp2 mRNAs were upregulated in SD rats. In Gunn rats, UGT1A mRNAs (Ugt1a1/6) and protein levels were quite low, but UGT2B mRNAs (Ugt2b1/2) and protein were prominently upregulated. In SD and Gunn rats, MRP2 mRNA and protein were upregulated to the same degree. These results suggest that MRP2 is an important contributor in development of the thyroid cellular hypertrophy in CLB-treated rats, and that UGT1A and UGT2B work in concert with MRP2 in the presence of MRP2 function to enable the effective elimination of thyroid hormones. -- Highlights: ► Role of UGT and MRP2 in thyroid pathology was investigated in clobazam-treated rats. ► Clobazam induced thyroid cellular hypertrophy in SD and Gunn rats, but not EHBR rats. ► Hepatic Mrp2 gene and protein were upregulated in SD and Gunn rats, but not EHBR rats. ► Neither serum thyroid hormones (T3/T4

  12. Exploring an interaction of adenosine A2A receptor variability with coffee and tea intake in Parkinson's disease.

    Science.gov (United States)

    Tan, E K; Lu, Z Y; Fook-Chong, S M C; Tan, E; Shen, H; Chua, E; Yih, Y; Teo, Y Y; Zhao, Y

    2006-09-05

    Caffeine is an adenosine receptor A1 and A2A receptor antagonist and a putative functional genetic variant of the A2A receptor (2592C > Tins) mediates caffeine-induced anxiety. Here we investigated the potential interaction of this A2A genetic variant with the quantity of coffee and tea intake and their relationship with the risk of PD. A total of 441 subjects consisting of 222 PD and 219 race, gender and age matched controls were included. A multivariate analysis of the variables including the 2592C > Tins A2A genotypes, age of onset, gender, and the quantity of tea and coffee intake, interaction of the A2A genotypes with coffee intake, interaction of A2A genotypes with tea intake demonstrated the quantity of coffee intake to be significantly associated with PD (P coffee and tea intake in modulating the risk of PD. The dose dependent protective effect of coffee intake in PD was independent of the 2592C > Tins A2A genotype suggesting that the pharmacogenetic action of caffeine in PD may be mediated differently from other caffeine-induced neurologic syndromes.

  13. AMP is an adenosine A1 receptor agonist.

    Science.gov (United States)

    Rittiner, Joseph E; Korboukh, Ilia; Hull-Ryde, Emily A; Jin, Jian; Janzen, William P; Frye, Stephen V; Zylka, Mark J

    2012-02-17

    Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5'-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5'-monophosphonate, ACP) directly activated the adenosine A(1) receptor (A(1)R). In contrast, AMP only activated the adenosine A(2B) receptor (A(2B)R) after hydrolysis to adenosine by ecto-5'-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A(1)R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A(1)R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A(1)R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A(1)R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine.

  14. Atomic structure and electronic properties of A2B2XY (A = Si-Pb, B = Cl-I, and XY = PN and SiS) inorganic double helices: first principles calculations.

    Science.gov (United States)

    Bijoy, T K; Murugan, P; Kumar, Vijay

    2018-03-05

    We study the structural stability and electronic properties of new classes of DNA-like inorganic double helices of the type A 2 B 2 XY (A = Si-Pb, B = Cl-I, and XY = PN and SiS) by employing first principles density functional theory (DFT) calculations including van der Waals interactions. In these quaternary double helices PN or SiS forms the inner helix while the AB helix wraps around the inner helix and the two are interconnected. We find that the bromides and iodides of Ge, Sn, and Pb as well as Pb 2 Cl 2 PN form structurally stable double helices while Ge 2 I 2 SiS as well as bromides and iodides of Sn and Pb have stable double helices. The atomic structures of different double helices have been analyzed in detail to understand the stability of these systems as there is up to about 80% difference in the interatomic distances in the two helices which is remarkable. Also in these new classes of double helices there is polar covalent bonding in the inner helix due to heteroatoms. We have calculated the DDEC6 partial atomic charges and bond orders which suggest strong covalent bonding in the inner helix. The electronic structure reveals that these double helices are semiconducting and in many cases the band gap is direct. Furthermore, we have studied the effects of doping and found that hole doping is the most appropriate way to tuning their electronic properties.

  15. Cholesterol 27-hydroxylase but not apolipoprotein apoE contributes to A2A adenosine receptor stimulated reverse cholesterol transport.

    Science.gov (United States)

    Bingham, Taiese Crystal; Parathath, Saj; Tian, Heather; Reiss, Allison; Chan, Edwin; Fisher, Edward A; Cronstein, Bruce N

    2012-02-01

    Movement of free cholesterol between the cellular compartment and acceptor is governed by cholesterol gradients that are determined by several enzymes and reverse cholesterol transport proteins. We have previously demonstrated that adenosine A(2A) receptors inhibit foam cell formation and stimulate production of cholesterol 27-hydroxylase (CYP27A1), an enzyme involved in the conversion of cholesterol to oxysterols. We therefore asked whether the effect of adenosine A(2A) receptors on foam cell formation in vitro is mediated by CYP27A1 or apoE, a carrier for cholesterol in the serum. We found that specific lentiviral siRNA infection markedly reduced apoE or 27-hydroxylase mRNA in THP-1 cells. Despite diminished apoE expression (p CYP27A1 KD cells (4 ± 2%; pCYP27A1 KD cells but reduced efflux in apoE KD cells. These results demonstrate that adenosine A(2A) receptor occupancy diminishes foam cell formation by increasing expression and function of CYP27A1.

  16. [Significance of the isoantigen A2 and immune anti-A1 antibodies in transfusiology].

    Science.gov (United States)

    Dashkova, N G; Ragimov, A A; Asoskova, T K

    2009-01-01

    The paper gives data on the frequency of A2 and A2B blood groups in the blood samples of 3590 donors and patients and on the carriage of irregular anti-A1 antibodies. To define the belonging of anti-A1 antibodies to various classes of immunoglobulins, their resistance and temperature optimum, at which the antibodies showed the highest activity, the authors examined the irregular anti-A1 antibodies-containing sera from 43 subjects with A2 and A2B blood groups. The necessity of identifying the carriage of irregular anti-A1 antibodies is determined by the fact that there may be posttransfusion reactions or complications in recipients, the carriers of such antibodies, who are transfused donor red blood cells containing the antigen A1. The risk of the development of such events is particularly great when anti-A1 antibodies are active at 37 degrees C and belong to the IgG class, i.e. they are immune; transfusion to a recipient is carried out during surgery under artificial hypothermia (below 28 degrees C). The red blood cells (A2 or A2B) from a donor having the same group should be selected for recipients having an A2 or A2B blood groups, respectively, and immune anti-A1 antibodies; if the latter are absent, in accordance with the instruction, there may be a selection of other-group donor red blood cells: 0 group red blood cells to recipients with A2 blood group and 0 or B group red blood cells to recipients with A2B blood group. An individual selection should be without fail made for the compatibility of bloods from a donor and a recipient in salt tests (at 4-8, 20-22, and 37 degrees C) and indirect Coombs' test. When plasma components (fresh frozen plasma, native plasma and its concentrate) are transfused to recipients with A2 and A2B blood groups having immune anti-A1 antibodies, one should use the same plasma group--A and AB, respectively.

  17. The A2B Adenosine Receptor Modulates the Epithelial– Mesenchymal Transition through the Balance of cAMP/PKA and MAPK/ERK Pathway Activation in Human Epithelial Lung Cells

    Directory of Open Access Journals (Sweden)

    Chiara Giacomelli

    2018-01-01

    Full Text Available The epithelial-mesenchymal transition (EMT is a complex process in which cell phenotype switches from the epithelial to mesenchymal one. The deregulations of this process have been related with the occurrence of different diseases such as lung cancer and fibrosis. In the last decade, several efforts have been devoted in understanding the mechanisms that trigger and sustain this transition process. Adenosine is a purinergic signaling molecule that has been involved in the onset and progression of chronic lung diseases and cancer through the A2B adenosine receptor subtype activation, too. However, the relationship between A2BAR and EMT has not been investigated, yet. Herein, the A2BAR characterization was carried out in human epithelial lung cells. Moreover, the effects of receptor activation on EMT were investigated in the absence and presence of transforming growth factor-beta (TGF-β1, which has been known to promote the transition. The A2BAR activation alone decreased and increased the expression of epithelial markers (E-cadherin and the mesenchymal one (Vimentin, N-cadherin, respectively, nevertheless a complete EMT was not observed. Surprisingly, the receptor activation counteracted the EMT induced by TGF-β1. Several intracellular pathways regulate the EMT: high levels of cAMP and ERK1/2 phosphorylation has been demonstrated to counteract and promote the transition, respectively. The A2BAR stimulation was able to modulated these two pathways, cAMP/PKA and MAPK/ERK, shifting the fine balance toward activation or inhibition of EMT. In fact, using a selective PKA inhibitor, which blocks the cAMP pathway, the A2BAR-mediated EMT promotion were exacerbated, and conversely the selective inhibition of MAPK/ERK counteracted the receptor-induced transition. These results highlighted the A2BAR as one of the receptors involved in the modulation of EMT process. Nevertheless, its activation is not enough to trigger a complete transition, its ability to

  18. The A2B Adenosine Receptor Modulates the Epithelial– Mesenchymal Transition through the Balance of cAMP/PKA and MAPK/ERK Pathway Activation in Human Epithelial Lung Cells

    Science.gov (United States)

    Giacomelli, Chiara; Daniele, Simona; Romei, Chiara; Tavanti, Laura; Neri, Tommaso; Piano, Ilaria; Celi, Alessandro; Martini, Claudia; Trincavelli, Maria L.

    2018-01-01

    The epithelial-mesenchymal transition (EMT) is a complex process in which cell phenotype switches from the epithelial to mesenchymal one. The deregulations of this process have been related with the occurrence of different diseases such as lung cancer and fibrosis. In the last decade, several efforts have been devoted in understanding the mechanisms that trigger and sustain this transition process. Adenosine is a purinergic signaling molecule that has been involved in the onset and progression of chronic lung diseases and cancer through the A2B adenosine receptor subtype activation, too. However, the relationship between A2BAR and EMT has not been investigated, yet. Herein, the A2BAR characterization was carried out in human epithelial lung cells. Moreover, the effects of receptor activation on EMT were investigated in the absence and presence of transforming growth factor-beta (TGF-β1), which has been known to promote the transition. The A2BAR activation alone decreased and increased the expression of epithelial markers (E-cadherin) and the mesenchymal one (Vimentin, N-cadherin), respectively, nevertheless a complete EMT was not observed. Surprisingly, the receptor activation counteracted the EMT induced by TGF-β1. Several intracellular pathways regulate the EMT: high levels of cAMP and ERK1/2 phosphorylation has been demonstrated to counteract and promote the transition, respectively. The A2BAR stimulation was able to modulated these two pathways, cAMP/PKA and MAPK/ERK, shifting the fine balance toward activation or inhibition of EMT. In fact, using a selective PKA inhibitor, which blocks the cAMP pathway, the A2BAR-mediated EMT promotion were exacerbated, and conversely the selective inhibition of MAPK/ERK counteracted the receptor-induced transition. These results highlighted the A2BAR as one of the receptors involved in the modulation of EMT process. Nevertheless, its activation is not enough to trigger a complete transition, its ability to affect different

  19. Theobromine-Induced Changes in A1 Purinergic Receptor Gene Expression and Distribution in a Rat Brain Alzheimer's Disease Model.

    Science.gov (United States)

    Mendiola-Precoma, Jesus; Padilla, Karla; Rodríguez-Cruz, Alfredo; Berumen, Laura C; Miledi, Ricardo; García-Alcocer, Guadalupe

    2017-01-01

    Dementia caused by Alzheimer's disease (AD) is mainly characterized by accumulation in the brain of extra- and intraneuronal amyloid-β (Aβ) and tau proteins, respectively, which selectively affect specific regions, particularly the neocortex and the hippocampus. Sporadic AD is mainly caused by an increase in apolipoprotein E, a component of chylomicrons, which are cholesterol transporters in the brain. Recent studies have shown that high lipid levels, especially cholesterol, are linked to AD. Adenosine is an atypical neurotransmitter that regulates a wide range of physiological functions by activating four P1 receptors (A1, A2A, A2B, and A3) and P2 purinergic receptors that are G protein-coupled. A1 receptors are involved in the inhibition of neurotransmitter release, which could be related to AD. The aim of the present work was to study the effects of a lard-enriched diet (LED) on cognitive and memory processes in adult rats (6 months of age) as well as the effect of theobromine on these processes. The results indicated that the fat-enriched diet resulted in a long-term deterioration in cognitive and memory functions. Increased levels of Aβ protein and IL-1β were also observed in the rats fed with a high-cholesterol diet, which were used to validate the AD animal model. In addition, the results of qPCR and immunohistochemistry indicated a decrease in gene expression and distribution of A1 purinegic receptor, respectively, in the hippocampus of LED-fed rats. Interestingly, theobromine, at both concentrations tested, restored A1 receptor levels and improved cognitive functions and Aβ levels for a dose of 30 mg/L drinking water.

  20. Striatal Pre- and Postsynaptic Profile of Adenosine A2A Receptor Antagonists

    Science.gov (United States)

    Quiroz, César; Beaumont, Vahri; Goldberg, Steven R.; Lluís, Carme; Cortés, Antoni; Franco, Rafael; Casadó, Vicent; Canela, Enric I.; Ferré, Sergi

    2011-01-01

    Striatal adenosine A2A receptors (A2ARs) are highly expressed in medium spiny neurons (MSNs) of the indirect efferent pathway, where they heteromerize with dopamine D2 receptors (D2Rs). A2ARs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A1 receptors (A1Rs). It has been hypothesized that postsynaptic A2AR antagonists should be useful in Parkinson's disease, while presynaptic A2AR antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A2AR antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261) showed no clear preference. Radioligand-binding experiments were performed in cells expressing A2AR-D2R and A1R-A2AR heteromers to determine possible differences in the affinity of these compounds for different A2AR heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A2AR when co-expressed with D2R than with A1R. KW-6002 showed the best relative affinity for A2AR co-expressed with D2R than co-expressed with A1R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile. On the basis of their preferential

  1. Striatal pre- and postsynaptic profile of adenosine A(2A receptor antagonists.

    Directory of Open Access Journals (Sweden)

    Marco Orru

    2011-01-01

    Full Text Available Striatal adenosine A(2A receptors (A(2ARs are highly expressed in medium spiny neurons (MSNs of the indirect efferent pathway, where they heteromerize with dopamine D(2 receptors (D(2Rs. A(2ARs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A(1 receptors (A(1Rs. It has been hypothesized that postsynaptic A(2AR antagonists should be useful in Parkinson's disease, while presynaptic A(2AR antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A(2AR antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261 showed no clear preference. Radioligand-binding experiments were performed in cells expressing A(2AR-D(2R and A(1R-A(2AR heteromers to determine possible differences in the affinity of these compounds for different A(2AR heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A(2AR when co-expressed with D(2R than with A(1R. KW-6002 showed the best relative affinity for A(2AR co-expressed with D(2R than co-expressed with A(1R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile

  2. Interactions between Calmodulin, Adenosine A2A, and Dopamine D2 Receptors*

    Science.gov (United States)

    Navarro, Gemma; Aymerich, Marisol S.; Marcellino, Daniel; Cortés, Antoni; Casadó, Vicent; Mallol, Josefa; Canela, Enric I.; Agnati, Luigi; Woods, Amina S.; Fuxe, Kjell; Lluís, Carmen; Lanciego, Jose Luis; Ferré, Sergi; Franco, Rafael

    2009-01-01

    The Ca2+-binding protein calmodulin (CaM) has been shown to bind directly to cytoplasmic domains of some G protein-coupled receptors, including the dopamine D2 receptor. CaM binds to the N-terminal portion of the long third intracellular loop of the D2 receptor, within an Arg-rich epitope that is also involved in the binding to Gi/o proteins and to the adenosine A2A receptor, with the formation of A2A-D2 receptor heteromers. In the present work, by using proteomics and bioluminescence resonance energy transfer (BRET) techniques, we provide evidence for the binding of CaM to the A2A receptor. By using BRET and sequential resonance energy transfer techniques, evidence was obtained for CaM-A2A-D2 receptor oligomerization. BRET competition experiments indicated that, in the A2A-D2 receptor heteromer, CaM binds preferentially to a proximal C terminus epitope of the A2A receptor. Furthermore, Ca2+ was found to induce conformational changes in the CaM-A2A-D2 receptor oligomer and to selectively modulate A2A and D2 receptor-mediated MAPK signaling in the A2A-D2 receptor heteromer. These results may have implications for basal ganglia disorders, since A2A-D2 receptor heteromers are being considered as a target for anti-parkinsonian agents. PMID:19632986

  3. N6-Cycloalkyl- and N6-bicycloalkyl-C5'(C2')-modified adenosine derivatives as high-affinity and selective agonists at the human A1 adenosine receptor with antinociceptive effects in mice.

    Science.gov (United States)

    Franchetti, Palmarisa; Cappellacci, Loredana; Vita, Patrizia; Petrelli, Riccardo; Lavecchia, Antonio; Kachler, Sonja; Klotz, Karl-Norbert; Marabese, Ida; Luongo, Livio; Maione, Sabatino; Grifantini, Mario

    2009-04-23

    To further investigate new potent and selective human A(1) adenosine receptor agonists, we have synthesized a series of 5'-chloro-5'-deoxy- and 5'-(2-fluorophenylthio)-5'-deoxy-N(6)-cycloalkyl(bicycloalkyl)-substituted adenosine and 2'-C-methyladenosine derivatives. These compounds were evaluated for affinity and efficacy at human A(1), A(2A), A(2B), and A(3) adenosine receptors. In the series of N(6)-cyclopentyl- and N(6)-(endo-norborn-2-yl)adenosine derivatives, 5'-chloro-5'-deoxy-CPA (1) and 5'-chloro-5'-deoxy-(+/-)-ENBA (3) displayed the highest affinity in the subnanomolar range and relevant selectivity for hA(1) vs the other human receptor subtypes. The higher affinity and selectivity of 5'-chloro-5'-deoxyribonucleoside derivatives 1 and 3 for hA(1) AR vs hA(3) AR compared to that of the parent 5'-hydroxy compounds CPA and (+/-)-ENBA was rationalized by a molecular modeling analysis. 5'-Chloro-5'-deoxy-(+/-)-ENBA, evaluated for analgesic activity in the formalin test in mice, was found to inhibit the first or the second phases of the nocifensive response induced by intrapaw injection of formalin at doses ranging between 1 and 2 mg/kg i.p.

  4. A2A Receptor Antagonism and Dyskinesia in Parkinson’s Disease

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    Micaela Morelli

    2012-01-01

    Full Text Available Dyskinesia, a major complication of treatment of Parkinson’s disease (PD, involves two phases: induction, which is responsible for dyskinesia onset, and expression, which underlies its clinical manifestation. The unique cellular and regional distribution of adenosine A2A receptors in basal ganglia areas that are richly innervated by dopamine, and their antagonistic role towards dopamine receptor stimulation, have positioned A2A receptor antagonists as an attractive nondopaminergic target to improve the motor deficits that characterize PD. In this paper, we describe the biochemical characteristics of A2A receptors and the effects of adenosine A2A antagonists in rodent and primate models of PD on L-DOPA-induced dyskinesia, together with relevant biomarker studies. We also review clinical trials of A2A antagonists as adjuncts to L-DOPA in PD patients with motor fluctuations. These studies have generally demonstrated that the addition of an A2A antagonist to a stable L-DOPA regimen reduces OFF time and mildly increases dyskinesia. However, limited clinical data suggest that the addition of an A2A antagonist along with a reduction of L-DOPA might maintain anti-Parkinsonian benefit and reduce dyskinesia. Whether A2A antagonists might reduce the development of dyskinesia has not yet been tested clinically.

  5. Adenosine A2A Receptor Modulates the Activity of Globus Pallidus Neurons in Rats

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    Hui-Ling Diao

    2017-11-01

    Full Text Available The globus pallidus is a central nucleus in the basal ganglia motor control circuit. Morphological studies have revealed the expression of adenosine A2A receptors in the globus pallidus. To determine the modulation of adenosine A2A receptors on the activity of pallidal neurons in both normal and parkinsonian rats, in vivo electrophysiological and behavioral tests were performed in the present study. The extracellular single unit recordings showed that micro-pressure administration of adenosine A2A receptor agonist, CGS21680, regulated the pallidal firing activity. GABAergic neurotransmission was involved in CGS21680-induced modulation of pallidal neurons via a PKA pathway. Furthermore, application of two adenosine A2A receptor antagonists, KW6002 or SCH442416, mainly increased the spontaneous firing of pallidal neurons, suggesting that endogenous adenosine system modulates the activity of pallidal neurons through adenosine A2A receptors. Finally, elevated body swing test (EBST showed that intrapallidal microinjection of adenosine A2A receptor agonist/antagonist induced ipsilateral/contralateral-biased swing, respectively. In addition, the electrophysiological and behavioral findings also revealed that activation of dopamine D2 receptors by quinpirole strengthened KW6002/SCH442416-induced excitation of pallidal activity. Co-application of quinpirole with KW6002 or SCH442416 alleviated biased swing in hemi-parkinsonian rats. Based on the present findings, we concluded that pallidal adenosine A2A receptors may be potentially useful in the treatment of Parkinson's disease.

  6. Adenosine A1 receptors promote vasa vasorum endothelial cell barrier integrity via Gi and Akt-dependent actin cytoskeleton remodeling.

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    Siddaramappa Nagavedi Umapathy

    Full Text Available In a neonatal model of hypoxic pulmonary hypertension, a dramatic pulmonary artery adventitial thickening, accumulation of inflammatory cells in the adventitial compartment, and angiogenic expansion of the vasa vasorum microcirculatory network are observed. These pathophysiological responses suggest that rapidly proliferating vasa vasorum endothelial cells (VVEC may exhibit increased permeability for circulating blood cells and macromolecules. However, the molecular mechanisms underlying these observations remain unexplored. Some reports implicated extracellular adenosine in the regulation of vascular permeability under hypoxic and inflammatory conditions. Thus, we aimed to determine the role of adenosine in barrier regulation of VVEC isolated from the pulmonary arteries of normoxic (VVEC-Co or chronically hypoxic (VVEC-Hyp neonatal calves.We demonstrate via a transendothelial electrical resistance measurement that exogenous adenosine significantly enhanced the barrier function in VVEC-Co and, to a lesser extent, in VVEC-Hyp. Our data from a quantitative reverse transcription polymerase chain reaction show that both VVEC-Co and VVEC-Hyp express all four adenosine receptors (A1, A2A, A2B, and A3, with the highest expression level of A1 receptors (A1Rs. However, A1R expression was significantly lower in VVEC-Hyp compared to VVEC-Co. By using an A1R-specific agonist/antagonist and siRNA, we demonstrate that A1Rs are mostly responsible for adenosine-induced enhancement in barrier function. Adenosine-induced barrier integrity enhancement was attenuated by pretreatment of VVEC with pertussis toxin and GSK690693 or LY294002, suggesting the involvement of Gi proteins and the PI3K-Akt pathway. Moreover, we reveal a critical role of actin cytoskeleton in VVEC barrier regulation by using specific inhibitors of actin and microtubule polymerization. Further, we show that adenosine pretreatment blocked the tumor necrosis factor alpha (TNF

  7. Adenosine A1 Receptors Promote Vasa Vasorum Endothelial Cell Barrier Integrity via Gi and Akt-Dependent Actin Cytoskeleton Remodeling

    Science.gov (United States)

    Siddaramappa Umapathy, Nagavedi; Kaczmarek, Elzbieta; Fatteh, Nooreen; Burns, Nana; Lucas, Rudolf; Stenmark, Kurt R.; Verin, Alexander D.; Gerasimovskaya, Evgenia V.

    2013-01-01

    Background In a neonatal model of hypoxic pulmonary hypertension, a dramatic pulmonary artery adventitial thickening, accumulation of inflammatory cells in the adventitial compartment, and angiogenic expansion of the vasa vasorum microcirculatory network are observed. These pathophysiological responses suggest that rapidly proliferating vasa vasorum endothelial cells (VVEC) may exhibit increased permeability for circulating blood cells and macromolecules. However, the molecular mechanisms underlying these observations remain unexplored. Some reports implicated extracellular adenosine in the regulation of vascular permeability under hypoxic and inflammatory conditions. Thus, we aimed to determine the role of adenosine in barrier regulation of VVEC isolated from the pulmonary arteries of normoxic (VVEC-Co) or chronically hypoxic (VVEC-Hyp) neonatal calves. Principal Findings We demonstrate via a transendothelial electrical resistance measurement that exogenous adenosine significantly enhanced the barrier function in VVEC-Co and, to a lesser extent, in VVEC-Hyp. Our data from a quantitative reverse transcription polymerase chain reaction show that both VVEC-Co and VVEC-Hyp express all four adenosine receptors (A1, A2A, A2B, and A3), with the highest expression level of A1 receptors (A1Rs). However, A1R expression was significantly lower in VVEC-Hyp compared to VVEC-Co. By using an A1R-specific agonist/antagonist and siRNA, we demonstrate that A1Rs are mostly responsible for adenosine-induced enhancement in barrier function. Adenosine-induced barrier integrity enhancement was attenuated by pretreatment of VVEC with pertussis toxin and GSK690693 or LY294002, suggesting the involvement of Gi proteins and the PI3K-Akt pathway. Moreover, we reveal a critical role of actin cytoskeleton in VVEC barrier regulation by using specific inhibitors of actin and microtubule polymerization. Further, we show that adenosine pretreatment blocked the tumor necrosis factor alpha (TNF

  8. Adenosine A2A Receptors Modulate Acute Injury and Neuroinflammation in Brain Ischemia

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    Felicita Pedata

    2014-01-01

    Full Text Available The extracellular concentration of adenosine in the brain increases dramatically during ischemia. Adenosine A2A receptor is expressed in neurons and glial cells and in inflammatory cells (lymphocytes and granulocytes. Recently, adenosine A2A receptor emerged as a potential therapeutic attractive target in ischemia. Ischemia is a multifactorial pathology characterized by different events evolving in the time. After ischemia the early massive increase of extracellular glutamate is followed by activation of resident immune cells, that is, microglia, and production or activation of inflammation mediators. Proinflammatory cytokines, which upregulate cell adhesion molecules, exert an important role in promoting recruitment of leukocytes that in turn promote expansion of the inflammatory response in ischemic tissue. Protracted neuroinflammation is now recognized as the predominant mechanism of secondary brain injury progression. A2A receptors present on central cells and on blood cells account for important effects depending on the time-related evolution of the pathological condition. Evidence suggests that A2A receptor antagonists provide early protection via centrally mediated control of excessive excitotoxicity, while A2A receptor agonists provide protracted protection by controlling massive blood cell infiltration in the hours and days after ischemia. Focus on inflammatory responses provides for adenosine A2A receptor agonists a wide therapeutic time-window of hours and even days after stroke.

  9. Adenosine A2A receptor antagonists and Parkinson's disease: state of the art and future directions.

    Science.gov (United States)

    Simola, N; Morelli, M; Pinna, A

    2008-01-01

    Adenosine A(2A) receptors present in the central nervous system have been implicated in the modulation of motor functions. Accordingly, adenosine A(2A) receptor antagonists currently constitute an attractive non-dopaminergic option for use in the treatment of Parkinson's disease (PD). The highly enriched distributions of adenosine A(2A) receptors in striatopallidal neurons, and their ability to form functional heteromeric complexes with dopamine D(2) and metabotropic glutamate mGlu5 receptors, render A(2A) receptor antagonists of particular interest in the modulation of motor behavior, whilst at the same time displaying a low predisposition to inducing non-motor side effects. Furthermore, adenosine A(2A) receptor antagonists appear to exert a marked efficacy on PD tremor and in reducing the progress of underlying neurodegeneration and maladaptive neuroplasticity that complicates standard dopamine replacement treatments in PD. Finally, recent evidence has illustrated an improvement of cognitive function as well as enhancement of attention in rodents following administration of A(2A) receptor antagonists. This article is aimed at examining preclinical studies describing these findings as well as reports from clinical trials, in order to provide a comprehensive review of the evidence suggesting that this class of drugs may represent an advance in the treatment of PD.

  10. Synthesis and biological evaluation of novel 1-deoxy-1-[6-[((hetero)arylcarbonyl)hydrazino]- 9H-purin-9-yl]-N-ethyl-beta-D-ribofuranuronamide derivatives as useful templates for the development of A2B adenosine receptor agonists.

    Science.gov (United States)

    Baraldi, Pier Giovanni; Preti, Delia; Tabrizi, Mojgan Aghazadeh; Fruttarolo, Francesca; Romagnoli, Romeo; Carrion, Maria Dora; Cara, Luisa Carlota Lopez; Moorman, Allan R; Varani, Katia; Borea, Pier Andrea

    2007-01-25

    The lack of molecules endowed with selective and potent agonistic activity toward the hA2B adenosine receptors has limited the studies on this pharmacological target and consequently the evaluation of its therapeutic potential. We report the design and the synthesis of the first potent (EC50 in the nanomolar range) and selective hA2B adenosine receptor agonists consisting of 1-deoxy-1-[6-[((hetero)arylcarbonyl)hydrazino]-9H-purin-9-yl]-N-ethyl-beta-D-ribofuranuronamide derivatives. The concurrent effect of 6-substitution of the purine nucleus with a ((hetero)arylcarbonyl)hydrazino function and a 2-chloro substitution has been investigated in such NECA derivatives.

  11. Decommissioning of NPP A-1

    International Nuclear Information System (INIS)

    Anon

    2009-01-01

    In this presentation the Operation history of A1 NPP, Project 'Decommissioning of A1 NPP' - I stage, Project 'Decommissioning of A1 NPP ' - II stage and Next stages of Project 'Decommissioning of A1 NPP ' are discussed.

  12. Pharmacological characterisation and inhibitory effects of (2R,3R,4S,5R)-2-(6-amino-2-{[(1S)-2-hydroxy-1-(phenylmethyl)ethyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3,4-furandiol, a novel ligand that demonstrates both adenosine A(2A) receptor agonist and adenosine A(3) receptor antagonist activity.

    Science.gov (United States)

    Bevan, Nicola; Butchers, Peter R; Cousins, Rick; Coates, Jill; Edgar, Emma V; Morrison, Val; Sheehan, Michael J; Reeves, Julian; Wilson, David J

    2007-06-14

    The pharmacological properties of the novel ligand, (2R,3R,4S,5R)-2-(6-amino-2-{[(1S)-2-hydroxy-1-(phenylmethyl)ethyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3,4-furandiol (I), at the human adenosine receptors were investigated using Chinese hamster ovary cell lines recombinantly expressing these receptors. Functional studies were performed using a cyclic AMP-coupled reporter gene system. Binding studies were performed using membranes from these cells. The effects of ligand (I) were also determined on functional responses of human neutrophils and eosinophils. Ligand (I) had a high affinity for the adenosine A(2A) receptor (pKi 7.8+/-0.2) and was a potent agonist at this receptor (pEC(50) 9.0+/-0.2). Ligand (I) had a similar affinity for the adenosine A(3) receptor (pKi 7.8+/-0.1) but displayed no agonist activity, acting instead as a competitive antagonist (pA(2) 8.3+/-0.04). Ligand (I) had lower affinity for adenosine A(1) and A(2B) receptors (pKiA(2A) receptor antagonist 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (CGS15943) with a pA(2) value (10.03+/-0.44) consistent with an effect on adenosine A(2A) receptors. Ligand (I) also inhibited the release of granule proteins from neutrophils and eosinophils (pEC(50) 8.7 and 8.9 respectively), albeit less potently than as an inhibitor of reactive oxygen species generation. In summary, ligand (I) is a potent and selective agonist for the adenosine A(2A) receptor and a competitive antagonist at the adenosine A(3) receptor. Ligand (I) has potent anti-inflammatory effects on human

  13. NCS-1 associates with adenosine A2A receptors and modulates receptor function

    Directory of Open Access Journals (Sweden)

    Gemma eNavarro

    2012-04-01

    Full Text Available Modulation of G protein-coupled receptor (GPCR signalling by local changes in intracellular calcium concentration is an established function of Calmodulin which is known to interact with many GPCRs. Less is known about the functional role of the closely related neuronal EF-hand Ca2+-sensor proteins that frequently associate with calmodulin targets with different functional outcome. In the present study we aimed to investigate if a target of calmodulin – the A2A adenosine receptor, is able to associate with two other neuronal calcium binding proteins, namely NCS-1 and caldendrin. Using bioluminescence resonance energy transfer and co-immunoprecipitation experiments we show the existence of A2A - NCS-1 complexes in living cells whereas caldendrin did not associate with A2A receptors under the conditions tested. Interestingly, NCS-1 binding modulated downstream A2A receptor intracellular signalling in a Ca2+-dependent manner. Taken together this study provides further evidence that neuronal Ca2+-sensor proteins play an important role in modulation of GPCR signalling.

  14. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors

    DEFF Research Database (Denmark)

    Gnad, Thorsten; Scheibler, Saskia; von Kügelgen, Ivar

    2014-01-01

    Brown adipose tissue (BAT) is specialized in energy expenditure, making it a potential target for anti-obesity therapies. Following exposure to cold, BAT is activated by the sympathetic nervous system with concomitant release of catecholamines and activation of β-adrenergic receptors. Because BAT...... therapies based on cold exposure or β-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmission might be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine in BAT from...... receptor is the most abundant adenosine receptor in human and murine BAT. Pharmacological blockade or genetic loss of A2A receptors in mice causes a decrease in BAT-dependent thermogenesis, whereas treatment with A2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation...

  15. AMP Is an Adenosine A1 Receptor Agonist*

    Science.gov (United States)

    Rittiner, Joseph E.; Korboukh, Ilia; Hull-Ryde, Emily A.; Jin, Jian; Janzen, William P.; Frye, Stephen V.; Zylka, Mark J.

    2012-01-01

    Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5′-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5′-monophosphonate, ACP) directly activated the adenosine A1 receptor (A1R). In contrast, AMP only activated the adenosine A2B receptor (A2BR) after hydrolysis to adenosine by ecto-5′-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A1R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A1R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A1R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A1R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine. PMID:22215671

  16. A2A adenosine receptor ligand binding and signalling is allosterically modulated by adenosine deaminase.

    Science.gov (United States)

    Gracia, Eduard; Pérez-Capote, Kamil; Moreno, Estefanía; Barkešová, Jana; Mallol, Josefa; Lluís, Carme; Franco, Rafael; Cortés, Antoni; Casadó, Vicent; Canela, Enric I

    2011-05-01

    A2ARs (adenosine A2A receptors) are highly enriched in the striatum, which is the main motor control CNS (central nervous system) area. BRET (bioluminescence resonance energy transfer) assays showed that A2AR homomers may act as cell-surface ADA (adenosine deaminase; EC 3.5.4.4)-binding proteins. ADA binding affected the quaternary structure of A2ARs present on the cell surface. ADA binding to adenosine A2ARs increased both agonist and antagonist affinity on ligand binding to striatal membranes where these proteins are co-expressed. ADA also increased receptor-mediated ERK1/2 (extracellular-signal-regulated kinase 1/2) phosphorylation. Collectively, the results of the present study show that ADA, apart from regulating the concentration of extracellular adenosine, may behave as an allosteric modulator that markedly enhances ligand affinity and receptor function. This powerful regulation may have implications for the physiology and pharmacology of neuronal A2ARs.

  17. Role of Microglia Adenosine A2A Receptors in Retinal and Brain Neurodegenerative Diseases

    Science.gov (United States)

    Santiago, Ana R.; Baptista, Filipa I.; Santos, Paulo F.; Cristóvão, Gonçalo; Ambrósio, António F.; Cunha, Rodrigo A.; Gomes, Catarina A.

    2014-01-01

    Neuroinflammation mediated by microglial cells in the brain has been commonly associated with neurodegenerative diseases. Whether this microglia-mediated neuroinflammation is cause or consequence of neurodegeneration is still a matter of controversy. However, it is unequivocal that chronic neuroinflammation plays a role in disease progression and halting that process represents a potential therapeutic strategy. The neuromodulator adenosine emerges as a promising targeting candidate based on its ability to regulate microglial proliferation, chemotaxis, and reactivity through the activation of its G protein coupled A2A receptor (A2AR). This is in striking agreement with the ability of A2AR blockade to control several brain diseases. Retinal degenerative diseases have been also associated with microglia-mediated neuroinflammation, but the role of A2AR has been scarcely explored. This review aims to compare inflammatory features of Parkinson's and Alzheimer's diseases with glaucoma and diabetic retinopathy, discussing the therapeutic potential of A2AR in these degenerative conditions. PMID:25132733

  18. Caffeine and a selective adenosine A2A receptor antagonist induce sensitization and cross-sensitization behavior associated with increased striatal dopamine in mice

    Directory of Open Access Journals (Sweden)

    Hsu Chih W

    2010-01-01

    Full Text Available Abstract Background Caffeine, a nonselective adenosine A1 and A2A receptor antagonist, is the most widely used psychoactive substance in the world. Evidence demonstrates that caffeine and selective adenosine A2A antagonists interact with the neuronal systems involved in drug reinforcement, locomotor sensitization, and therapeutic effect in Parkinson's disease (PD. Evidence also indicates that low doses of caffeine and a selective adenosine A2A antagonist SCH58261 elicit locomotor stimulation whereas high doses of these drugs exert locomotor inhibition. Since these behavioral and therapeutic effects are mediated by the mesolimbic and nigrostriatal dopaminergic pathways which project to the striatum, we hypothesize that low doses of caffeine and SCH58261 may modulate the functions of dopaminergic neurons in the striatum. Methods In this study, we evaluated the neuroadaptations in the striatum by using reverse-phase high performance liquid chromatography (HPLC to quantitate the concentrations of striatal dopamine and its metabolites, dihydroxylphenylacetic acid (DOPAC and homovanilic acid (HVA, and using immunoblotting to measure the level of phosphorylation of tyrosine hydroxylase (TH at Ser31, following chronic caffeine and SCH58261 sensitization in mice. Moreover, to validate further that the behavior sensitization of caffeine is through antagonism at the adenosine A2A receptor, we also evaluate whether chronic pretreatment with a selective adenosine A2A antagonist SCH58261 or a selective adenosine A1 antagonist DPCPX can sensitize the locomotor stimulating effects of caffeine. Results Chronic treatments with low dose caffeine (10 mg/kg or SCH58261 (2 mg/kg increased the concentrations of dopamine, DOPAC and HVA, concomitant with increased TH phosphorylation at Ser31 and consequently enhanced TH activity in the striatal tissues in both caffeine- and SCH58261-sensitized mice. In addition, chronic caffeine or SCH58261 administration induced

  19. Adenosine A(2A) receptor up-regulates retinal wave frequency via starburst amacrine cells in the developing rat retina.

    Science.gov (United States)

    Huang, Pin-Chien; Hsiao, Yu-Tien; Kao, Shao-Yen; Chen, Ching-Feng; Chen, Yu-Chieh; Chiang, Chung-Wei; Lee, Chien-Fei; Lu, Juu-Chin; Chern, Yijuang; Wang, Chih-Tien

    2014-01-01

    Developing retinas display retinal waves, the patterned spontaneous activity essential for circuit refinement. During the first postnatal week in rodents, retinal waves are mediated by synaptic transmission between starburst amacrine cells (SACs) and retinal ganglion cells (RGCs). The neuromodulator adenosine is essential for the generation of retinal waves. However, the cellular basis underlying adenosine's regulation of retinal waves remains elusive. Here, we investigated whether and how the adenosine A(2A) receptor (A(2A)R) regulates retinal waves and whether A(2A)R regulation of retinal waves acts via presynaptic SACs. We showed that A(2A)R was expressed in the inner plexiform layer and ganglion cell layer of the developing rat retina. Knockdown of A(2A)R decreased the frequency of spontaneous Ca²⁺ transients, suggesting that endogenous A(2A)R may up-regulate wave frequency. To investigate whether A(2A)R acts via presynaptic SACs, we targeted gene expression to SACs by the metabotropic glutamate receptor type II promoter. Ca²⁺ transient frequency was increased by expressing wild-type A(2A)R (A2AR-WT) in SACs, suggesting that A(2A)R may up-regulate retinal waves via presynaptic SACs. Subsequent patch-clamp recordings on RGCs revealed that presynaptic A(2A)R-WT increased the frequency of wave-associated postsynaptic currents (PSCs) or depolarizations compared to the control, without changing the RGC's excitability, membrane potentials, or PSC charge. These findings suggest that presynaptic A(2A)R may not affect the membrane properties of postsynaptic RGCs. In contrast, by expressing the C-terminal truncated A(2A)R mutant (A(2A)R-ΔC) in SACs, the wave frequency was reduced compared to the A(2A)R-WT, but was similar to the control, suggesting that the full-length A(2A)R in SACs is required for A(2A)R up-regulation of retinal waves. A(2A)R up-regulates the frequency of retinal waves via presynaptic SACs, requiring its full-length protein structure. Thus, by

  20. Reduced adenosine A2a receptor-mediated efferent arteriolar vasodilation contributes to diabetes-induced glomerular hyperfiltration.

    Science.gov (United States)

    Persson, Patrik; Hansell, Peter; Palm, Fredrik

    2015-01-01

    Diabetes is associated with increased risk for development of kidney disease, and an increased glomerular filtration rate is an early indication of altered kidney function. Here we determine whether reduced adenosine A2a receptor-mediated vasodilation of the efferent arteriole contributes to the increased glomerular filtration rate in diabetes. The glomerular filtration rate, renal blood flow, and proximal tubular stop flow pressure were investigated in control and streptozotocin-diabetic rats during baseline and after administration of the adenosine A2a receptor antagonist ZM241385 or the adenosine A2a receptor agonist CGS21680. The diabetes-induced glomerular hyperfiltration was reduced by 24% following A2a receptor stimulation but was unaffected by A2a receptor inhibition. Contrarily, glomerular filtration rate in controls increased by 22% after A2a receptor inhibition and was unaffected by A2a stimulation. The increased glomerular filtration rate after A2a receptor inhibition in controls and decreased glomerular filtration rate after A2a receptor activation in diabetics were caused by increased and decreased stop flow pressure, respectively. None of the interventions affected renal blood flow. Thus, the normal adenosine A2a receptor-mediated tonic vasodilation of efferent arterioles is abolished in the diabetic kidney. This causes increased efferent arteriolar resistance resulting in increased filtration fraction and hyperfiltration.

  1. Insulin-Increased L-Arginine Transport Requires A2A Adenosine Receptors Activation in Human Umbilical Vein Endothelium

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    Guzmán-Gutiérrez, Enrique; Westermeier, Francisco; Salomón, Carlos; González, Marcelo; Pardo, Fabián; Leiva, Andrea; Sobrevia, Luis

    2012-01-01

    Adenosine causes vasodilation of human placenta vasculature by increasing the transport of arginine via cationic amino acid transporters 1 (hCAT-1). This process involves the activation of A2A adenosine receptors (A2AAR) in human umbilical vein endothelial cells (HUVECs). Insulin increases hCAT-1 activity and expression in HUVECs, and A2AAR stimulation increases insulin sensitivity in subjects with insulin resistance. However, whether A2AAR plays a role in insulin-mediated increase in L-arginine transport in HUVECs is unknown. To determine this, we first assayed the kinetics of saturable L-arginine transport (1 minute, 37°C) in the absence or presence of nitrobenzylthioinosine (NBTI, 10 µmol/L, adenosine transport inhibitor) and/or adenosine receptors agonist/antagonists. We also determined hCAT-1 protein and mRNA expression levels (Western blots and quantitative PCR), and SLC7A1 (for hCAT-1) reporter promoter activity. Insulin and NBTI increased the extracellular adenosine concentration, the maximal velocity for L-arginine transport without altering the apparent K m for L-arginine transport, hCAT-1 protein and mRNA expression levels, and SLC7A1 transcriptional activity. An A2AAR antagonist ZM-241385 blocked these effects. ZM241385 inhibited SLC7A1 reporter transcriptional activity to the same extent in cells transfected with pGL3-hCAT-1−1606 or pGL3-hCAT-1−650 constructs in the presence of NBTI + insulin. However, SLC7A1 reporter activity was increased by NBTI only in cells transfected with pGL3-hCAT-1−1606, and the ZM-241385 sensitive fraction of the NBTI response was similar in the absence or in the presence of insulin. Thus, insulin modulation of hCAT-1 expression and activity requires functional A2AAR in HUVECs, a mechanism that may be applicable to diseases associated with fetal insulin resistance, such as gestational diabetes. PMID:22844517

  2. Insulin-increased L-arginine transport requires A(2A adenosine receptors activation in human umbilical vein endothelium.

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    Enrique Guzmán-Gutiérrez

    Full Text Available Adenosine causes vasodilation of human placenta vasculature by increasing the transport of arginine via cationic amino acid transporters 1 (hCAT-1. This process involves the activation of A(2A adenosine receptors (A(2AAR in human umbilical vein endothelial cells (HUVECs. Insulin increases hCAT-1 activity and expression in HUVECs, and A(2AAR stimulation increases insulin sensitivity in subjects with insulin resistance. However, whether A(2AAR plays a role in insulin-mediated increase in L-arginine transport in HUVECs is unknown. To determine this, we first assayed the kinetics of saturable L-arginine transport (1 minute, 37°C in the absence or presence of nitrobenzylthioinosine (NBTI, 10 µmol/L, adenosine transport inhibitor and/or adenosine receptors agonist/antagonists. We also determined hCAT-1 protein and mRNA expression levels (Western blots and quantitative PCR, and SLC7A1 (for hCAT-1 reporter promoter activity. Insulin and NBTI increased the extracellular adenosine concentration, the maximal velocity for L-arginine transport without altering the apparent K(m for L-arginine transport, hCAT-1 protein and mRNA expression levels, and SLC7A1 transcriptional activity. An A2AAR antagonist ZM-241385 blocked these effects. ZM241385 inhibited SLC7A1 reporter transcriptional activity to the same extent in cells transfected with pGL3-hCAT-1(-1606 or pGL3-hCAT-1(-650 constructs in the presence of NBTI + insulin. However, SLC7A1 reporter activity was increased by NBTI only in cells transfected with pGL3-hCAT-1(-1606, and the ZM-241385 sensitive fraction of the NBTI response was similar in the absence or in the presence of insulin. Thus, insulin modulation of hCAT-1 expression and activity requires functional A(2AAR in HUVECs, a mechanism that may be applicable to diseases associated with fetal insulin resistance, such as gestational diabetes.

  3. Cardioprotection of controlled and cardiac-specific over-expression of A(2A-adenosine receptor in the pressure overload.

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    Eman A Hamad

    Full Text Available Adenosine binds to three G protein-coupled receptors (R located on the cardiomyocyte (A(1-R, A(2A-R and A(3-R and provides cardiac protection during both ischemic and load-induced stress. While the role of adenosine receptor-subtypes has been well defined in the setting of ischemia-reperfusion, far less is known regarding their roles in protecting the heart during other forms of cardiac stress. Because of its ability to increase cardiac contractility and heart rate, we hypothesized that enhanced signaling through A(2A-R would protect the heart during the stress of transverse aortic constriction (TAC. Using a cardiac-specific and inducible promoter, we selectively over-expressed A(2A-R in FVB mice. Echocardiograms were obtained at baseline, 2, 4, 8, 12, 14 weeks and hearts were harvested at 14 weeks, when WT mice developed a significant decrease in cardiac function, an increase in end systolic and diastolic dimensions, a higher heart weight to body weight ratio (HW/BW, and marked fibrosis when compared with sham-operated WT. More importantly, these changes were significantly attenuated by over expression of the A(2A-R. Furthermore, WT mice also demonstrated marked increases in the hypertrophic genes β-myosin heavy chain (β-MHC, and atrial natriuretic factor (ANF--changes that are mediated by activation of the transcription factor GATA-4. Levels of the mRNAs encoding β-MHC, ANP, and GATA-4 were significantly lower in myocardium from A(2A-R TG mice after TAC when compared with WT and sham-operated controls. In addition, three inflammatory factors genes encoding cysteine dioxygenase, complement component 3, and serine peptidase inhibitor, member 3N, were enhanced in WT TAC mice, but their expression was suppressed in A(2A-R TG mice. A(2A-R over-expression is protective against pressure-induced heart failure secondary to TAC. These cardioprotective effects are associated with attenuation of GATA-4 expression and inflammatory factors. The A(2A

  4. Adenosine A2A receptor blockade Prevents Rotenone-Induced Motor Impairment in a Rat Model of Parkinsonism

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    Ahmed M Fathalla

    2016-02-01

    Full Text Available Pharmacological studies implicate the blockade of adenosine receptorsas an effective strategy for reducing Parkinson's disease (PD symptoms. The objective of this study is to elucidate the possible protective effects of ZM241385 and 8-cyclopentyl-1,3-dipropylxanthine, two selective A2Aand A1 receptor antagonists, on a rotenone rat model of PD. Rats were split into four groups: vehicle control (1 ml/kg/48 h, rotenone(1.5 mg/kg/48 h, s.c., ZM241385 (3.3 mg/kg/day, i.p and 8-cyclopentyl-1,3-dipropylxanthine (5 mg/kg/day, i.p. After that, animals were subjected to behavioral (stride length and grid walking and biochemical (measuring concentration of dopamine levels using high performance liquid chromatography. In the rotenone group, rats displayed a reduced motor activity and disturbed movement coordination in the behavioral tests and a decreased dopamine concentration as foundby high performance liquid chromatography. The effect of rotenone was partially preventedin the ZM241385 group, but not with 8-cyclopentyl-1,3-dipropylxanthine administration. The administration of ZM241385 has led toan improvement improved of motor function and movement coordination (a partial increase of stride length and partial decrease in the number of foot slips and an increase in dopamine concentration in the rotenone-injected rats. However, the 8-cyclopentyl-1,3-dipropylxanthine and rotenone groups were not significantly different. These results indicate that selective A2Areceptor blockade by ZM241385, but not A1receptor blockadeby 8-cyclopentyl-1,3-dipropylxanthine, may treat PD motor symptoms. This reinforces the potential use of A2A receptor antagonists as a treatment strategy for PD patients.. This may provide a more selective treatment strategy for PD patients.

  5. Graft versus host disease: New insights into A2A receptor agonist therapy

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    Karlie R. Jones

    2015-01-01

    Full Text Available Allogeneic transplantation can cure many disorders, including sickle cell disease, chronic granulomatous disease (CGD, severe combined immunodeficiency (SCID and many types of cancers. However, there are several associated risks that can result in severe immunological reactions and, in some cases, death. Much of this morbidity is related to graft versus host disease (GVHD [1]. GVHD is an immune mediated reaction in which donor T cells recognize the host as antigenically foreign, causing donor T cells to expand and attack host tissues. The current method of treating recent transplant patients with immunosuppressants to prevent this reaction has met with only partial success, emphasizing a need for new methods of GVHD treatment and prevention. Recently, a novel strategy has emerged targeting adenosine A2A receptors (A2AR through the use of adenosine agonists. These agonists have been shown in vitro to increase the TGFβ-induced generation of FoxP3+ regulatory T cells (Tregs and in vivo to improve weight gain and mortality as well as inhibit the release of pro-inflammatory cytokines in GVHD murine models [2,3]. Positive results involving A2AR agonists in vitro and in vivo are promising, suggesting that A2AR agonists should be a part of the management of clinical GvHD.

  6. Dialysis delivery of an adenosine A2A agonist into the pontine reticular formation of C57BL/6J mouse increases pontine acetylcholine release and sleep.

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    Coleman, Christal G; Baghdoyan, Helen A; Lydic, Ralph

    2006-03-01

    In vivo microdialysis in C57BL/6J (B6) mouse was used to test the hypothesis that activating adenosine A(2A) receptors in the pontine reticular formation (PRF) increases acetylcholine (ACh) release and rapid eye movement (REM) sleep. Eight concentrations of the adenosine A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680; CGS) were delivered to the PRF and ACh in the PRF was quantified. ACh release was significantly increased by dialysis with 3 mum CGS and significantly decreased by dialysis with 10 and 100 microm CGS. Co-administration of the adenosine A(2A) receptor antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385; 30 nM) blocked the CGS-induced increase in ACh release. In a second series of experiments, CGS (3 microm) was delivered by dialysis to the PRF for 2 h while recording sleep and wakefulness. CGS significantly decreased time in wakefulness (-51% in h 1; -54% in h 2), increased time in non-rapid eye movement (NREM) sleep (90% in h 1; 151% in h 2), and increased both time in REM sleep (331% in h 2) and the number of REM sleep episodes (488% in h 2). The enhancement of REM sleep is consistent with the interpretation that adenosine A(2A) receptors in the PRF of the B6 mouse contribute to REM sleep regulation, in part, by increasing ACh release in the PRF. A(2A) receptor activation may promote NREM sleep via GABAergic inhibition of arousal promoting neurons in the PRF.

  7. The effect of caffeine to increase reaction time in the rat during a test of attention is mediated through antagonism of adenosine A2A receptors.

    Science.gov (United States)

    Higgins, Guy A; Grzelak, Michael E; Pond, Annamarie J; Cohen-Williams, Mary E; Hodgson, Robert A; Varty, Geoffrey B

    2007-12-11

    Caffeine produces effects on cognitive function particularly relating to aspects of attention such as reaction time. Considering the plasma exposure levels following regular caffeine intake, and the affinity of caffeine for known protein targets, these effects are likely mediated by either the adenosine A(1) or A(2A) receptor. In the present studies, two rat strains [Long-Evans (LE) and CD] were trained to asymptote performance in a test of selective attention, the 5-choice serial reaction time task (5-CSRTT). Next, the effects of caffeine were compared to the selective A(2A) antagonists, SCH 412348 and KW-6002 (Istradefylline), and the A(1) antagonist, DPCPX. Further studies compared the psychostimulant effects of each drug. Finally, we tested the A(2A) agonist, CGS-21680, on 5-CSRTT performance and given the antipsychotic potential of this drug class, studied the interaction between CGS-21680 and amphetamine in this task. Caffeine (3-10mg/kg IP) increased reaction time in both LE and CD rats, with no effect on accuracy, an effect replicated by SCH 412348 (0.1-1mg/kg PO) and KW-6002 (1-3mg/kg PO), but not DPCPX (3-30 mg/kg PO). At least with SCH 412348, these effects were at doses that were not overtly psychostimulant. In contrast, CGS-21680 (0.03-0. 3mg/kg IP) slowed reaction speed and increased omissions. Interestingly, at a comparatively low dose of 0.03 mg/kg, CGS-21680 attenuated the increased premature responding produced by amphetamine (1mg/kg IP). The present results suggest that the attention-enhancing effects of caffeine are mediated through A(2A) receptor blockade, and selective A(2A) receptor antagonists may have potential as therapies for attention-related disorders. Furthermore, the improvement in response control in amphetamine-treated rats following CGS-21680 pretreatment supports the view that A(2A) agonists have potential as novel antipsychotics.

  8. Overexpression of adenosine A2A receptors in rats: effects on depression, locomotion and anxiety

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    Joana E Coelho

    2014-06-01

    Full Text Available Adenosine A2A receptors (A2AR are a sub-type of receptors enriched in basal ganglia, activated by the neuromodulator adenosine, which interact with dopamine D2 receptors. Although this reciprocal antagonistic interaction is well established in motor function, the outcome in dopamine-related behaviors remains uncertain, in particular in depression and anxiety. We have demonstrated an upsurge of A2AR associated to aging and chronic stress. Furthermore, Alzheimer’s disease patients present A2AR accumulation in cortical areas together with depressive signs. We now tested the impact of overexpressing A2AR in forebrain neurons on dopamine related behavior, namely depression. Adult male rats overexpressing human A2AR under the control of CaMKII promoter [Tg(CaMKII-hA2AR] and aged-matched wild-types (WT of the same strain (Sprague-Dawley were studied. The forced swimming test (FST, sucrose preference test (SPT and the open-field test (OFT were performed to evaluate behavioral despair, anhedonia, locomotion and anxiety. Tg(CaMKII-hA2AR animals spent more time floating and less time swimming in the FST and presented a decreased sucrose preference at 48h in the SPT. They also covered higher distances in the OFT and spent more time in the central zone than the WT. The results indicate that Tg(CaMKII-hA2AR rats exhibit depressive-like behavior, hyperlocomotion and altered exploratory behavior. This A2AR overexpression may explain the depressive signs found in aging, chronic stress and Alzheimer’s disease.

  9. Allosteric mechanisms within the adenosine A2A-dopamine D2 receptor heterotetramer

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    Ferré, Sergi; Bonaventura, Jordi; Tomasi, Dardo; Navarro, Gemma; Moreno, Estefanía; Cortés, Antonio; Lluís, Carme; Casadó, Vicent; Volkow, Nora D.

    2017-01-01

    The structure constituted by a G protein coupled receptor (GPCR) homodimer and a G protein provides a main functional unit and oligomeric entities can be viewed as multiples of dimers. For GPCR heteromers, experimental evidence supports a tetrameric structure, comprised of two different homodimers, each able to signal with its preferred G protein. GPCR homomers and heteromers can act as the conduit of allosteric interactions between orthosteric ligands. The well-known agonist/agonist allosteric interaction in the adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromer, by which A2AR agonists decrease the affinity of D2R agonists, gave the first rationale for the use of A2AR antagonists in Parkinson’s disease. We review new pharmacological findings that can be explained in the frame of a tetrameric structure of the A2AR-D2R heteromer: first, ligand-independent allosteric modulations by the D2R that result in changes of the binding properties of A2AR ligands; second, differential modulation of the intrinsic efficacy of D2R ligands for G protein-dependent and independent signaling; third, the canonical antagonistic Gs-Gi interaction within the frame of the heteromer; and fourth, the ability of A2AR antagonists, including caffeine, to also exert the same allosteric modulations of D2R ligands than A2AR agonists, while A2AR agonists and antagonists counteract each other’s effects. These findings can have important clinical implications when evaluating the use of A2AR antagonists. They also call for the need of monitoring caffeine intake when evaluating the effect of D2R ligands, when used as therapeutic agents in neuropsychiatric disorders or as probes in imaging studies. PMID:26051403

  10. Overexpression of Adenosine A2A Receptors in Rats: Effects on Depression, Locomotion, and Anxiety

    Science.gov (United States)

    Coelho, Joana E.; Alves, Pedro; Canas, Paula M.; Valadas, Jorge S.; Shmidt, Tatiana; Batalha, Vânia L.; Ferreira, Diana G.; Ribeiro, Joaquim A.; Bader, Michael; Cunha, Rodrigo A.; do Couto, Frederico Simões; Lopes, Luísa V.

    2014-01-01

    Adenosine A2A receptors (A2AR) are a sub-type of receptors enriched in basal ganglia, activated by the neuromodulator adenosine, which interact with dopamine D2 receptors. Although this reciprocal antagonistic interaction is well-established in motor function, the outcome in dopamine-related behaviors remains uncertain, in particular in depression and anxiety. We have demonstrated an upsurge of A2AR associated to aging and chronic stress. Furthermore, Alzheimer’s disease patients present A2AR accumulation in cortical areas together with depressive signs. We now tested the impact of overexpressing A2AR in forebrain neurons on dopamine-related behavior, namely depression. Adult male rats overexpressing human A2AR under the control of CaMKII promoter [Tg(CaMKII-hA2AR)] and aged-matched wild-types (WT) of the same strain (Sprague-Dawley) were studied. The forced swimming test (FST), sucrose preference test (SPT), and the open-field test (OFT) were performed to evaluate behavioral despair, anhedonia, locomotion, and anxiety. Tg(CaMKII-hA2AR) animals spent more time floating and less time swimming in the FST and presented a decreased sucrose preference at 48 h in the SPT. They also covered higher distances in the OFT and spent more time in the central zone than the WT. The results indicate that Tg(CaMKII-hA2AR) rats exhibit depressive-like behavior, hyperlocomotion, and altered exploratory behavior. This A2AR overexpression may explain the depressive signs found in aging, chronic stress, and Alzheimer’s disease. PMID:24982640

  11. Selective adenosine A2A receptor agonists and antagonists protect against spinal cord injury through peripheral and central effects

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    Esposito Emanuela

    2011-04-01

    Full Text Available Abstract Background Permanent functional deficits following spinal cord injury (SCI arise both from mechanical injury and from secondary tissue reactions involving inflammation. Enhanced release of adenosine and glutamate soon after SCI represents a component in the sequelae that may be responsible for resulting functional deficits. The role of adenosine A2A receptor in central ischemia/trauma is still to be elucidated. In our previous studies we have demonstrated that the adenosine A2A receptor-selective agonist CGS21680, systemically administered after SCI, protects from tissue damage, locomotor dysfunction and different inflammatory readouts. In this work we studied the effect of the adenosine A2A receptor antagonist SCH58261, systemically administered after SCI, on the same parameters. We investigated the hypothesis that the main action mechanism of agonists and antagonists is at peripheral or central sites. Methods Spinal trauma was induced by extradural compression of SC exposed via a four-level T5-T8 laminectomy in mouse. Three drug-dosing protocols were utilized: a short-term systemic administration by intraperitoneal injection, a chronic administration via osmotic minipump, and direct injection into the spinal cord. Results SCH58261, systemically administered (0.01 mg/kg intraperitoneal. 1, 6 and 10 hours after SCI, reduced demyelination and levels of TNF-α, Fas-L, PAR, Bax expression and activation of JNK mitogen-activated protein kinase (MAPK 24 hours after SCI. Chronic SCH58261 administration, by mini-osmotic pump delivery for 10 days, improved the neurological deficit up to 10 days after SCI. Adenosine A2A receptors are physiologically expressed in the spinal cord by astrocytes, microglia and oligodendrocytes. Soon after SCI (24 hours, these receptors showed enhanced expression in neurons. Both the A2A agonist and antagonist, administered intraperitoneally, reduced expression of the A2A receptor, ruling out the possibility that the

  12. 3H-[1,2,4]-Triazolo[5,1-i]purin-5-amine derivatives as adenosine A2A antagonists.

    Science.gov (United States)

    Silverman, Lisa S; Caldwell, John P; Greenlee, William J; Kiselgof, Eugenia; Matasi, Julius J; Tulshian, Deen B; Arik, Leyla; Foster, Carolyn; Bertorelli, Rosalia; Monopoli, Angela; Ongini, Ennio

    2007-03-15

    A novel series of 3-substituted-8-aryl-[1,2,4]-triazolo[5,1-i]purin-5-amine analogs related to Sch 58261 was synthesized in order to identify potent adenosine A(2A) receptor antagonists with improved selectivity over the A(1) receptor, physiochemical properties, and pharmacokinetic profiles as compared to those of Sch 58261. As a result of structural modifications, numerous analogs with excellent in vitro binding affinities and selectivities were identified. Moreover, compound 27 displayed both superior in vitro and highly promising in vivo profiles.

  13. Adenosine A2A Receptor Deletion Blocks the Beneficial Effects of Lactobacillus reuteri in Regulatory T-Deficient Scurfy Mice

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    Baokun He

    2017-12-01

    Full Text Available The lack of a functional Foxp3 transcription factor and regulatory T (Treg cells causes lethal, CD4+ T cell-driven autoimmune diseases in scurfy (SF mice and humans. Recent studies have shown that adenosine A2A receptor activation limits inflammation and tissue damage, thereby playing an anti-inflammatory role. However, the role of the adenosine A2A receptor in the development of disease in SF mice remains unclear. Using a genetic approach, we found that adenosine A2A receptor deletion in SF mice (SF⋅A2A-/- does not affect early life events, the development of a lymphoproliferative disorder, or hyper-production of pro-inflammatory cytokines seen in the Treg-deficiency state. As shown previously, Lactobacillus reuteri DSM 17938 treatment prolonged survival and reduced multiorgan inflammation in SF mice. In marked contrast, A2A receptor deletion completely blocked these beneficial effects of L. reuteri in SF mice. Altogether, these results suggest that although absence of the adenosine A2A receptor does not affect the development of disease in SF mice, it plays a critical role in the immunomodulation by L. reuteri in Treg-deficiency disease. The adenosine A2A receptor and its activation may have a role in treating other Treg dysfunction-mediated autoimmune diseases.

  14. Adenosine A2A Receptor Deletion Blocks the Beneficial Effects of Lactobacillus reuteri in Regulatory T-Deficient Scurfy Mice

    Science.gov (United States)

    He, Baokun; Hoang, Thomas K.; Tran, Dat Q.; Rhoads, Jon Marc; Liu, Yuying

    2017-01-01

    The lack of a functional Foxp3 transcription factor and regulatory T (Treg) cells causes lethal, CD4+ T cell-driven autoimmune diseases in scurfy (SF) mice and humans. Recent studies have shown that adenosine A2A receptor activation limits inflammation and tissue damage, thereby playing an anti-inflammatory role. However, the role of the adenosine A2A receptor in the development of disease in SF mice remains unclear. Using a genetic approach, we found that adenosine A2A receptor deletion in SF mice (SF⋅A2A-/-) does not affect early life events, the development of a lymphoproliferative disorder, or hyper-production of pro-inflammatory cytokines seen in the Treg-deficiency state. As shown previously, Lactobacillus reuteri DSM 17938 treatment prolonged survival and reduced multiorgan inflammation in SF mice. In marked contrast, A2A receptor deletion completely blocked these beneficial effects of L. reuteri in SF mice. Altogether, these results suggest that although absence of the adenosine A2A receptor does not affect the development of disease in SF mice, it plays a critical role in the immunomodulation by L. reuteri in Treg-deficiency disease. The adenosine A2A receptor and its activation may have a role in treating other Treg dysfunction-mediated autoimmune diseases. PMID:29270168

  15. Identification and analysis of CYP7A1, CYP17A1, CYP20A1, CYP27A1 and CYP51A1 in cynomolgus macaques.

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    Uno, Yasuhiro; Hosaka, Shinya; Yamazaki, Hiroshi

    2014-12-01

    Cytochromes P450 (P450) are important for not only drug metabolism and toxicity, but also biosynthesis and metabolism of cholesterol and bile acids, and steroid synthesis. In cynomolgus macaques, widely used in biomedical research, we have characterized P450 cDNAs, which were isolated as expressed sequence tags of cynomolgus macaque liver. In this study, cynomolgus CYP7A1, CYP17A1, CYP20A1, CYP27A1 and CYP51A1 cDNAs were characterized by sequence analysis, phylogenetic analysis and tissue expression pattern. By sequence analysis, these five cynomolgus P450s had high sequence identities (94-99%) to the human orthologs in amino acids. By phylogenetic analysis, each cynomolgus P450 was more closely related to the human ortholog as compared with the dog or rat ortholog. By quantitative polymerase chain reaction, among the 10 tissue types, CYP7A1 and CYP17A1 mRNAs were preferentially expressed in liver and adrenal gland, respectively. Cynomolgus CYP27A1 and CYP51A1 mRNAs were most abundantly expressed in liver and testis, respectively. Cynomolgus CYP20A1 mRNA was expressed in all the tissues, including brain and liver. Tissue expression patterns of each cynomolgus P450 were generally similar to that of the human ortholog. These results suggest the molecular similarities of CYP7A1, CYP17A1, CYP20A1, CYP27A1 and CYP51A1 between cynomolgus macaques and humans.

  16. Key modulatory role of presynaptic adenosine A2A receptors in cortical neurotransmission to the striatal direct pathway.

    Science.gov (United States)

    Quiroz, César; Luján, Rafael; Uchigashima, Motokazu; Simoes, Ana Patrícia; Lerner, Talia N; Borycz, Janusz; Kachroo, Anil; Canas, Paula M; Orru, Marco; Schwarzschild, Michael A; Rosin, Diane L; Kreitzer, Anatol C; Cunha, Rodrigo A; Watanabe, Masahiko; Ferré, Sergi

    2009-11-18

    Basal ganglia processing results from a balanced activation of direct and indirect striatal efferent pathways, which are controlled by dopamine D1 and D2 receptors, respectively. Adenosine A2A receptors are considered novel antiparkinsonian targets, based on their selective postsynaptic localization in the indirect pathway, where they modulate D2 receptor function. The present study provides evidence for the existence of an additional, functionally significant, segregation of A2A receptors at the presynaptic level. Using integrated anatomical, electrophysiological, and biochemical approaches, we demonstrate that presynaptic A2A receptors are preferentially localized in cortical glutamatergic terminals that contact striatal neurons of the direct pathway, where they exert a selective modulation of corticostriatal neurotransmission. Presynaptic striatal A2A receptors could provide a new target for the treatment of neuropsychiatric disorders.

  17. Key Modulatory Role of Presynaptic Adenosine A2A Receptors in Cortical Neurotransmission to the Striatal Direct Pathway

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    César Quiroz

    2009-01-01

    Full Text Available Basal ganglia processing results from a balanced activation of direct and indirect striatal efferent pathways, which are controlled by dopamine D1 and D2 receptors, respectively. Adenosine A2A receptors are considered novel antiparkinsonian targets, based on their selective postsynaptic localization in the indirect pathway, where they modulate D2 receptor function. The present study provides evidence for the existence of an additional, functionally significant, segregation of A2A receptors at the presynaptic level. Using integrated anatomical, electrophysiological, and biochemical approaches, we demonstrate that presynaptic A2A receptors are preferentially localized in cortical glutamatergic terminals that contact striatal neurons of the direct pathway, where they exert a selective modulation of corticostriatal neurotransmission. Presynaptic striatal A2A receptors could provide a new target for the treatment of neuropsychiatric disorders.

  18. The importance of the adenosine A(2A) receptor-dopamine D(2) receptor interaction in drug addiction.

    Science.gov (United States)

    Filip, M; Zaniewska, M; Frankowska, M; Wydra, K; Fuxe, K

    2012-01-01

    Drug addiction is a serious brain disorder with somatic, psychological, psychiatric, socio-economic and legal implications in the developed world. Illegal (e.g., psychostimulants, opioids, cannabinoids) and legal (alcohol, nicotine) drugs of abuse create a complex behavioral pattern composed of drug intake, withdrawal, seeking and relapse. One of the hallmarks of drugs that are abused by humans is that they have different mechanisms of action to increase dopamine (DA) neurotransmission within the mesolimbic circuitry of the brain and indirectly activate DA receptors. Among the DA receptors, D(2) receptors are linked to drug abuse and addiction because their function has been proven to be correlated with drug reinforcement and relapses. The recognition that D(2) receptors exist not only as homomers but also can form heteromers, such as with the adenosine (A)(2A) receptor, that are pharmacologically and functionally distinct from their constituent receptors, has significantly expanded the range of potential drug targets and provided new avenues for drug design in the search for novel drug addiction therapies. The aim of this review is to bring current focus on A(2A) receptors, their physiology and pharmacology in the central nervous system, and to discuss the therapeutic relevance of these receptors to drug addiction. We concentrate on the contribution of A(2A) receptors to the effects of different classes of drugs of abuse examined in preclinical behavioral experiments carried out with pharmacological and genetic tools. The consequences of chronic drug treatment on A(2A) receptor-assigned functions in preclinical studies are also presented. Finally, the neurochemical mechanism of the interaction between A(2A) receptors and drugs of abuse in the context of the heteromeric A(2A)-D(2) receptor complex is discussed. Taken together, a significant amount of experimental analyses provide evidence that targeting A(2A) receptors may offer innovative translational strategies

  19. GDNF control of the glutamatergic cortico-striatal pathway requires tonic activation of adenosine A2A Receptors

    Science.gov (United States)

    Gomes, Catarina A.R.V.; Simões, Patrícia F.; Canas, Paula M.; Quiroz, César; Sebastião, Ana M.; Ferré, Sergi; Cunha, Rodrigo A.; Ribeiro, Joaquim A.

    2009-01-01

    Glial cell line-derived neurotrophic factor (GDNF) affords neuroprotection in Parkinson’s disease in accordance with its ability to bolster nigrostriatal innervation. We previously found that GDNF facilitates dopamine release in a manner dependent on adenosine A2A receptor activation. Since motor dysfunction also involves modifications of striatal glutamatergic innervation, we now tested if GDNF and its receptor system, Ret (rearranged during transfection) and GFRα1 (GDNF family receptor alpha 1) controlled the cortico-striatal glutamatergic pathway in an A2A receptor-dependent manner. GDNF (10 ng/ml) enhanced (by ≈13%) glutamate release from rat striatal nerve endings, an effect potentiated (up to ≈ 30%) by the A2A receptor agonist CGS 21680 (10 nM) and prevented by the A2A receptor antagonist, SCH 58261 (50 nM). Triple immunocytochemical studies revealed that Ret and GFRα1 were located in 50% of rat striatal glutamatergic terminals (immunopositive for vesicular glutamate transporters-1/2), where they were found to be co-located with A2A receptors. Activation of the glutamatergic system upon in vivo electrical stimulation of the rat cortico-striatal input induced striatal Ret phosphoprylation that was prevented by pre-treatment with the A2A receptor antagonist, MSX-3 (3 mg/kg). The results provide the first functional and morphological evidence that GDNF controls cortico-striatal glutamatergic pathways in a manner largely dependent on the co-activation of adenosine A2A receptors. PMID:19141075

  20. A1 and A2 Sub-Types of Blood Group 'A': A Reflection of their Prevalence in North Karnataka Region.

    Science.gov (United States)

    Giriyan, Sujata S; Agrawal, Akanksha; Bajpai, Richa; Nirala, Niraj Kumar

    2017-05-01

    Landsteiner ABO system of blood groups is most important for transfusion medicine and has subtypes of A Antigen, A1 and A2, upon which further groups of A and AB have been classified. Of individuals with A antigen, approximately 20% belong to A2 while rest 80% belong to A1. Anti-A1 Lectin, a cold agglutinin which destroys A1 cells is clinically significant when they react at 37°C, causing transfusion reactions. To assess the prevalence of A1 and A2 subgroups in the population. This was two year retrospective analysis of blood groups of donors coming to the blood bank of Karnataka Institute of Medical Science, Hubli, Karnataka, India. The data of the subgroups A and AB was analysed. 20,864 donors were analysed. Of 5466 (26.20%) of A group, 5406 (98.90%) belonged to A1 subgroup and only 60 (1.10%) belonged to A2 subgroup. Of 1708 donors with blood group AB, 1532 (89.70%) belonged to A1B subgroup and 176 (10.30%) belonged to A2B. It was noted that A2 in AB blood-group, as A2B, was more frequent in occurrence than presence of A2 as an A blood group. Rhesus negative frequency in these subgroups was also reported. Having known the prevalence of A1 and A2 subgroups and incorporating them into the ABO grouping system can limit these minor, yet dangerous, transfusion incompatibilities.

  1. [The regulative effcets of A2a adenosine receptor on expression of SOCS-3 in rats of hypoxic pulmonary hypertension].

    Science.gov (United States)

    Fan, R; Huang, X Y; Du, K Y; Fan, Y F; Wang, L X

    2016-06-01

    To study the regulative effects and mechanism of A2aAR on expression of suppressor of cytokinesignaling-3(SOCS-3) in hypoxic pulmonary hypertension rats. Sprague-Daeley rats were randomly divided into 3 groups: a normal control group, a hypoxia group, and a hypoxia with selective agonists of A2aAR group. Animals in the hypoxia groups were housed in a chamber with 8%- 11% O2 and 1%-3% CO2 for 8 hours (8: 00 AM to 4: 00 PM) daily for 28 days. They were treated intraperitoneally with either 4 ml/kg weight of normal saline or 0.2 mg/kg weight of CGS-21680 30 minutes before exposure to hypoxia. Four weeks later, mean pulmonary artery pressure (mPAP), mean carotid arterial pressure (mCAP) and right ventricular rate [RV/(LV+ S)] were measured. The expression of A2aAR and SOCS-3 in pulmonary arterioles was measured by immunohistochemistry. The expression of A2aAR mRNA and SOCS-3 mRNA in lung tissues were measured by real time RT-PCR. The expression of A2aAR protein and SOCS-3 protein in lung tissues were measured by Western blot. The mPAP in the hypoxia group was [(20.9±3.9)mmHg, 1 mmHg=0.133 kPa], significantly higher than the normal control group [(12.6±6.6)mmHg](Ppulmonary arterioles in the hypoxia group were (0.134±0.034) and (0.119±0.011), both significantly higher than the normal group(Prats further increased the expression levels of A2aAR and SOCS-3 to about 2-fold higher than the normal controls. Furthermore, protein levels of A2aAR and SOCS-3 in the lung tissue were determined using Western blot. A similar increase was observed in hypoxia-induced pulmonary hypertension, and CGS-21680 treatment group showed the highest levels of these 2 proteins. A2aAR activation prevents hypoxia-induced pulmonary hypertension, and its mechanisms are related to the activation of A2aAR SOCS-3 signaling pathway.

  2. Cleavage of a recombinant human immunoglobulin A2 (IgA2)-IgA1 hybrid antibody by certain bacterial IgA1 proteases

    DEFF Research Database (Denmark)

    Senior, B; Dunlop, JI; Batten, MR

    2000-01-01

    , Streptococcus pneumoniae, S. sanguis, Neisseria meningitidis types 1 and 2, N. gonorrhoeae types 1 and 2, and Haemophilus influenzae type 2. Thus, for these enzymes the recognition site for IgA1 cleavage is contained within half of the IgA1 hinge region; additional distal elements, if required, are provided...... by either an IgA1 or an IgA2 framework. In contrast, the IgA2/A1 hybrid appeared to be resistant to cleavage with S. oralis and some H. influenzae type 1 IgA1 proteases, suggesting these enzymes require additional determinants for efficient substrate recognition....

  3. Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1Receptor Heteromers in the Dorsal Striatum.

    Science.gov (United States)

    Moreno, Estefanía; Chiarlone, Anna; Medrano, Mireia; Puigdellívol, Mar; Bibic, Lucka; Howell, Lesley A; Resel, Eva; Puente, Nagore; Casarejos, María J; Perucho, Juan; Botta, Joaquín; Suelves, Nuria; Ciruela, Francisco; Ginés, Silvia; Galve-Roperh, Ismael; Casadó, Vicent; Grandes, Pedro; Lutz, Beat; Monory, Krisztina; Canela, Enric I; Lluís, Carmen; McCormick, Peter J; Guzmán, Manuel

    2018-04-01

    The dorsal striatum is a key node for many neurobiological processes such as motor activity, cognitive functions, and affective processes. The proper functioning of striatal neurons relies critically on metabotropic receptors. Specifically, the main adenosine and endocannabinoid receptors present in the striatum, ie, adenosine A 2A receptor (A 2A R) and cannabinoid CB 1 receptor (CB 1 R), are of pivotal importance in the control of neuronal excitability. Facilitatory and inhibitory functional interactions between striatal A 2A R and CB 1 R have been reported, and evidence supports that this cross-talk may rely, at least in part, on the formation of A 2A R-CB 1 R heteromeric complexes. However, the specific location and properties of these heteromers have remained largely unknown. Here, by using techniques that allowed a precise visualization of the heteromers in situ in combination with sophisticated genetically modified animal models, together with biochemical and pharmacological approaches, we provide a high-resolution expression map and a detailed functional characterization of A 2A R-CB 1 R heteromers in the dorsal striatum. Specifically, our data unveil that the A 2A R-CB 1 R heteromer (i) is essentially absent from corticostriatal projections and striatonigral neurons, and, instead, is largely present in striatopallidal neurons, (ii) displays a striking G protein-coupled signaling profile, where co-stimulation of both receptors leads to strongly reduced downstream signaling, and (iii) undergoes an unprecedented dysfunction in Huntington's disease, an archetypal disease that affects striatal neurons. Altogether, our findings may open a new conceptual framework to understand the role of coordinated adenosine-endocannabinoid signaling in the indirect striatal pathway, which may be relevant in motor function and neurodegenerative diseases.

  4. A2A adenosine receptor antagonism enhances synaptic and motor effects of cocaine via CB1 cannabinoid receptor activation.

    Directory of Open Access Journals (Sweden)

    Alessandro Tozzi

    Full Text Available BACKGROUND: Cocaine increases the level of endogenous dopamine (DA in the striatum by blocking the DA transporter. Endogenous DA modulates glutamatergic inputs to striatal neurons and this modulation influences motor activity. Since D2 DA and A2A-adenosine receptors (A2A-Rs have antagonistic effects on striatal neurons, drugs targeting adenosine receptors such as caffeine-like compounds, could enhance psychomotor stimulant effects of cocaine. In this study, we analyzed the electrophysiological effects of cocaine and A2A-Rs antagonists in striatal slices and the motor effects produced by this pharmacological modulation in rodents. PRINCIPAL FINDINGS: Concomitant administration of cocaine and A2A-Rs antagonists reduced glutamatergic synaptic transmission in striatal spiny neurons while these drugs failed to produce this effect when given in isolation. This inhibitory effect was dependent on the activation of D2-like receptors and the release of endocannabinoids since it was prevented by L-sulpiride and reduced by a CB1 receptor antagonist. Combined application of cocaine and A2A-R antagonists also reduced the firing frequency of striatal cholinergic interneurons suggesting that changes in cholinergic tone might contribute to this synaptic modulation. Finally, A2A-Rs antagonists, in the presence of a sub-threshold dose of cocaine, enhanced locomotion and, in line with the electrophysiological experiments, this enhanced activity required activation of D2-like and CB1 receptors. CONCLUSIONS: The present study provides a possible synaptic mechanism explaining how caffeine-like compounds could enhance psychomotor stimulant effects of cocaine.

  5. A-1 Test Stand work

    Science.gov (United States)

    2010-01-01

    Employees at NASA's John C. Stennis Space Center work to maneuver a structural steam beam into place on the A-1 Test Stand on Jan. 13. The beam was one of several needed to form the thrust takeout structure that will support a new thrust measurement system being installed on the stand for future rocket engine testing. Once lifted onto the stand, the beams had to be hoisted into place through the center of the test stand, with only two inches of clearance on each side. The new thrust measurement system represents a state-of-the-art upgrade from the equipment installed more than 40 years ago when the test stand was first constructed.

  6. Frecuencia de los grupos sanguíneos A1, A2, Aint, B y O en individuos normales

    Directory of Open Access Journals (Sweden)

    García Rosasco, Marcela

    2001-01-01

    Full Text Available Se definen como A intermedio (Aint los hematíes que comparten caracteres con A1 y A2. Existen diferencias cualitativas y cuantitativas en los epitopes A. Los hematíes A1 son aglutinados por la lectina de Dolichus biflorus (anti-A1, los A2 por la lectina de Ulex europaeus (anti-H, en tanto los hematíes Aint, son variablemente aglutinados por ambas de manera inesperada. El objetivo del presente trabajo fue determinar la frecuencia de fenotipos A1, Aint, A2, B y O en individuos normales de la ciudad de Rosario (Argentina.Se realizó una búsqueda de individuos Aint en estos individuos de acuerdo a la reacción con las lectinas mencionadas. Se estudiaron 1301 muestras frente a reactivos monoclonales comerciales anti-A, anti-B, anti-AB y lectinas anti-A1 y anti-H. De las muestras estudiadas resultaron 703 O (54,04%, 468 A (35,97%; 106 B (8,15%; 18 A1B (1,38% y 6 A2B (0,46%. Las muestras A se subdividieron en 346 A1 (73,93%; 82 A2 (17,52% y 40 Aint (8,55%. Nuestros resultados concuerdan con observaciones previas sobre la marcada heterogeneidad de los hematíes Aint. El reconocimiento de subgrupos débiles del grupo A reviste importancia en la práctica forense y en el estudio de la dinámica de poblaciones. El estudio de la variante Aint es relevante en Inmunogenética Poblacional, por su contribución al conocimiento del mestizaje con poblaciones negras.

  7. The adenosine A2A receptor agonist CGS 21680 exhibits antipsychotic-like activity in Cebus apella monkeys

    DEFF Research Database (Denmark)

    Andersen, M B; Fuxe, K; Werge, T

    2002-01-01

    The adenosine A2A receptor agonist CGS 21680 has shown effects similar to dopamine antagonists in behavioural assays in rats predictive for antipsychotic activity, without induction of extrapyramidal side-effects (EPS). In the present study, we examined whether this functional dopamine antagonism...

  8. Synthesis and Properties of a New Water-Soluble Prodrug of the Adenosine A2A Receptor Antagonist MSX-2

    Directory of Open Access Journals (Sweden)

    Christa E. Müller

    2008-02-01

    Full Text Available The compound L-valine-3-{8-[(E-2-[3-methoxyphenylethenyl]-7-methyl-1-propargylxanthine-3-yl}propyl ester hydrochloride (MSX-4 was synthesized as an aminoacid ester prodrug of the adenosine A2A receptor antagonist MSX-2. It was found to bestable in artificial gastric acid, but readily cleaved by pig liver esterase.

  9. 6-(2-Furanyl)-9H-purin-2-amine derivatives as A2A adenosine antagonists.

    Science.gov (United States)

    Kiselgof, Eugenia; Tulshian, Deen B; Arik, Leyla; Zhang, Hongtao; Fawzi, Ahmad

    2005-04-15

    Structure-activity relationships have been investigated through substitutions at the 9-position of the 2-amino-6-(2-furanyl) purine (5) to identify novel and selective A(2A) adenosine receptor antagonists. Several potent and selective antagonists were identified. In particular, compounds 20, 25, and 26 show very high affinity with excellent selectivity.

  10. Low Self-Confidence and Diabetes Mismanagement in Youth with Type 1 Diabetes Mediate the Relationship between Behavioral Problems and Elevated HbA1c

    Directory of Open Access Journals (Sweden)

    Minke M. A. Eilander

    2016-01-01

    Full Text Available Introduction. Previous studies indicated an association between behavior problems (internalizing, externalizing and glycemic control (HbA1c in youth with type 1 diabetes (T1D. The aim of this study is to examine if this association is mediated by self-confidence and mismanagement of diabetes. Methods. Problem behavior was assessed with the Strengths and Difficulties Questionnaire. Mediating variables were assessed using the Confidence in Diabetes Self-Care-Youth and Diabetes Mismanagement Questionnaire. HbA1c was derived from hospital charts. Bootstrap mediation analysis for multiple mediation was utilized. Results. 88 youths with T1D, age 11–15 y, participated. The relation between both overall problem behavior and externalizing behavior problems and HbA1c was mediated through confidence in diabetes self-care and mismanagement (a1b1+a2b2  path; point estimate = 0.50 BCa CI 95% 0.25–0.85; a1b1+a2b2  path; point estimate = 0.73 BCa CI 95% 0.36–1.25. Conclusions. Increased problem behavior in youth with T1D is associated with elevated HbA1c and mediated by low self-confidence and diabetes mismanagement. Screening for problem behavior and mismanagement and assisting young patients in building confidence seem indicated to optimize glycemic control.

  11. The adenosine A2A receptor agonist CGS 21680 exhibits antipsychotic-like activity in Cebus apella monkeys

    DEFF Research Database (Denmark)

    Andersen, M B; Fuxe, K; Werge, T

    2002-01-01

    The adenosine A2A receptor agonist CGS 21680 has shown effects similar to dopamine antagonists in behavioural assays in rats predictive for antipsychotic activity, without induction of extrapyramidal side-effects (EPS). In the present study, we examined whether this functional dopamine antagonism......-induced behaviours (unrest, stereotypies, arousal) were unaffected. EPS were not observed at any dose. At 0.05 mg/kg CGS 21680 produced vomiting. The two lower doses did not produce observable side-effects. Though the differential effect on amphetamine- and apomorphine-induced behaviours is intriguing, CGS 21680...... showed a functional anti-dopaminergic effect in Cebus apella monkeys without production of EPS. This further substantiates that adenosine A2A receptor agonists may have potential as antipsychotics with atypical profiles....

  12. A Meta-Analysis of Adenosine A2A Receptor Antagonists on Levodopa-Induced Dyskinesia In Vivo

    Directory of Open Access Journals (Sweden)

    Wen-Wen Wang

    2017-12-01

    Full Text Available BackgroundLong-term use of levodopa (l-dopa is inevitably complicated with highly disabling fluctuations and drug-induced dyskinesias, which pose major challenges to the existing drug therapy of Parkinson’s disease.MethodsIn this study, we conducted a systematic review and meta-analysis to assess the efficacy of A2A receptor antagonists on reducing l-dopa-induced dyskinesias (LID.ResultsNine studies with a total of 152 animals were included in this meta-analysis. Total abnormal involuntary movements (AIM score, locomotor activity, and motor disability were reported as outcome measures in 5, 5, and 3 studies, respectively. Combined standardized mean difference (SMD estimates were calculated using a random-effects model. We pooled the whole data and found that, when compared to l-dopa alone, A2A receptor antagonists plus l-dopa treatment showed no effect on locomotor activity (SMD −0.00, 95% confidence interval (CI: −2.52 to 2.52, p = 1.0, superiority in improvement of motor disability (SMD −5.06, 95% CI: −9.25 to −0.87, p = 0.02 and more effective in control of AIM (SMD −1.82, 95% CI: −3.38 to −0.25, p = 0.02.ConclusionTo sum up, these results demonstrated that A2A receptor antagonists appear to have efficacy in animal models of LID. However, large randomized clinical trials testing the effects of A2A receptor antagonists in LID patients are always warranted.

  13. An introduction to A1-homotopy theory

    International Nuclear Information System (INIS)

    Morel, F.

    2003-01-01

    This contribution covers simplicial sheaves, Quillen's homotopical algebra, unstable A 1 homotopy theory, connectivity and A 1 -localisation, stable A 1 homotopy theory of S 1 -spectra and P 1 -spectra

  14. Temperature, salinity, velocity including ADCP ice tracking, and bottom pressure collected by Bering Strait Moorings A1W, A1, A1E, A2W, A2, A4W, A4, A3 from 2009-08-26 to 2010-08-03 (NCEI Accession 0138582)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — This is an archive of data from moorings deployed in Bering Strait from summer 2009 to summer 2010. Mooring deployments were funded by the NOAA RUSALCA (Russian-US...

  15. Selective Activation of Adenosine A2A Receptors on Immune Cells by a CD73-Dependent Prodrug Suppresses Joint Inflammation in Experimental Rheumatoid Arthritis.

    NARCIS (Netherlands)

    Flogel, U.; Burghoff, S.; Lent, P.L.E.M. van; Temme, S.; Galbarz, L.; Ding, Z.; El-Tayeb, A.; Huels, S.; Bonner, F.; Borg, N. van den; Jacoby, C.; Muller, C.E.; Berg, W.B. van den; Schrader, J.

    2012-01-01

    Adenosine A(2A) receptor (A(2A)R) agonists are both highly effective anti-inflammatory agents and potent vasodilators. To separate these two activities, we have synthesized phosphorylated A(2A)R agonists (prodrugs) that require the presence of ecto-5'-nucleotidase (CD73) to become activated. In the

  16. A1C Test and Diabetes

    Science.gov (United States)

    ... Diagnosis The A1C Test & Diabetes The A1C Test & Diabetes On this page: What is the A1C test? ... the A1C test used to diagnose type 2 diabetes and prediabetes? Health care professionals can use the ...

  17. An A2A adenosine receptor agonist, ATL313, reduces inflammation and improves survival in murine sepsis models

    Directory of Open Access Journals (Sweden)

    Linden Joel

    2008-10-01

    Full Text Available Abstract Background The pathophysiology of sepsis is due in part to early systemic inflammation. Here we describe molecular and cellular responses, as well as survival, in A2A adenosine receptor (AR agonist treated and untreated animals during experimental sepsis. Methods Sepsis was induced in mice by intraperitoneal inoculation of live bacteria (Escherichia coli or Staphylococcus aureus or lipopolysaccharide (LPS. Mice inoculated with live bacteria were treated with an A2A AR agonist (ATL313 or phosphate buffered saline (PBS, with or without the addition of a dose of ceftriaxone. LPS inoculated mice were treated with ATL313 or PBS. Serum cytokines and chemokines were measured sequentially at 1, 2, 4, 8, and 24 hours after LPS was administered. In survival studies, mice were followed until death or for 7 days. Results There was a significant survival benefit in mice infected with live E. coli (100% vs. 20%, p = 0.013 or S. aureus (60% vs. 20%, p = 0.02 when treated with ATL313 in conjunction with an antibiotic versus antibiotic alone. ATL313 also improved survival from endotoxic shock when compared to PBS treatment (90% vs. 40%, p = 0.005. The serum concentrations of TNF-α, MIP-1α, MCP-1, IFN-γ, and IL-17 were decreased by ATL313 after LPS injection (p p p Conclusion Further studies are warranted to determine the clinical utility of ATL313 as a novel treatment for sepsis.

  18. Adenosine A(2A) receptor gene (ADORA2A) variants may increase autistic symptoms and anxiety in autism spectrum disorder.

    Science.gov (United States)

    Freitag, Christine M; Agelopoulos, Konstantin; Huy, Ellen; Rothermundt, Matthias; Krakowitzky, Petra; Meyer, Jobst; Deckert, Jürgen; von Gontard, Alexander; Hohoff, Christa

    2010-01-01

    Autism spectrum disorders (ASDs) are heterogeneous disorders presenting with increased rates of anxiety. The adenosine A(2A) receptor gene (ADORA2A) is associated with panic disorder and is located on chromosome 22q11.23. Its gene product, the adenosine A(2A) receptor, is strongly expressed in the caudate nucleus, which also is involved in ASD. As autistic symptoms are increased in individuals with 22q11.2 deletion syndrome, and large 22q11.2 deletions and duplications have been observed in ASD individuals, in this study, 98 individuals with ASD and 234 control individuals were genotyped for eight single-nucleotide polymorphisms in ADORA2A. Nominal association with the disorder was observed for rs2236624-CC, and phenotypic variability in ASD symptoms was influenced by rs3761422, rs5751876 and rs35320474. In addition, association of ADORA2A variants with anxiety was replicated for individuals with ASD. Findings point toward a possible mediating role of ADORA2A variants on phenotypic expression in ASD that need to be replicated in a larger sample.

  19. Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency–induced autoimmunity via adenosine A2A receptors

    Science.gov (United States)

    Hoang, Thomas K.; Tian, Xiangjun; Luo, Meng; Zhou, Jain; Tatevian, Nina; Molina, Jose G.; Blackburn, Michael R.; Gomez, Thomas H.

    2017-01-01

    Regulatory T (T reg) cell deficiency causes lethal, CD4+ T cell–driven autoimmune diseases. Stem cell transplantation is used to treat these diseases, but this procedure is limited by the availability of a suitable donor. The intestinal microbiota drives host immune homeostasis by regulating the differentiation and expansion of T reg, Th1, and Th2 cells. It is currently unclear if T reg cell deficiency–mediated autoimmune disorders can be treated by targeting the enteric microbiota. Here, we demonstrate that Foxp3+ T reg cell deficiency results in gut microbial dysbiosis and autoimmunity over the lifespan of scurfy (SF) mouse. Remodeling microbiota with Lactobacillus reuteri prolonged survival and reduced multiorgan inflammation in SF mice. L. reuteri changed the metabolomic profile disrupted by T reg cell deficiency, and a major effect was to restore levels of the purine metabolite inosine. Feeding inosine itself prolonged life and inhibited multiorgan inflammation by reducing Th1/Th2 cells and their associated cytokines. Mechanistically, the inhibition of inosine on the differentiation of Th1 and Th2 cells in vitro depended on adenosine A2A receptors, which were also required for the efficacy of inosine and of L. reuteri in vivo. These results reveal that the microbiota–inosine–A2A receptor axis might represent a potential avenue for combatting autoimmune diseases mediated by T reg cell dysfunction. PMID:27994068

  20. Adenosine A2A receptor-dependent proliferation of pulmonary endothelial cells is mediated through calcium mobilization, PI3-kinase and ERK1/2 pathways

    International Nuclear Information System (INIS)

    Ahmad, Aftab; Schaack, Jerome B.; White, Carl W.; Ahmad, Shama

    2013-01-01

    Highlights: •A 2A receptor-induced pulmonary endothelial growth is mediated by PI3K and ERK1/2. •Cytosolic calcium mobilization is also critical for pulmonary endothelial growth. •Effectors of A 2A receptor, like tyrosine kinases and cAMP increase PI3K/Akt signaling. •Activation of A 2A receptor can contribute to vascular remodeling. -- Abstract: Hypoxia and HIF-2α-dependent A 2A receptor expression and activation increase proliferation of human lung microvascular endothelial cells (HLMVECs). This study was undertaken to investigate the signaling mechanisms that mediate the proliferative effects of A 2A receptor. A 2A receptor-mediated proliferation of HLMVECs was inhibited by intracellular calcium chelation, and by specific inhibitors of ERK1/2 and PI3-kinase (PI3K). The adenosine A 2A receptor agonist CGS21680 caused intracellular calcium mobilization in controls and, to a greater extent, in A 2A receptor-overexpressing HLMVECs. Adenoviral-mediated A 2A receptor overexpression as well as receptor activation by CGS21680 caused increased PI3K activity and Akt phosphorylation. Cells overexpressing A 2A receptor also manifested enhanced ERK1/2 phosphorylation upon CGS21680 treatment. A 2A receptor activation also caused enhanced cAMP production. Likewise, treatment with 8Br-cAMP increased PI3K activity. Hence A 2A receptor-mediated cAMP production and PI3K and Akt phosphorylation are potential mediators of the A 2A -mediated proliferative response of HLMVECs. Cytosolic calcium mobilization and ERK1/2 phosphorylation are other critical effectors of HLMVEC proliferation and growth. These studies underscore the importance of adenosine A 2A receptor in activation of survival and proliferative pathways in pulmonary endothelial cells that are mediated through PI3K/Akt and ERK1/2 pathways

  1. Activation of A2aR attenuates bleomycin-induced pulmonary fibrosis via the SDF-1/CXCR4 axis-related pathway.

    Science.gov (United States)

    Chen, Yanfan; Yu, Xiaoming; He, Yicheng; Zhang, Lin; Huang, Xiaoying; Xu, Xiaomei; Chen, Mayun; Chen, Xiang; Wang, Liangxing

    2017-01-01

    Previous studies in our lab have demonstrated that Adenosine A2a receptor (A 2a R) gene-knockout mice were vulnerable to pulmonary fibrosis induced by bleomycin (BLM). Inhibition of the SDF-1/CXCR4 axis has been reported to protect the lungs from fibrogenesis in BLM-exposed mice. Little is yet known about the relationships between A 2a R and the SDF-1/CXCR4 axis in idiopathic pulmonary fibrosis (IPF). This study probes the role of A 2a R in the fibrotic process and explores the relationship between A 2a R and the SDF-1/CXCR4 axis in BLM-induced pulmonary fibrosis in mice. In the study, A 2a R-/- and A 2a R+/+ BALB/c mice were exposed to BLM by intratracheal instillation, and CGS-21680 (CGS), an A 2a R agonist, was administered daily for 28 days to the A 2a R+/+ mice in the BLM-induced fibrosis group. Activation of A 2a R produced an anti-fibrotic effect as indicated by the evaluations of the lung architecture, microstructure and ultrastructure. The quantitative analysis indicated that treatment with CGS significantly reduced the collagen content in lungs. To explore the potential mechanisms, the expression levels of A 2a R, SDF-1, and CXCR4 were subsequently determined using ELISA, in situ hybridization (ISH), immunohistochemical staining and western blotting techniques. Administration of CGS markedly suppressed the elevated expression levels of SDF-1 and CXCR4. Moreover, the A 2a R-/- mice developed more severe pulmonary fibrosis than the normal mice when exposed to BLM. Furthermore, the SDF-1/CXCR4 axis was aberrantly uninhibited in the knockout mice. Together, these findings indicated that A 2a R alleviated BLM-induced lung fibrosis, at least partially via the SDF-1/CXCR4 pathway, which could be a potential therapeutic target for the treatment of IPF.

  2. A1 and A2 Sub-Types of Blood Group ‘A’: A Reflection of their Prevalence in North Karnataka Region

    Science.gov (United States)

    Giriyan, Sujata S; Bajpai, Richa; Nirala, Niraj Kumar

    2017-01-01

    Introduction Landsteiner ABO system of blood groups is most important for transfusion medicine and has subtypes of A Antigen, A1 and A2, upon which further groups of A and AB have been classified. Of individuals with A antigen, approximately 20% belong to A2 while rest 80% belong to A1. Anti-A1 Lectin, a cold agglutinin which destroys A1 cells is clinically significant when they react at 37°C, causing transfusion reactions. Aim To assess the prevalence of A1 and A2 subgroups in the population. Materials and Methods This was two year retrospective analysis of blood groups of donors coming to the blood bank of Karnataka Institute of Medical Science, Hubli, Karnataka, India. The data of the subgroups A and AB was analysed. Results 20,864 donors were analysed. Of 5466 (26.20%) of A group, 5406 (98.90%) belonged to A1 subgroup and only 60 (1.10%) belonged to A2 subgroup. Of 1708 donors with blood group AB, 1532 (89.70%) belonged to A1B subgroup and 176 (10.30%) belonged to A2B. It was noted that A2 in AB blood-group, as A2B, was more frequent in occurrence than presence of A2 as an A blood group. Rhesus negative frequency in these subgroups was also reported. Conclusion Having known the prevalence of A1 and A2 subgroups and incorporating them into the ABO grouping system can limit these minor, yet dangerous, transfusion incompatibilities. PMID:28658771

  3. Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer.

    Science.gov (United States)

    Bonaventura, Jordi; Navarro, Gemma; Casadó-Anguera, Verònica; Azdad, Karima; Rea, William; Moreno, Estefanía; Brugarolas, Marc; Mallol, Josefa; Canela, Enric I; Lluís, Carme; Cortés, Antoni; Volkow, Nora D; Schiffmann, Serge N; Ferré, Sergi; Casadó, Vicent

    2015-07-07

    Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2AR agonists, but also A2AR antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A2AR-D2R heteromers as heterotetramers, constituted by A2AR and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2AR antagonists behaved as A2AR agonists and decreased D2R function in the brain.

  4. Adenosine A2A Receptors Control Glutamatergic Synaptic Plasticity in Fast Spiking Interneurons of the Prefrontal Cortex

    Directory of Open Access Journals (Sweden)

    Amber Kerkhofs

    2018-03-01

    Full Text Available Adenosine A2A receptors (A2AR are activated upon increased synaptic activity to assist in the implementation of long-term plastic changes at synapses. While it is reported that A2AR are involved in the control of prefrontal cortex (PFC-dependent behavior such as working memory, reversal learning and effort-based decision making, it is not known whether A2AR control glutamatergic synapse plasticity within the medial PFC (mPFC. To elucidate that, we tested whether A2AR blockade affects long-term plasticity (LTP of excitatory post-synaptic potentials in pyramidal neurons and fast spiking (FS interneurons in layer 5 of the mPFC and of population spikes. Our results show that A2AR are enriched at mPFC synapses, where their blockade reversed the direction of plasticity at excitatory synapses onto layer 5 FS interneurons from LTP to long-term depression, while their blockade had no effect on the induction of LTP at excitatory synapses onto layer 5 pyramidal neurons. At the network level, extracellularly induced LTP of population spikes was reduced by A2AR blockade. The interneuron-specificity of A2AR in controlling glutamatergic synapse LTP may ensure that during periods of high synaptic activity, a proper excitation/inhibition balance is maintained within the mPFC.

  5. Distribution of the a2, a3, and a5 nicotinic acetylcholine receptor subunits in the chick brain

    Directory of Open Access Journals (Sweden)

    Torrão A.S.

    1997-01-01

    Full Text Available Nicotinic acetylcholine receptors (nAChRs are ionotropic receptors comprised of a and ß subunits. These receptors are widely distributed in the central nervous system, and previous studies have revealed specific patterns of localization for some nAChR subunits in the vertebrate brain. In the present study we used immunohistochemical methods and monoclonal antibodies to localize the a2, a3, and a5 nAChR subunits in the chick mesencephalon and diencephalon. We observed a differential distribution of these three subunits in the chick brain, and showed that the somata and neuropil of many central structures contain the a5 nAChR subunit. The a2 and a3 subunits, on the other hand, exhibited a more restricted distribution than a5 and other subunits previously studied, namely a7, a8 and ß2. The patterns of distribution of the different nAChR subunits suggest that neurons in many brain structures may contain several subtypes of nAChRs and that in a few regions one particular subtype may determine the cholinergic nicotinic responses

  6. Globally Accurate Potential Energy Surface for HCS(A2A'') by Extrapolation to Complete Basis Set Limit.

    Science.gov (United States)

    Zhang, Lu-Lu; Song, Yu-Zhi; Gao, Shou-Bao; Meng, Qing-Tian

    2018-04-16

    A global potential energy surface (PES) representation of the C( 3 P) + SH(X 2 ∏) → H( 2 S) + CS(a 3 ∏) system is developed by fitting a wealth of accurate ab initio energies calculated at the multireference configuration interaction level using aug-cc-pVQZ and aug-cc-pV5Z basis sets via extrapolation to the complete basis set limit. The topographical features of the present PES are examined in detail and found to be in good agreement with previous calculations available in the literature. By utilizing the PES of HCS(A2A''), the corresponding reaction is investigated using quasi-classical trajectory (QCT) method in the collision energy range of 0.08 - 1.0 eV. The minimum energy paths (MEPs) calculated based on the present PES indicate that the titled reaction is exothermic, with the exothermicity being ∼ 0.204 eV. The calculation for the capture time indicates that at lower collision energy, the reaction is mainly governed by the indirect mechanism, while for higher collision energy, the direct mechanism and indirect mechanisms coexist with the latter being the dominant contributor.

  7. Robust hepatitis C genotype 3a cell culture releasing adapted intergenotypic 3a/2a (S52/JFH1) viruses

    DEFF Research Database (Denmark)

    Gottwein, Judith; Scheel, Troels; Høgh, Mette

    2007-01-01

    (immunostaining), HCV RNA titers (real-time PCR), and infectivity titers (50% tissue culture infectious dose). The role of mutations identified by sequencing of recovered S52/JFH1 viruses was analyzed by reverse genetics studies. RESULTS: S52/JFH1 and J6/JFH viruses passaged in Huh7.5 cells showed comparable......BACKGROUND & AIMS: Recently, full viral life cycle hepatitis C virus (HCV) cell culture systems were developed for strain JFH1 (genotype 2a) and an intragenotypic 2a/2a genome (J6/JFH). We aimed at exploiting the unique JFH1 replication characteristics to develop culture systems for genotype 3a......, which has a high prevalence worldwide. METHODS: Huh7.5 cells were transfected with RNA transcripts of an intergenotypic 3a/JFH1 recombinant with core, E1, E2, p7, and NS2 of the 3a reference strain S52, and released viruses were passaged. Cultures were examined for HCV core and/or NS5A expression...

  8. Robust hepatitis C genotype 3a cell culture releasing adapted intergenotypic 3a/2a (S52/JFH1) viruses

    DEFF Research Database (Denmark)

    Gottwein, J.M.; Scheel, Troels Kasper Høyer; Hoegh, A.M.

    2007-01-01

    BACKGROUND & AIMS: Recently, full viral life cycle hepatitis C virus (HCV) cell culture systems were developed for strain JFH1 (genotype 2a) and an intragenotypic 2a/2a genome (J6/JFH). We aimed at exploiting the unique JFH1 replication characteristics to develop culture systems for genotype 3a......, which has a high prevalence worldwide. METHODS: Huh7.5 cells were transfected with RNA transcripts of an intergenotypic 3a/JFH1 recombinant with core, E1, E2, p7, and NS2 of the 3a reference strain S52, and released viruses were passaged. Cultures were examined for HCV core and/or NS5A expression...... (immunostaining), HCV RNA titers (real-time PCR), and infectivity titers (50% tissue culture infectious dose). The role of mutations identified by sequencing of recovered S52/JFH1 viruses was analyzed by reverse genetics studies. RESULTS: S52/JFH1 and J6/JFH viruses passaged in Huh7.5 cells showed comparable...

  9. Led Astray by Hemoglobin A1c

    Directory of Open Access Journals (Sweden)

    Jean Chen MD

    2016-01-01

    Full Text Available Hemoglobin A1c (A1c is used frequently to diagnose and treat diabetes mellitus. Therefore, it is important be aware of factors that may interfere with the accuracy of A1c measurements. This is a case of a rare hemoglobin variant that falsely elevated a nondiabetic patient’s A1c level and led to a misdiagnosis of diabetes. A 67-year-old male presented to endocrine clinic for further management after he was diagnosed with diabetes based on an elevated A1c of 10.7%, which is approximately equivalent to an average blood glucose of 260 mg/dL. Multiple repeat A1c levels remained >10%, but his home fasting and random glucose monitoring ranged from 92 to 130 mg/dL. Hemoglobin electrophoresis and subsequent genetic analysis diagnosed the patient with hemoglobin Wayne, a rare hemoglobin variant. This variant falsely elevates A1c levels when A1c is measured using cation-exchange high-performance liquid chromatography. When the boronate affinity method was applied instead, the patient’s A1c level was actually 4.7%. Though hemoglobin Wayne is clinically silent, this patient was erroneously diagnosed with diabetes and started on an antiglycemic medication. Due to this misdiagnosis, the patient was at risk of escalation in his “diabetes management” and hypoglycemia. Therefore, it is important that providers are aware of factors that may result in hemoglobin A1c inaccuracy including hemoglobin variants.

  10. Reversibility of Intersystem Crossing in the {a}1A1(000) and {a}1A1(010) States of Methylene, CH_2

    Science.gov (United States)

    Le, Anh T.; Sears, Trevor; Hall, Gregory

    2015-06-01

    The lowest energy singlet ( {a}1A1) and triplet ( {X}3B1) electronic states of methylene, CH_2, are only separated by 3150 wn, but differ greatly in chemical reactivity. Overall methylene reaction rates and chemical behavior are therefore strongly dependent on collisionally-mediated singlet-triplet interconversion. Collisions with inert partners tend to depopulate the excited singlet state and populate vibrationally excited triplet levels in CH_2. This process is generally considered as irreversible for large molecules, however, this is not the case for small molecules such as CH_2. An investigation of the decay kinetics of CH_2 in the presence of argon and various amounts of oxygen has been carried out using transient frequency modulation (FM) absorption spectroscopy, to monitor ortho and para rotational levels in both the {a}1A1(000) and {a}1A1(010) states. In the {a}1A1(000) state, all observed rotational levels follow double exponential decay kinetics, a direct consequence of reversible intersystem crossing. The relative amplitude of the slower decay component is an indicator of how quickly the reverse crossing from excited triplet levels becomes significant during the reaction and relaxation of singlet methylene. The para rotational levels show more obvious signs of reversibility than ortho rotational levels. Adding oxygen enhances the visibility of reversibility for both ortho and para levels. However, in the {a}1A1(010) state where the FM signal is 5-10 times smaller than the {a}1A1(000) state, there is no evidence of double exponential decay kinetics. Acknowledgments: Work at Brookhaven National Laboratory was carried out under Contract No. DE-AC02-98CH10886 and DE-SC0012704 with the U.S. Department of Energy and supported by its Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences and Biosciences.

  11. Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress.

    Science.gov (United States)

    Kaster, Manuella P; Machado, Nuno J; Silva, Henrique B; Nunes, Ana; Ardais, Ana Paula; Santana, Magda; Baqi, Younis; Müller, Christa E; Rodrigues, Ana Lúcia S; Porciúncula, Lisiane O; Chen, Jiang Fan; Tomé, Ângelo R; Agostinho, Paula; Canas, Paula M; Cunha, Rodrigo A

    2015-06-23

    The consumption of caffeine (an adenosine receptor antagonist) correlates inversely with depression and memory deterioration, and adenosine A2A receptor (A2AR) antagonists emerge as candidate therapeutic targets because they control aberrant synaptic plasticity and afford neuroprotection. Therefore we tested the ability of A2AR to control the behavioral, electrophysiological, and neurochemical modifications caused by chronic unpredictable stress (CUS), which alters hippocampal circuits, dampens mood and memory performance, and enhances susceptibility to depression. CUS for 3 wk in adult mice induced anxiogenic and helpless-like behavior and decreased memory performance. These behavioral changes were accompanied by synaptic alterations, typified by a decrease in synaptic plasticity and a reduced density of synaptic proteins (synaptosomal-associated protein 25, syntaxin, and vesicular glutamate transporter type 1), together with an increased density of A2AR in glutamatergic terminals in the hippocampus. Except for anxiety, for which results were mixed, CUS-induced behavioral and synaptic alterations were prevented by (i) caffeine (1 g/L in the drinking water, starting 3 wk before and continued throughout CUS); (ii) the selective A2AR antagonist KW6002 (3 mg/kg, p.o.); (iii) global A2AR deletion; and (iv) selective A2AR deletion in forebrain neurons. Notably, A2AR blockade was not only prophylactic but also therapeutically efficacious, because a 3-wk treatment with the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) reversed the mood and synaptic dysfunction caused by CUS. These results herald a key role for synaptic A2AR in the control of chronic stress-induced modifications and suggest A2AR as candidate targets to alleviate the consequences of chronic stress on brain function.

  12. Quantification of adenosine A2A receptors in the human brain using [11C]TMSX and positron emission tomography

    International Nuclear Information System (INIS)

    Naganawa, Mika; Kimura, Yuichi; Oda, Keiichi; Ishii, Kenji; Ishiwata, Kiichi; Mishina, Masahiro; Manabe, Yoshitsugu; Chihara, Kunihiro

    2007-01-01

    [7-methyl- 11 C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([ 11 C]TMSX) is a positron-emitting adenosine A 2A receptor (A2AR) antagonist for visualisation of A2AR distribution by positron emission tomography (PET). The aims of this paper were to use a kinetic model to analyse the behaviour of [ 11 C]TMSX in the brain and to examine the applicability of the Logan plot. We also studied the applicability of a simplified Logan plot by omitting metabolite correction and arterial blood sampling. The centrum semiovale was used as a reference region on the basis of a post-mortem study showing that it has a negligibly low density of A2ARs. Compartmental analysis was performed in five normal subjects. Parametric images of A2AR binding potential (BP) were also generated using a Logan plot with or without metabolite correction and with or without arterial blood sampling. To omit arterial blood sampling, we applied a method to extract the plasma-related information using independent component analysis (EPICA). The estimated K 1 /k 2 was confirmed to be common in the centrum semiovale and main cortices. The three-compartment model was well fitted to the other regions using the fixed value of K 1 /k 2 estimated from the centrum semiovale. The estimated BPs using the Logan plot matched those derived from compartment analysis. Without the metabolite correction, the estimate of BP underestimated the true value by 5%. The estimated BPs agreed regardless of arterial blood sampling. A three-compartment model with a reference region, the centrum semiovale, describes the kinetic behaviour of [ 11 C]TMSX PET images. A2ARs in the human brain can be visualised as a BP image using [ 11 C]TMSX PET without arterial blood sampling. (orig.)

  13. High cleavage efficiency of a 2A peptide derived from porcine teschovirus-1 in human cell lines, zebrafish and mice.

    Directory of Open Access Journals (Sweden)

    Jin Hee Kim

    Full Text Available When expression of more than one gene is required in cells, bicistronic or multicistronic expression vectors have been used. Among various strategies employed to construct bicistronic or multicistronic vectors, an internal ribosomal entry site (IRES has been widely used. Due to the large size and difference in expression levels between genes before and after IRES, however, a new strategy was required to replace IRES. A self-cleaving 2A peptide could be a good candidate to replace IRES because of its small size and high cleavage efficiency between genes upstream and downstream of the 2A peptide. Despite the advantages of the 2A peptides, its use is not widespread because (i there are no publicly available cloning vectors harboring a 2A peptide gene and (ii comprehensive comparison of cleavage efficiency among various 2A peptides reported to date has not been performed in different contexts. Here, we generated four expression plasmids each harboring different 2A peptides derived from the foot-and-mouth disease virus, equine rhinitis A virus, Thosea asigna virus and porcine teschovirus-1, respectively, and evaluated their cleavage efficiency in three commonly used human cell lines, zebrafish embryos and adult mice. Western blotting and confocal microscopic analyses revealed that among the four 2As, the one derived from porcine teschovirus-1 (P2A has the highest cleavage efficiency in all the contexts examined. We anticipate that the 2A-harboring cloning vectors we generated and the highest efficiency of the P2A peptide we demonstrated would help biomedical researchers easily adopt the 2A technology when bicistronic or multicistronic expression is required.

  14. Blood Test: Hemoglobin A1C

    Science.gov (United States)

    ... Staying Safe Videos for Educators Search English Español Blood Test: Hemoglobin A1c KidsHealth / For Parents / Blood Test: Hemoglobin ... Análisis de sangre: hemoglobina A1c What Is a Blood Test? A blood test is when a sample of ...

  15. NPP A-1 decommissioning - Phase I

    International Nuclear Information System (INIS)

    Krstenik, A.; Blazek, J.

    2000-01-01

    Nuclear power plant A-1 with output 150 MW e , with metallic natural uranium fuelled, CO 2 cooled and heavy water moderated reactor had been prematurely finally shut down in 1977. It is necessary to mention that neither operator nor regulatory and other authorities have been prepared for the solution of such situation. During next two consecutive years after shutdown main effort of operator focused on technical and administrative activities which are described in the previous paper together with approach, condition and constraints for NPP A-1 decommissioning as well as the work and research carried out up to the development and approval of the Project for NPP A-1 decommissioning - I. phase. Subject of this paper is description of: (1) An approach to NPP A -1 decommissioning; (2) An approach to development of the project for NPP A-1 decommissioning; (3) Project - tasks, scope, objectives; (4) Mode of the Project realisation; (5) Progress achieved up to the 1999 year. (authors)

  16. Transient hemolysis due to anti-D and anti-A1 produced by engrafted donor's lymphocytes after allogeneic unmanipulated haploidentical hematopoietic stem cell transplantation.

    Science.gov (United States)

    Bailén, Rebeca; Kwon, Mi; Pérez-Corral, Ana María; Pascual, Cristina; Buño, Ismael; Balsalobre, Pascual; Serrano, David; Gayoso, Jorge; Díez-Martín, José Luis; Anguita, Javier

    2017-10-01

    Development of de novo alloantibodies against recipient's red blood cell (RBC) antigens by engrafted donor's lymphocytes is a known phenomenon in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). This situation is usually clinically insignificant. We report a case of early clinically relevant hemolytic anemia in a blood group A 1 D+ patient, due to a limited production of anti-D and anti-A 1 produced by nonpreviously sensitized newly engrafted donor's immune system. A 31-year-old Caucasian woman, blood group A 1 , D+, with Hodgkin's lymphoma, received an unmanipulated haploidentical allogeneic peripheral blood HSCT after a nonmyeloablative conditioning regimen. Donor blood group was A 2 B, D-. The patient had an uneventful course until Day +34, when she developed clinically significant hemolytic anemia with a positive direct antiglobulin test. Anti-D and anti-A 1 produced by the donor-engrafted lymphocytes were detected both in serum and in eluate. The hemolysis produced an accelerated group change, turning the patient's ABO group into A 2 B 2 weeks after the detection of the alloantibodies. As the residual patient's RBCs progressively disappeared, anti-D and anti-A 1 production decreased and were not detected in serum by Day +41. This case illustrates that de novo alloantibody production against ABO and D antigens by the newly engrafted donor's lymphocytes can occasionally cause clinically significant anemia. To our knowledge, this is the first case reported of clinically significant hemolytic anemia due to a transient anti-D anti-A 1 alloimmunization after T-cell-repleted haploidentical HSCT. © 2017 AABB.

  17. Adenosine A(2A receptors measured with [C]TMSX PET in the striata of Parkinson's disease patients.

    Directory of Open Access Journals (Sweden)

    Masahiro Mishina

    Full Text Available Adenosine A(2A receptors (A2ARs are thought to interact negatively with the dopamine D(2 receptor (D2R, so selective A2AR antagonists have attracted attention as novel treatments for Parkinson's disease (PD. However, no information about the receptor in living patients with PD is available. The purpose of this study was to investigate the relationship between A2ARs and the dopaminergic system in the striata of drug-naïve PD patients and PD patients with dyskinesia, and alteration of these receptors after antiparkinsonian therapy. We measured binding ability of striatal A2ARs using positron emission tomography (PET with [7-methyl-(11C]-(E-8-(3,4,5-trimethoxystyryl-1,3,7-trimethylxanthine ([(11C]TMSX in nine drug-naïve patients with PD, seven PD patients with mild dyskinesia and six elderly control subjects using PET. The patients and eight normal control subjects were also examined for binding ability of dopamine transporters and D2Rs. Seven of the drug-naïve patients underwent a second series of PET scans following therapy. We found that the distribution volume ratio of A2ARs in the putamen were larger in the dyskinesic patients than in the control subjects (p<0.05, Tukey-Kramer post hoc test. In the drug-naïve patients, the binding ability of the A2ARs in the putamen, but not in the head of caudate nucleus, was significantly lower on the more affected side than on the less affected side (p<0.05, paired t-test. In addition, the A2ARs were significantly increased after antiparkinsonian therapy in the bilateral putamen of the drug-naïve patients (p<0.05, paired t-test but not in the bilateral head of caudate nucleus. Our study demonstrated that the A2ARs in the putamen were increased in the PD patients with dyskinesia, and also suggest that the A2ARs in the putamen compensate for the asymmetrical decrease of dopamine in drug-naïve PD patients and that antiparkinsonian therapy increases the A2ARs in the putamen. The A2ARs may play an

  18. Adenosine A2A Receptor Up-Regulates Retinal Wave Frequency via Starburst Amacrine Cells in the Developing Rat Retina

    Science.gov (United States)

    Huang, Pin-Chien; Hsiao, Yu-Tien; Kao, Shao-Yen; Chen, Ching-Feng; Chen, Yu-Chieh; Chiang, Chung-Wei; Lee, Chien-fei; Lu, Juu-Chin; Chern, Yijuang; Wang, Chih-Tien

    2014-01-01

    Background Developing retinas display retinal waves, the patterned spontaneous activity essential for circuit refinement. During the first postnatal week in rodents, retinal waves are mediated by synaptic transmission between starburst amacrine cells (SACs) and retinal ganglion cells (RGCs). The neuromodulator adenosine is essential for the generation of retinal waves. However, the cellular basis underlying adenosine's regulation of retinal waves remains elusive. Here, we investigated whether and how the adenosine A2A receptor (A2AR) regulates retinal waves and whether A2AR regulation of retinal waves acts via presynaptic SACs. Methodology/Principal Findings We showed that A2AR was expressed in the inner plexiform layer and ganglion cell layer of the developing rat retina. Knockdown of A2AR decreased the frequency of spontaneous Ca2+ transients, suggesting that endogenous A2AR may up-regulate wave frequency. To investigate whether A2AR acts via presynaptic SACs, we targeted gene expression to SACs by the metabotropic glutamate receptor type II promoter. Ca2+ transient frequency was increased by expressing wild-type A2AR (A2AR-WT) in SACs, suggesting that A2AR may up-regulate retinal waves via presynaptic SACs. Subsequent patch-clamp recordings on RGCs revealed that presynaptic A2AR-WT increased the frequency of wave-associated postsynaptic currents (PSCs) or depolarizations compared to the control, without changing the RGC's excitability, membrane potentials, or PSC charge. These findings suggest that presynaptic A2AR may not affect the membrane properties of postsynaptic RGCs. In contrast, by expressing the C-terminal truncated A2AR mutant (A2AR-ΔC) in SACs, the wave frequency was reduced compared to the A2AR-WT, but was similar to the control, suggesting that the full-length A2AR in SACs is required for A2AR up-regulation of retinal waves. Conclusions/Significance A2AR up-regulates the frequency of retinal waves via presynaptic SACs, requiring its full

  19. Adenosine A(2A receptor up-regulates retinal wave frequency via starburst amacrine cells in the developing rat retina.

    Directory of Open Access Journals (Sweden)

    Pin-Chien Huang

    Full Text Available BACKGROUND: Developing retinas display retinal waves, the patterned spontaneous activity essential for circuit refinement. During the first postnatal week in rodents, retinal waves are mediated by synaptic transmission between starburst amacrine cells (SACs and retinal ganglion cells (RGCs. The neuromodulator adenosine is essential for the generation of retinal waves. However, the cellular basis underlying adenosine's regulation of retinal waves remains elusive. Here, we investigated whether and how the adenosine A(2A receptor (A(2AR regulates retinal waves and whether A(2AR regulation of retinal waves acts via presynaptic SACs. METHODOLOGY/PRINCIPAL FINDINGS: We showed that A(2AR was expressed in the inner plexiform layer and ganglion cell layer of the developing rat retina. Knockdown of A(2AR decreased the frequency of spontaneous Ca²⁺ transients, suggesting that endogenous A(2AR may up-regulate wave frequency. To investigate whether A(2AR acts via presynaptic SACs, we targeted gene expression to SACs by the metabotropic glutamate receptor type II promoter. Ca²⁺ transient frequency was increased by expressing wild-type A(2AR (A2AR-WT in SACs, suggesting that A(2AR may up-regulate retinal waves via presynaptic SACs. Subsequent patch-clamp recordings on RGCs revealed that presynaptic A(2AR-WT increased the frequency of wave-associated postsynaptic currents (PSCs or depolarizations compared to the control, without changing the RGC's excitability, membrane potentials, or PSC charge. These findings suggest that presynaptic A(2AR may not affect the membrane properties of postsynaptic RGCs. In contrast, by expressing the C-terminal truncated A(2AR mutant (A(2AR-ΔC in SACs, the wave frequency was reduced compared to the A(2AR-WT, but was similar to the control, suggesting that the full-length A(2AR in SACs is required for A(2AR up-regulation of retinal waves. CONCLUSIONS/SIGNIFICANCE: A(2AR up-regulates the frequency of retinal waves via

  20. The neuronal Ca(2+) -binding protein 2 (NECAB2) interacts with the adenosine A(2A) receptor and modulates the cell surface expression and function of the receptor.

    Science.gov (United States)

    Canela, Laia; Luján, Rafael; Lluís, Carme; Burgueño, Javier; Mallol, Josefa; Canela, Enric I; Franco, Rafael; Ciruela, Francisco

    2007-09-01

    Heptaspanning membrane also known as G protein-coupled receptors (GPCR) do interact with a variety of intracellular proteins whose function is regulate receptor traffic and/or signaling. Using a yeast two-hybrid screen, NECAB2, a neuronal calcium binding protein, was identified as a binding partner for the adenosine A(2A) receptor (A(2A)R) interacting with its C-terminal domain. Co-localization, co-immunoprecipitation and pull-down experiments showed a close and specific interaction between A(2A)R and NECAB2 in both transfected HEK-293 cells and also in rat striatum. Immunoelectron microscopy detection of NECAB2 and A(2A)R in the rat striatopallidal structures indicated that both proteins are co-distributed in the same glutamatergic nerve terminals. The interaction of NECAB2 with A(2A)R modulated the cell surface expression, the ligand-dependent internalization and the receptor-mediated activation of the MAPK pathway. Overall, these results show that A(2A)R interacts with NECAB2 in striatal neurones co-expressing the two proteins and that the interaction is relevant for A(2A)R function.

  1. Up-regulation of striatal adenosine A2A receptors with iron deficiency in rats. Effects on locomotion and cortico-striatal neurotransmission

    Science.gov (United States)

    Quiroz, César; Pearson, Virginia; Gulyani, Seema; Allen, Richard; Earley, Christopher; Ferré, Sergi

    2010-01-01

    Brain iron deficiency leads to altered dopaminergic function in experimental animals, which can provide a mechanistic explanation for iron deficiency-related human sensory-motor disorders, such as Restless Legs Syndrome (RLS). However, mechanisms linking both conditions have not been determined. Considering the strong modulation exerted by adenosine on dopamine signaling, one connection could involve changes in adenosine receptor expression or function. In the striatum, presynaptic A2A receptors are localized in glutamatergic terminals contacting GABAergic dynorphinergic neurons and their function can be analyzed by the ability of A2A receptor antagonists to block the motor output induced by cortical electrical stimulation. Postsynaptic A2A receptors are localized in the dendritic field of GABAergic enkephalinergic neurons and their function can be analyzed by studying the ability of A2A receptor antagonists to produce locomotor activity and to counteract striatal ERK1/2 phosphorylation induced by cortical electrical stimulation. Increased density of striatal A2A receptors was found in rats fed during three weeks with an iron-deficient diet during the post-weaning period. In iron-deficient rats, the selective A2A receptor antagonist MSX-3, at doses of 1 and 3 mg/kg, was more effective at blocking motor output induced by cortical electrical stimulation (presynaptic A2A receptor-mediated effect) and at enhancing locomotor activation and blocking striatal ERK phosphorylation induced by cortical electrical stimulation (postsynaptic A2A receptor-mediated effects). These results indicate that brain iron deficiency induces a functional up-regulation of both striatal pre- and postsynaptic A2A receptor, which could be involved in sensory-motor disorders associated with iron deficiency such as RLS. PMID:20385128

  2. Up-regulation of striatal adenosine A(2A) receptors with iron deficiency in rats: effects on locomotion and cortico-striatal neurotransmission.

    Science.gov (United States)

    Quiroz, César; Pearson, Virginia; Gulyani, Seema; Allen, Richard; Earley, Christopher; Ferré, Sergi

    2010-07-01

    Brain iron deficiency leads to altered dopaminergic function in experimental animals, which can provide a mechanistic explanation for iron deficiency-related human sensory-motor disorders, such as Restless Legs Syndrome (RLS). However, mechanisms linking both conditions have not been determined. Considering the strong modulation exerted by adenosine on dopamine signaling, one connection could involve changes in adenosine receptor expression or function. In the striatum, presynaptic A(2A) receptors are localized in glutamatergic terminals contacting GABAergic dynorphinergic neurons and their function can be analyzed by the ability of A(2A) receptor antagonists to block the motor output induced by cortical electrical stimulation. Postsynaptic A(2A) receptors are localized in the dendritic field of GABAergic enkephalinergic neurons and their function can be analyzed by studying the ability of A(2A) receptor antagonists to produce locomotor activity and to counteract striatal ERK1/2 phosphorylation induced by cortical electrical stimulation. Increased density of striatal A(2A) receptors was found in rats fed during 3 weeks with an iron-deficient diet during the post-weaning period. In iron-deficient rats, the selective A(2A) receptor antagonist MSX-3, at doses of 1 and 3 mg/kg, was more effective at blocking motor output induced by cortical electrical stimulation (presynaptic A(2A) receptor-mediated effect) and at enhancing locomotor activation and blocking striatal ERK phosphorylation induced by cortical electrical stimulation (postsynaptic A(2A) receptor-mediated effects). These results indicate that brain iron deficiency induces a functional up-regulation of both striatal pre- and postsynaptic A(2A) receptor, which could be involved in sensory-motor disorders associated with iron deficiency such as RLS. Copyright 2010. Published by Elsevier Inc.

  3. 32 CFR 352a.1 - Purpose.

    Science.gov (United States)

    2010-07-01

    ... DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.1 Purpose. Pursuant to the authority vested in the... Finance and Accounting Service (DFAS) as an Agency of the Department of Defense with responsibilities, functions, authorities, and relationships. ...

  4. A2B : Identifying movement patterns from largescale Wi-Fi based location data

    NARCIS (Netherlands)

    van der Spek, S.C.; Verbree, E.; Bon, M.; den Duijn, X.A.; Dukai, B.; Griffioen, S.J.; Kang, Y; Vermeer, M.; Gartner, G.; Huang, H.

    2016-01-01

    The distribution of people in buildings, the occupancy of lecture-, work- and study places and the accessibility of facilities are essential information at university campuses who have to cope with limited and even shrinking budgets and huge, rising real estate costs. Only little insight is gained

  5. Adenosine enhances sweet taste through A2B receptors in the taste bud.

    Science.gov (United States)

    Dando, Robin; Dvoryanchikov, Gennady; Pereira, Elizabeth; Chaudhari, Nirupa; Roper, Stephen D

    2012-01-04

    Mammalian taste buds use ATP as a neurotransmitter. Taste Receptor (type II) cells secrete ATP via gap junction hemichannels into the narrow extracellular spaces within a taste bud. This ATP excites primary sensory afferent fibers and also stimulates neighboring taste bud cells. Here we show that extracellular ATP is enzymatically degraded to adenosine within mouse vallate taste buds and that this nucleoside acts as an autocrine neuromodulator to selectively enhance sweet taste. In Receptor cells in a lingual slice preparation, Ca(2+) mobilization evoked by focally applied artificial sweeteners was significantly enhanced by adenosine (50 μM). Adenosine had no effect on bitter or umami taste responses, and the nucleoside did not affect Presynaptic (type III) taste cells. We also used biosensor cells to measure transmitter release from isolated taste buds. Adenosine (5 μM) enhanced ATP release evoked by sweet but not bitter taste stimuli. Using single-cell reverse transcriptase (RT)-PCR on isolated vallate taste cells, we show that many Receptor cells express the adenosine receptor, Adora2b, while Presynaptic (type III) and Glial-like (type I) cells seldom do. Furthermore, Adora2b receptors are significantly associated with expression of the sweet taste receptor subunit, Tas1r2. Adenosine is generated during taste stimulation mainly by the action of the ecto-5'-nucleotidase, NT5E, and to a lesser extent, prostatic acid phosphatase. Both these ecto-nucleotidases are expressed by Presynaptic cells, as shown by single-cell RT-PCR, enzyme histochemistry, and immunofluorescence. Our findings suggest that ATP released during taste reception is degraded to adenosine to exert positive modulation particularly on sweet taste.

  6. Major dorsoventral differences in the modulation of the local CA1 hippocampal network by NMDA, mGlu5, adenosine A2A and cannabinoid CB1 receptors.

    Science.gov (United States)

    Kouvaros, S; Papatheodoropoulos, C

    2016-03-11

    Recent research points to diversification in the local neuronal circuitry between dorsal (DH) and ventral (VH) hippocampus that may be involved in the large-scale functional segregation along the long axis of the hippocampus. Here, using CA1 field recordings from rat hippocampal slices, we show that activation of N-methyl-d-aspartate receptors (NMDARs) reduced excitatory transmission more in VH than in DH, with an adenosine A1 receptor-independent mechanism, and reduced inhibition and enhanced postsynaptic excitability only in DH. Strikingly, co-activation of metabotropic glutamate receptor-5 (mGluR5) with NMDAR, by CHPG and NMDA respectively, strongly potentiated the effects of NMDAR in DH but had not any potentiating effect in VH. Furthermore, the synergistic actions in DH were occluded by blockade of adenosine A2A receptors (A2ARs) by their antagonist ZM 241385 demonstrating a tonic action of these receptors in DH. Exogenous activation of A2ARs by 4-[2-[[6-amino-9-(N-ethyl-β-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride (CGS 21680) did not change the effects of mGluR5-NMDAR co-activation in either hippocampal pole. Importantly, blockade of cannabinoid CB1 receptors (CB1Rs) by their antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide (AM 281) restricted the synergistic actions of mGluR5-NMDARs on excitatory synaptic transmission and postsynaptic excitability and abolished their effect on inhibition. Furthermore, AM 281 increased the excitatory transmission only in DH indicating that CB1Rs were tonically active in DH but not VH. Removing the magnesium ions from the perfusion medium neither stimulated the interaction between mGluR5 and NMDAR in VH nor augmented the synergy of the two receptors in DH. These findings show that the NMDAR-dependent modulation of fundamental parameters of the local neuronal network, by mGluR5, A2AR and CB1R, markedly differs between DH and VH. We

  7. A Novel Antagonist of the Immune Checkpoint Protein Adenosine A2a Receptor Restores Tumor-Infiltrating Lymphocyte Activity in the Context of the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Melanie Mediavilla-Varela

    2017-07-01

    Full Text Available BACKGROUND: Therapeutic strategies targeting immune checkpoint proteins have led to significant responses in patients with various tumor types. The success of these studies has led to the development of various antibodies/inhibitors for the different checkpoint proteins involved in immune evasion of the tumor. Adenosine present in high concentrations in the tumor microenvironment activates the immune checkpoint adenosine A2a receptor (A2aR, leading to the suppression of antitumor responses. Inhibition of this checkpoint has the potential to enhance antitumor T-cell responsiveness. METHODS: We developed a novel A2aR antagonist (PBF-509 and tested its antitumor response in vitro, in a mouse model, and in non-small cell lung cancer patient samples. RESULTS: Our studies showed that PBF-509 is highly specific to the A2aR as well as inhibitory of A2aR function in an in vitro model. In a mouse model, we found that lung metastasis was decreased after treatment with PBF-509 compared with its control. Furthermore, freshly resected tumor-infiltrating lymphocytes from lung cancer patients showed increased A2aR expression in CD4+ cells and variable expression in CD8+ cells. Ex vivo studies showed an increased responsiveness of human tumor-infiltrating lymphocytes when PBF-509 was combined with anti-PD-1 or anti-PD-L1. CONCLUSIONS: Our studies demonstrate that inhibition of the A2aR using the novel inhibitor PBF-509 could lead to novel immunotherapeutic strategies in non-small cell lung cancer.

  8. Baicalin attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A2A receptor-induced SDF-1/CXCR4/PI3K/AKT signaling.

    Science.gov (United States)

    Huang, Xiaoying; Wu, Peiliang; Huang, Feifei; Xu, Min; Chen, Mayun; Huang, Kate; Li, Guo-Ping; Xu, Manhuan; Yao, Dan; Wang, Liangxing

    2017-08-03

    Baicalin, an important flavonoid in Scutellaria baicalensis Georgi extracts, exerts a variety of pharmacological effects. In this study, we explored the effects of baicalin on chronic hypoxia-induced pulmonary arterial hypertension (PAH) and investigated the mechanism underlying these effects. Moreover, we examined whether the inflammatory response was mediated by the A 2A receptor (A 2A R) and stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-induced phosphatidyl inositol-3-kinase (PI3K) signaling in vivo. We established a hypoxia-induced pulmonary hypertension (HPH) mouse model by subjecting wild-type (WT) and A 2A R knockout (A 2A R -/- ) animals to chronic hypoxia, and we examined the effects of a 4-week treatment with baicalin or the A 2A R agonist CGS21680 in these animals. Invasive hemodynamic parameters, the right ventricular hypertrophy index, pulmonary congestion, the pulmonary arterial remodeling index, blood gas parameters, A 2A R expression, and the expression of SDF-1/CXCR4/PI3K/protein kinase B (PKB; AKT) signaling components were measured. Compared with WT mice, A 2A R -/- mice exhibited increased right ventricular systolic pressure (RVSP), right ventricle-to-left ventricle plus septum [RV/(LV + S)] ratio, RV weight-to-body weight (RV/BW) ratio, and lung wet weight-to-body weight (Lung/BW) ratio in the absence of an altered mean carotid arterial pressure (mCAP). These changes were accompanied by increases in pulmonary artery wall area and thickness and reductions in arterial oxygen pressure (P a O 2 ) and hydrogen ion concentration (pH). In the HPH model, A 2A R -/- mice displayed increased CXCR4, SDF-1, phospho-PI3K, and phospho-AKT expression compared with WT mice. Treating WT and A 2A R -/- HPH mice with baicalin or CGS21680 attenuated the hypoxia-induced increases in RVSP, RV/(LV + S) and Lung/BW, as well as pulmonary arterial remodeling. Additionally, baicalin or CGS21680 alone could reverse the hypoxia

  9. 10 CFR Appendix A to Part 71 - Determination of A1 and A2

    Science.gov (United States)

    2010-01-01

    ... 10 Energy 2 2010-01-01 2010-01-01 false Determination of A1 and A2 A Appendix A to Part 71 Energy... are not intended to be the regulatory standard. Where values of A1 and A2 are unlimited, it is for...×101 3.1×107 8.4×108 C-14 4.0×101 1.1×103 3.0 8.1×101 1.6×10−1 4.5 Ca-41 Calcium (20) Unlimited...

  10. Studies of membrane topology of mitochondrial cholesterol hydroxylases CYPs 27A1 and 11A1

    Science.gov (United States)

    Mast, Natalia; Liao, Wei-Li; Turko, Illarion V.

    2010-01-01

    Mitochondrial cytochrome P450 enzymes (CYP or P450, EC 1.14.13.15) play an important role in metabolism of cholesterol. CYP27A1 hydroxylates cholesterol at position 27 and, thus, initiates cholesterol removal from many extrahepatic tissues. CYP11A1 is a steroidogenic P450 that converts cholesterol to pregnenolone, the first step in the biosynthesis of all steroid hormones. We utilized a new approach to study membrane topology of CYPs 27A1 and 11A1. This approach involves heterologous expression of membrane-bound P450 in E. coli, isolation of the P450-containing E. coli membranes, treatment of the membranes with protease, removal of the digested soluble portion and extraction of the membrane-associated peptides, which are then identified by mass spectrometry. By using this approach, we found four membrane-interacting peptides in CYP27A1, and two peptides in CYP11A1. Peptides in CYP27A1 represent a contiguous portion of the polypeptide chain (residues 210-251) corresponding to the putative F-G loop and adjacent portions of the F and G helices. Peptides in CYP11A1 are from the putative F-G loop (residues 218-225) and the C-terminal portion of the G helix (residues 238-250). This data is consistent with those obtained previously by us and others and provide new information about membrane topology of CYPs 27A1 and 11A1. PMID:18791760

  11. Greater adenosine A2A receptor densities in cardiac and skeletal muscle in endurance-trained men: a [11C]TMSX PET study

    International Nuclear Information System (INIS)

    Mizuno, Masaki; Kimura, Yuichi; Tokizawa, Ken; Ishii, Kenji; Oda, Keiichi; Sasaki, Toru; Nakamura, Yoshio; Muraoka, Isao; Ishiwata, Kiichi

    2005-01-01

    We examined the densities of adenosine A 2A receptors in cardiac and skeletal muscles between untrained and endurance-trained subjects using positron emission tomography (PET) and [7-methyl- 11 C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([ 11 C]TMSX), a newly developed radioligand for mapping adenosine A 2A receptors. Five untrained and five endurance-trained subjects participated in this study. The density of adenosine A 2A receptors was evaluated as the distribution volume of [ 11 C]TMSX in cardiac and triceps brachii muscles in the resting state using PET. The distribution volume of [ 11 C]TMSX in the myocardium was significantly greater than in the triceps brachii muscle in both groups. Further, distribution volumes [ 11 C]TMSX in the trained subjects were significantly grater than those in untrained subjects (myocardium, 3.6±0.3 vs. 3.1±0.4 ml g -1 ; triceps brachii muscle, 1.7±0.3 vs. 1.2±0.2 ml g -1 , respectively). These results indicate that the densities of adenosine A 2A receptors in the cardiac and skeletal muscles are greater in the endurance-trained men than in the untrained men

  12. Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway.

    Science.gov (United States)

    Canas, Paula M; Porciúncula, Lisiane O; Cunha, Geanne M A; Silva, Carla G; Machado, Nuno J; Oliveira, Jorge M A; Oliveira, Catarina R; Cunha, Rodrigo A

    2009-11-25

    Alzheimer's disease (AD) is characterized by memory impairment, neurochemically by accumulation of beta-amyloid peptide (namely Abeta(1-42)) and morphologically by an initial loss of nerve terminals. Caffeine consumption prevents memory dysfunction in different models, which is mimicked by antagonists of adenosine A(2A) receptors (A(2A)Rs), which are located in synapses. Thus, we now tested whether A(2A)R blockade prevents the early Abeta(1-42)-induced synaptotoxicity and memory dysfunction and what are the underlying signaling pathways. The intracerebral administration of soluble Abeta(1-42) (2 nmol) in rats or mice caused, 2 weeks later, memory impairment (decreased performance in the Y-maze and object recognition tests) and a loss of nerve terminal markers (synaptophysin, SNAP-25) without overt neuronal loss, astrogliosis, or microgliosis. These were prevented by pharmacological blockade [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261); 0.05 mg . kg(-1) . d(-1), i.p.; for 15 d] in rats, and genetic inactivation of A(2A)Rs in mice. Moreover, these were synaptic events since purified nerve terminals acutely exposed to Abeta(1-42) (500 nm) displayed mitochondrial dysfunction, which was prevented by A(2A)R blockade. SCH58261 (50 nm) also prevented the initial synaptotoxicity (loss of MAP-2, synaptophysin, and SNAP-25 immunoreactivity) and subsequent loss of viability of cultured hippocampal neurons exposed to Abeta(1-42) (500 nm). This A(2A)R-mediated control of neurotoxicity involved the control of Abeta(1-42)-induced p38 phosphorylation and was independent from cAMP/PKA (protein kinase A) pathway. Together, these results show that A(2A)Rs play a crucial role in the development of Abeta-induced synaptotoxicity leading to memory dysfunction through a p38 MAPK (mitogen-activated protein kinase)-dependent pathway and provide a molecular basis for the benefits of caffeine consumption in AD.

  13. Differential effects of presynaptic versus postsynaptic adenosine A2A receptor blockade on Δ9-tetrahydrocannabinol (THC) self-administration in squirrel monkeys.

    Science.gov (United States)

    Justinová, Zuzana; Redhi, Godfrey H; Goldberg, Steven R; Ferré, Sergi

    2014-05-07

    Different doses of an adenosine A2A receptor antagonist MSX-3 [3,7-dihydro-8-[(1E)-2-(3-ethoxyphenyl)ethenyl]-7 methyl-3-[3-(phosphooxy)propyl-1-(2 propynil)-1H-purine-2,6-dione] were found previously to either decrease or increase self-administration of cannabinoids delta-9-tetrahydrocannabinol (THC) or anandamide in squirrel monkeys. It was hypothesized that the decrease observed with a relatively low dose of MSX-3 was related to blockade of striatal presynaptic A2A receptors that modulate glutamatergic neurotransmission, whereas the increase observed with a higher dose was related to blockade of postsynaptic A2A receptors localized in striatopallidal neurons. This hypothesis was confirmed in the present study by testing the effects of the preferential presynaptic and postsynaptic A2A receptor antagonists SCH-442416 [2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] and KW-6002 [(E)-1, 3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione], respectively, in squirrel monkeys trained to intravenously self-administer THC. SCH-442416 produced a significant shift to the right of the THC self-administration dose-response curves, consistent with antagonism of the reinforcing effects of THC. Conversely, KW-6002 produced a significant shift to the left, consistent with potentiation of the reinforcing effects of THC. These results show that selectively blocking presynaptic A2A receptors could provide a new pharmacological approach to the treatment of marijuana dependence and underscore corticostriatal glutamatergic neurotransmission as a possible main mechanism involved in the rewarding effects of THC.

  14. Activation of Adenosine Receptor A2A Increases HSC Proliferation and Inhibits Death and Senescence by Down-regulation of p53 and Rb

    Directory of Open Access Journals (Sweden)

    Md. Kaimul eAhsan

    2014-04-01

    Full Text Available Background & Aims: During fibrosis hepatic stellate cells (HSC undergo activation, proliferation and senescence but the regulation of these important processes is poorly understood. The adenosine A2A receptor (A2A is known to be present on HSC, and its activation results in liver fibrosis. In this study, we tested if A2A has a role in the regulation of HSC proliferation, apoptosis, senescence, and the relevant molecular mechanism.Methods: The ability of adenosine to regulate p53 and Rb protein levels, proliferation, apoptosis and senescence was tested in the human HSC cell line LX-2 and rat primary HSC.Results: Adenosine receptor activation down-regulates p53 and Rb protein levels, increases BrdU incorporation and increases cell survival in LX-2 cells and in primary rat HSC. These effects of NECA were reproduced by an adenosine A2A receptor specific agonist (CGS21680 and blocked by a specific antagonist (ZM241385. By day twenty-one of culture primary rat HSC entered senescence and expressed -gal which was significantly inhibited by NECA. Furthermore, NECA induced down regulation of p53 and Rb and Rac1, and decreased phosphorylation of p44-42 MAP Kinase in LX-2 cells and primary rat HSC. These effects were reproduced by the cAMP analog 8-Bromo-cAMP, and the adenylyl cyclase activator forskolin, and were blocked by PKA inhibitors.Conclusions: These results demonstrate that A2A receptor regulates a number of HSC fate decisions and induces greater HSC proliferation, reduces apoptosis and senescence by decreasing p53 and Rb through cAMP-PKA/Rac1/p38 MAPK pathway. This provides a mechanism for adenosine induced HSC regulation and liver fibrosis.

  15. Decommissioning of NPP A1 - HWGCR type

    International Nuclear Information System (INIS)

    Burclova, J.

    1998-01-01

    Prototype nuclear power plant A-1 located at Jaslovske Bohunice, was a HWGCR with channel type reactor KS 150 (refuelling during operation) and capacity of 143 MWe. Single unit has been constructed with reactor hall building containing reactor vessel, heavy water system and equipment for spent fuel handling. Another compartment of main building contents coolant system piping, six steam generators and six turbo compressors, the turbine hall was equipped by three turbines. Unit also shares liquid radwaste treatment and storage buildings and ventilation systems including chimney. It started operation in 1972 and was shutdown in 1977 after primary coolant system integrity accident. In 1979 a final decision was made to decommission this plant. The absence of waste treatment technologies and repository and not sufficient storage capacity affected the planning and realization of decommissioning for NPP A-1. The decommissioning policy for the first stage is for lack of regulations based on 'case by case' strategy. For these reasons and for not existence of Decommissioning Found until 1995 the preferred decommissioning option is based on differed decommissioning with safe enclosure of confinement. Transfer of undamaged spent fuel cooled in organic coolant to Russia was finished in 1990. It was necessary to develop new technology for the damaged fuel preparation for transport. The barriers check-up and dismantling of secondary circuit and cooling towers was performed during 1989/90. The complex plan for the first phase of A-1 decommissioning - the status with treated operational radwaste, removed contamination and restored treated waste and spent fuel (in case of interruption of transfer to Russia) was developed in 1993-1994. Under this project bituminization of all liquid operational radwaste (concentrates) was performed during 1995/96, vitrification of inorganic spent fuel coolant started at 1996, decontamination of spent fuel pool coolant occurs (under AEA Technology

  16. Hyperparathyroidism complicating CYP 24A1 mutations.

    Science.gov (United States)

    Loyer, Camille; Leroy, Clara; Molin, Arnaud; Odou, Marie-Françoise; Huglo, Damien; Lion, Georges; Ernst, Olivier; Hoffmann, Maxime; Porchet, Nicole; Carnaille, Bruno; Pattou, François; Kottler, Marie-Laure; Vantyghem, Marie-Christine

    2016-10-01

    CYP24A1 gene mutations induce infantile hypercalcemia, with high 1,25(OH) 2 D contrasting with low PTH levels. The adult phenotype is not well known. Two unrelated adult patients were referred for nephrolithiasis, hypertension, hypercalcemia, hypercalciuria, normal 25-OHD levels, and inappropriate PTH levels (22 to 92pg/mL;N: 15-68) suggesting primary hyperparathyroidism, leading to surgery. Hypercalciuria improved despite persistent hypercalcemia, treated with cinacalcet. The ratio 25-OHD 3 /24-25-(OH)2D 3 >100 (Nhyperparathyroidism with moderately increased PTH level, adenoma and/or slightly increased parathyroid glands. Surgery decreased calciuria and improved kidney function. Cinacalcet was partially effective on hypercalcemia since PTH was inappropriate. This novel phenotype, a phenocopy of hyperparathyroidism, might evolve in few cases towards hyperparathyroidism despite random association of the 2 diseases cannot be excluded. Copyright © 2016. Published by Elsevier Masson SAS.

  17. Ultraviolet A1 phototherapy: One center's experience

    Directory of Open Access Journals (Sweden)

    Sasi Kiran Attili

    2017-01-01

    Full Text Available Background: Ultraviolet A1(UVA1 phototherapy is increasingly being used in the treatment of morphea, atopic dermatitis, lupus and some other recalcitrant dermatoses. We present a retrospective review of our experience with this modality. Aim: To evaluate the treatment response rates for various dermatoses and adverse effects of UVA1 phototherapy. Methods: We reviewed phototherapy notes along with electronic and/or paper case records for all patients treated with UVA1 phototherapy from October 1996 to December 2008. Results: A total of 269 patients (outcomes available for 247 had 361 treatment courses (treatment data available for 317 courses over this period. We found phototherapy to be beneficial in 28 (53% of 53 patients with atopic dermatitis and 19 (51% of 37 patients with morphea. A beneficial outcome was recorded in all six (100% cases of urticaria and six (85.7% of seven patients treated for a polymorphic light eruption. Benefit was also recorded in systemic lupus erythematosus (8 (44.4% of 18, lichen sclerosus (6 (42.9% of 14, mastocytosis (2 (33.3% of 6, necrobiosis lipoidica (4 (30.8% of 13, granuloma annulare (2 (25% of 8, scleroderma (2 (22.2% of 9 and keloids (1 (7.7% of 13. Overall, treatment was well tolerated with no patients having to stop treatment due to adverse effects. Limitations: This is a retrospective study with no control group. Subjective/recall bias is quite possible as a number of patients were followed up over the phone. Conclusions: Our data suggest that ultraviolet A1 can be considered for the treatment of selected dermatoses. However, long-term malignancy risk is as yet unknown.

  18. Combining MOD10A1 and MYD10A1 Images For Snow Cover Area Monitoring

    Science.gov (United States)

    Tekeli, A. E.

    2008-12-01

    MOD10A1 and MYD10A1 daily snow cover maps at 500 m resolution are available from MODIS sensors on Terra and Aqua satellites. Aqua obtains the image of same region approximately three hours after Terra over Turkey region. MODIS is an optic sensor and cloud cover degrades the usability of derived snow cover maps. Moreover, spectral similarity between clouds and snow complicates their separability in visible imagery. Fortunately, dynamic behavior of clouds enables their discrimination from snow stationary on the surface. Combined use of MOD10A1 and MYD10A1 images mostly reduces the cloud cover present in one image alone and provides better representation of surface snow cover. Comparison of merged images with in situ data indicated higher hit ratios. The individual comparison of MOD10A1 and MYD10A1 images with ground data each yielded 31% hit ratio whereas, the merged images provided 38%. One-day shifts in comparisons increased hit ratios to 52 % and 46% whereas and two-day shifts gave 77 % and 79 % for MOD10A1 and MYD10A1 respectively. Merged maps yielded 54% and 83% for one and two day shifts. The improvement provided by the merging technique is found to be 7% for the present day, 7 % for one- day and 5% for two-day shifts for the whole season. Monthly decomposition resulted 25% improvement as the maximum. The snow cover product obtained by merging Terra and Aqua satellites provided higher hit ratios, as expected.

  19. Lumbar sympathectomy reduces vascular permeability, possibly through decreased adenosine receptor A2a expression in the hind plantar skin of rats.

    Science.gov (United States)

    Zheng, Zhifang; Liu, Yishu; Zhu, Lulu; Tang, Jianbing; Huang, Wenhua; Cheng, Biao

    2018-01-01

    The effect of lumbar sympathectomy for the treatment of lower limb ischemia remains a matter of controversy. Sprague-Dawley rats were subjected to lumbar sympathectomy, after which Evans blue dye was injected into the hind plantar skin. Extravasation of dye was measured and compared with rats undergoing sham operation. Hind plantar skin was processed for HE staining, immunohistochemistry, and Western blot. In sympathectomized rats, blue stained areas in hind plantar skin and concentrations of Evans blue were significantly less than that of sham sympathectomy (control) rats, both 2 weeks and 3 months after surgery. Expression of prostaglandin E2, bradykinin, bradykinin B2 receptor, and adenosine triphosphate were not significantly different between the sympathectomized and control groups. Adenosine receptor A2a expression was significantly reduced in the sympathectomized group both 2 weeks and 3 months after surgery. Vascular permeability in the hind plantar skin of rats decreases following lumbar sympathectomy, possibly via reduced expression of adenosine receptor A2a.

  20. Treadmill desks: A 1-year prospective trial.

    Science.gov (United States)

    Koepp, Gabriel A; Manohar, Chinmay U; McCrady-Spitzer, Shelly K; Ben-Ner, Avner; Hamann, Darla J; Runge, Carlisle F; Levine, James A

    2013-04-01

    Sedentariness is associated with weight gain and obesity. A treadmill desk is the combination of a standing desk and a treadmill that allow employees to work while walking at low speed. The hypothesis was that a 1-year intervention with treadmill desks is associated with an increase in employee daily physical activity (summation of all activity per minute) and a decrease in daily sedentary time (zero activity). Employees (n = 36; 25 women, 11 men) with sedentary jobs (87 ± 27 kg, BMI 29 ± 7 kg/m(2) , n = 10 Lean BMI 30 kg/m(2) ) volunteered to have their traditional desk replaced with a treadmill desk to promote physical activity for 1 year. Daily physical activity (using accelerometers), work performance, body composition, and blood variables were measured at Baseline and 6 and 12 months after the treadmill desk intervention. Subjects who used the treadmill desk increased daily physical activity from baseline 3,353 ± 1,802 activity units (AU)/day to, at 6 months, 4,460 ± 2,376 AU/day (P office workers without affecting work performance. Copyright © 2012 The Obesity Society.

  1. A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep.

    Science.gov (United States)

    Rétey, J V; Adam, M; Khatami, R; Luhmann, U F O; Jung, H H; Berger, W; Landolt, H-P

    2007-05-01

    Caffeine is the most widely used stimulant in Western countries. Some people voluntarily reduce caffeine consumption because it impairs the quality of their sleep. Studies in mice revealed that the disruption of sleep after caffeine is mediated by blockade of adenosine A2A receptors. Here we show in humans that (1) habitual caffeine consumption is associated with reduced sleep quality in self-rated caffeine-sensitive individuals, but not in caffeine-insensitive individuals; (2) the distribution of distinct c.1083T>C genotypes of the adenosine A2A receptor gene (ADORA2A) differs between caffeine-sensitive and -insensitive adults; and (3) the ADORA2A c.1083T>C genotype determines how closely the caffeine-induced changes in brain electrical activity during sleep resemble the alterations observed in patients with insomnia. These data demonstrate a role of adenosine A2A receptors for sleep in humans, and suggest that a common variation in ADORA2A contributes to subjective and objective responses to caffeine on sleep.

  2. Chronic methamphetamine treatment induces oxytocin receptor up-regulation in the amygdala and hypothalamus via an adenosine A2A receptor-independent mechanism.

    Science.gov (United States)

    Zanos, Panos; Wright, Sherie R; Georgiou, Polymnia; Yoo, Ji Hoon; Ledent, Catherine; Hourani, Susanna M; Kitchen, Ian; Winsky-Sommerer, Raphaelle; Bailey, Alexis

    2014-04-01

    There is mounting evidence that the neuropeptide oxytocin is a possible candidate for the treatment of drug addiction. Oxytocin was shown to reduce methamphetamine self-administration, conditioned place-preference, hyperactivity and reinstatement in rodents, highlighting its potential for the management of methamphetamine addiction. Thus, we hypothesised that the central endogenous oxytocinergic system is dysregulated following chronic methamphetamine administration. We tested this hypothesis by examining the effect of chronic methamphetamine administration on oxytocin receptor density in mice brains with the use of quantitative receptor autoradiographic binding. Saline (4ml/kg/day, i.p.) or methamphetamine (1mg/kg/day, i.p.) was administered daily for 10 days to male, CD1 mice. Quantitative autoradiographic mapping of oxytocin receptors was carried out with the use of [(125)I]-vasotocin in brain sections of these animals. Chronic methamphetamine administration induced a region specific upregulation of oxytocin receptor density in the amygdala and hypothalamus, but not in the nucleus accumbens and caudate putamen. As there is evidence suggesting an involvement of central adenosine A2A receptors on central endogenous oxytocinergic function, we investigated whether these methamphetamine-induced oxytocinergic neuroadaptations are mediated via an A2A receptor-dependent mechanism. To test this hypothesis, autoradiographic oxytocin receptor binding was carried out in brain sections of male CD1 mice lacking A2A receptors which were chronically treated with methamphetamine (1mg/kg/day, i.p. for 10 days) or saline. Similar to wild-type animals, chronic methamphetamine administration induced a region-specific upregulation of oxytocin receptor binding in the amygdala and hypothalamus of A2A receptor knockout mice and no genotype effect was observed. These results indicate that chronic methamphetamine use can induce profound neuroadaptations of the oxytocinergic receptor

  3. Evaluation of Immunoglobulin A1 (IgA1) Protease and IgA1 Protease-Inhibitory Activity in Human Female Genital Infection with Neisseria gonorrhoeae

    OpenAIRE

    Hedges, Spencer R.; Mayo, Matthew S.; Kallman, Lisa; Mestecky, Jiri; Hook, Edward W.; Russell, Michael W.

    1998-01-01

    Immunoglobulin A1 (IgA1) protease, an enzyme that selectively cleaves human IgA1, may be a virulence factor for pathogenic organisms such as Neisseria gonorrhoeae. Host protection from the effects of IgA1 protease includes antibody-mediated inhibition of IgA1 protease activity, and it is believed that the relative balance between IgA1 protease and inhibitory antibodies contributes to the pathogenesis of disease caused by IgA1 protease-producing organisms. We have examined the levels of these ...

  4. Evaluation of LLTR Series II tests A-1A and A-1B test results

    International Nuclear Information System (INIS)

    Shoopak, B.F.; Amos, J.C.; Norvell, T.J.

    1980-03-01

    The standard methodology, with minor modifications provides conservative yet realistic predictions of leaksite and other sodium system pressures in the LLTR Series II vessel and piping. The good agreement between predicted and measured pressures indicates that the TRANSWRAP/RELAP modeling developed from the Series I tests is applicable to larger scale units prototypical of the Clinch River steam generator design. Calculated sodium system pressures are sensitive to several modeling parameters including rupture disc modeling, acoustic velocity in the test vessel, and flow rate from the rupture tube. The acoustic velocity which produced best agreement with leaksite pressures was calculated based on the shroud diameter and shroud wall thickness. The corresponding rupture tube discharge coefficient was that of the standard design methodology developed from Series I testing. As found in Series I testing, the Series II data suggests that the leading edge of the flow in the relief line is two phase for a single, doubled-ended guillotine tube rupture. The steam generator shroud acts as if it is relatively transparent to the transmission of radial pressures to the vessel wall. Slightly lower sodium system maximum pressures measured during Test A-1b compared to Test A-1a are attributed to premature failure (failure at a lower pressure) of the rupture disc in contact with the sodium for test A-1b. The delay in failure of the second disc in Test A-1b, which was successfully modeled with TRANSWRAP, is attributed to the limited energy in the nitrogen injection

  5. The A1 adenosine receptor as a new player in microglia physiology.

    Science.gov (United States)

    Luongo, L; Guida, F; Imperatore, R; Napolitano, F; Gatta, L; Cristino, L; Giordano, C; Siniscalco, D; Di Marzo, V; Bellini, G; Petrelli, R; Cappellacci, L; Usiello, A; de Novellis, V; Rossi, F; Maione, S

    2014-01-01

    The purinergic system is highly involved in the regulation of microglial physiological processes. In addition to the accepted roles for the P2 X4,7 and P2 Y12 receptors activated by adenosine triphosphate (ATP) and adenosine diphosphate, respectively, recent evidence suggests a role for the adenosine A2A receptor in microglial cytoskeletal rearrangements. However, the expression and function of adenosine A1 receptor (A1AR) in microglia is still unclear. Several reports have demonstrated possible expression of A1AR in microglia, but a new study has refuted such evidence. In this study, we investigated the presence and function of A1AR in microglia using biomolecular techniques, live microscopy, live calcium imaging, and in vivo electrophysiological approaches. The aim of this study was to clarify the expression of A1AR in microglia and to highlight its possible roles. We found that microglia express A1AR and that it is highly upregulated upon ATP treatment. Moreover, we observed that selective stimulation of A1AR inhibits the morphological activation of microglia, possibly by suppressing the Ca(2+) influx induced by ATP treatment. Finally, we recorded the spontaneous and evoked activity of spinal nociceptive-specific neuron before and after application of resting or ATP-treated microglia, with or without preincubation with a selective A1AR agonist. We found that the microglial cells, pretreated with the A1AR agonist, exhibit lower capability to facilitate the nociceptive neurons, as compared with the cells treated with ATP alone. Copyright © 2013 Wiley Periodicals, Inc.

  6. Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment.

    Directory of Open Access Journals (Sweden)

    Yi-Ming Shao

    Full Text Available Parkinson's disease (PD is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects. In this study, new chemical entities targeting both human A2A adenosine receptor and dopamine D2 receptor were designed and evaluated. Two computational methods, namely support vector machine (SVM models and Tanimoto similarity-based clustering analysis, were integrated for the identification of compounds containing indole-piperazine-pyrimidine (IPP scaffold. Subsequent synthesis and testing resulted in compounds 5 and 6, which acted as human A2A adenosine receptor binders in the radioligand competition assay (Ki = 8.7-11.2 μM as well as human dopamine D2 receptor binders in the artificial cell membrane assay (EC50 = 22.5-40.2 μM. Moreover, compound 5 showed improvement in movement and mitigation of the loss of dopaminergic neurons in Drosophila models of PD. Furthermore, in vitro toxicity studies on compounds 5 and 6 did not reveal any mutagenicity (up to 100 μM, hepatotoxicity (up to 30 μM or cardiotoxicity (up to 30 μM.

  7. Comparison of palmar fixed-angle plate fixation with K-wire fixation of distal radius fractures (AO A2, A3, C1) in elderly patients.

    Science.gov (United States)

    Goehre, F; Otto, W; Schwan, S; Mendel, T; Vergroesen, P P; Lindemann-Sperfeld, L

    2014-03-01

    The objective of this prospective, randomized, controlled trial was to compare the results of two operative techniques used for the treatment of unstable distal radius fractures in elderly patients classified as AO types A2, A3, and C1. Patients were treated with either fixed-angle volar plates or K-wires using a combined Kapandji and Willenegger technique. The functional results were determined after 3, 6, and 12 months. We included 40 patients aged over 65 years. Twenty-one patients were treated with plate fixation and 19 with K-wire fixation. The functional results, after 1 year, were nearly the same in both treatment groups, suggesting that either method is suitable for the treatment of unstable distal radius fractures of AO types A2, A3, and C1 in elderly patients. Sixteen of 21 patients with plate fixation and 17 of 19 patients with K-wire fixation present good results as assessed by the Castaing score. The median DASH score was three in both groups after 1 year. The patients with plate fixation were able to resume activities of daily living 4 weeks earlier. The most common complication was an intermediate post-traumatic median nerve irritation. Both methods are suitable for the treatment of elderly patients with unstable distal radius fractures of AO types A2, A3, and C1. If early functional post-operative care is important, palmar fixed-angle plate fixation is an ideal treatment approach. Otherwise, K-wire fixation is an effective, minimally invasive method with comparable clinical results.

  8. Evaluation of Immunoglobulin A1 (IgA1) Protease and IgA1 Protease-Inhibitory Activity in Human Female Genital Infection with Neisseria gonorrhoeae

    Science.gov (United States)

    Hedges, Spencer R.; Mayo, Matthew S.; Kallman, Lisa; Mestecky, Jiri; Hook, Edward W.; Russell, Michael W.

    1998-01-01

    Immunoglobulin A1 (IgA1) protease, an enzyme that selectively cleaves human IgA1, may be a virulence factor for pathogenic organisms such as Neisseria gonorrhoeae. Host protection from the effects of IgA1 protease includes antibody-mediated inhibition of IgA1 protease activity, and it is believed that the relative balance between IgA1 protease and inhibitory antibodies contributes to the pathogenesis of disease caused by IgA1 protease-producing organisms. We have examined the levels of these two opposing factors in genital tract secretions and sera from women with uncomplicated infection with N. gonorrhoeae. When IgA1 in cervical mucus was examined by Western blotting, no evidence of cleavage fragments characteristic of IgA1 protease activity was seen in gonococcus-infected or control patients. Cleavage fragments typical of IgA1 protease were detected, however, after the addition of exogenous IgA1 protease to cervical mucus. Degraded IgA1 was detected in some vaginal wash samples, but the fragment pattern was not typical of IgA1 protease activity. All N. gonorrhoeae isolates from the infected patients produced IgA1 protease in vitro. All but two serum samples and 16 of 65 cervical mucus samples displayed inhibitory activity against gonococcal IgA1 protease, but there was no significant difference in the level of inhibitory activity between gonococcus-infected and noninfected patients in either cervical mucus or serum. There was no difference in the levels of IgA1 protease-inhibitory activity in serum or cervical mucus collected from patients at recruitment and 2 weeks later. These results suggest that cleavage of IgA1 by gonococcal IgA1 protease within the lumen of the female lower genital tract is unlikely to be a significant factor in the pathogenesis of infections by N. gonorrhoeae. PMID:9826361

  9. High frequency of the DRD2/ANKK1 A1 allele in Mexican Native Amerindians and Mestizos and its association with alcohol consumption.

    Science.gov (United States)

    Panduro, Arturo; Ramos-Lopez, Omar; Campollo, Octavio; Zepeda-Carrillo, Eloy Alfonso; Gonzalez-Aldaco, Karina; Torres-Valadez, Rafael; Roman, Sonia

    2017-03-01

    Mexico has an ancient tradition of alcohol drinking influenced by genetic and sociocultural factors. This study aimed to determine the distribution of the DRD2/ANKK1 TaqIA polymorphism in Mexican populations and to analyze its association with heavy drinking. In a cross-sectional and analytical study, 680 unrelated subjects including two Native Amerindians groups (87 Nahuas and 139 Huicholes), and two Mestizos groups (158 subjects from Tepic, Nayarit and 296 subjects from Guadalajara, Jalisco) were enrolled. DRD2/ANKK1 genotyping was performed by PCR-RFLP and allelic discrimination assays. Genetic analyses were conducted by Arlequin and Structure software. Heavy drinking was defined as ≥300g alcohol/week. The association of the DRD2/ANKK1 TaqIA polymorphism with heavy drinking was estimated. Heavy drinking was prevalent in 64.7% of the study population. The DRD2/ANKK1 A1 allele prevailed in 67% and 65% of Nahuas and Huicholes, respectively and 51% and 47.3% in Mestizos from Tepic and Guadalajara, respectively. Heavy drinking was associated with the A1A1 genotype in the Mestizos of Guadalajara (A1A1 vs. A1A2 OR=4.79, 95%CI 1.81-12.68, p=0.0006; A1A1 vs. A1A2+A2A2, OR=4.09, 95%CI 1.56-10.68, p=0.0021) and in the Mestizos from Tepic (A1A1 vs. A1A2, OR=5.92, 95%CI 2.12-16.49, p=0.0002); A2A2, OR=14.56, 95%CI 3.57-59.24, p=0.00004); A1A2+A2A2, OR=6.68, 95%CI 2.42-18.42, p=0.00005). In Native Amerindians, a lack of association was found. High frequencies of the DRD2/ANKK1 A1 allele were present in Mexican populations. Native Amerindians exhibited the highest frequencies of the A1 allele documented worldwide to date. The A1A1 genotype was associated with heavy drinking in Mestizos. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Guía de aplicación de la Escala Leonhardt para niños ciegos de 0 a 2 años

    OpenAIRE

    Leonhardt Gallego, Mercè; Forns, María

    2007-01-01

    La escala Leonhardt-2003 consta de 195 items, organizados en cinco parámetros que se corresponden con distintas áreas de desarrollo aplicadas a niños ciegos de 0 a 2 años. Fue elaborada a partir del desarrollo de niños ciegos congénitos nacidos a término y niños ciegos congénitos prematuros sin deficiencias asociadas.La escala pretende tener un valor diagnóstico y mide postura-motricidad, sentido auditivo, sentido táctil y motricidad fina, desarrollo cognitivo y hábitos.

  11. 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine inhibit TNF-α and CXCL10 production from activated primary murine microglia via A2A receptors.

    Science.gov (United States)

    Newell, Elizabeth A; Exo, Jennifer L; Verrier, Jonathan D; Jackson, Travis C; Gillespie, Delbert G; Janesko-Feldman, Keri; Kochanek, Patrick M; Jackson, Edwin K

    2015-01-12

    Some cells, tissues and organs release 2',3'-cAMP (a positional isomer of 3',5'-cAMP) and convert extracellular 2',3'-cAMP to 2'-AMP plus 3'-AMP and convert these AMPs to adenosine (called the extracellular 2',3'-cAMP-adenosine pathway). Recent studies show that microglia have an extracellular 2',3'-cAMP-adenosine pathway. The goal of the present study was to investigate whether the extracellular 2',3'-cAMP-adenosine pathway could have functional consequences on the production of cytokines/chemokines by activated microglia. Experiments were conducted in cultures of primary murine microglia. In the first experiment, the effect of 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine on LPS-induced TNF-α and CXCL10 production was determined. In the next experiment, the first protocol was replicated but with the addition of 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX) (0.1 μM; antagonist of adenosine receptors). The last experiment compared the ability of 2-chloro-N(6)-cyclopentyladenosine (CCPA) (10 μM; selective A1 agonist), 5'-N-ethylcarboxamide adenosine (NECA) (10 μM; agonist for all adenosine receptor subtypes) and CGS21680 (10 μM; selective A2A agonist) to inhibit LPS-induced TNF-α and CXCL10 production. (1) 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine similarly inhibited LPS-induced TNF-α and CXCL10 production; (2) DPSPX nearly eliminated the inhibitory effects of 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine on LPS-induced TNF-α and CXCL10 production; (3) CCPA did not affect LPS-induced TNF-α and CXCL10; (4) NECA and CGS21680 similarly inhibited LPS-induced TNF-α and CXCL10 production. 2',3'-cAMP and its metabolites (3'-AMP, 2'-AMP and adenosine) inhibit LPS-induced TNF-α and CXCL10 production via A2A-receptor activation. Adenosine and its precursors, via A2A receptors, likely suppress TNF-α and CXCL10 production by activated microglia in brain diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. 2’,3’-cAMP, 3’-AMP, 2’-AMP and Adenosine Inhibit TNF-α and CXCL10 Production From Activated Primary Murine Microglia via A2A Receptors

    Science.gov (United States)

    Newell, Elizabeth A.; Exo, Jennifer L.; Verrier, Jonathan D.; Jackson, Travis C.; Gillespie, Delbert G.; Janesko-Feldman, Keri; Kochanek, Patrick M.

    2014-01-01

    Background Some cells, tissues and organs release 2’,3’-cAMP (a positional isomer of 3’,5’-cAMP) and convert extracellular 2’,3’-cAMP to 2’-AMP plus 3’-AMP and convert these AMPs to adenosine (called the extracellular 2’,3’-cAMP-adenosine pathway). Recent studies show that microglia have an extracellular 2’,3’-cAMP-adenosine pathway. The goal of the present study was to investigate whether the extracellular 2’,3’-cAMP-adenosine pathway could have functional consequences on the production of cytokines/chemokines by activated microglia. Methods Experiments were conducted in cultures of primary murine microglia. In the first experiment, the effect of 2’,3’-cAMP, 3’-AMP, 2’-AMP and adenosine on LPS-induced TNF-α and CXCL10 production was determined. In the next experiment, the first protocol was replicated but with the addition of 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX) (0.1 µM; antagonist of adenosine receptors). The last experiment compared the ability of 2-chloro-N6-cyclopentyladenosine (CCPA) (10 µM; selective A1 agonist), 5’-N-ethylcarboxamide adenosine (NECA) (10 µM; agonist for all adenosine receptor subtypes) and CGS21680 (10 µM; selective A2A agonist) to inhibit LPS-induced TNF-α and CXCL10 production. Results 1) 2’,3’-cAMP, 3’-AMP, 2’-AMP and adenosine similarly inhibited LPS-induced TNF-α and CXCL10 production; 2) DPSPX nearly eliminated the inhibitory effects of 2’,3’-cAMP, 3’-AMP, 2’-AMP and adenosine on LPS-induced TNF-α and CXCL10 production; 3) CCPA did not affect LPS-induced TNF-α and CXCL10; 4) NECA and CGS21680 similarly inhibited LPS-induced TNF-α and CXCL10 production. Conclusions 2’,3’-cAMP and its metabolites (3’-AMP, 2’-AMP and adenosine) inhibit LPS-induced TNF-α and CXCL10 production via A2A-receptor activation. Adenosine and its precursors, via A2A receptors, likely suppress TNF-α and CXCL10 production by activated microglia in brain diseases. PMID:25451117

  13. Polymorphisms of UGT1A1*6, UGT1A1*27 & UGT1A1*28 in three major ethnic groups from Malaysia.

    Science.gov (United States)

    Teh, L K; Hashim, H; Zakaria, Z A; Salleh, M Z

    2012-08-01

    Genetic polymorphisms of uridine diphosphate glucuronyltransferase 1A1 (UGT1A1) have been associated with a wide variation of responses among patients prescribed with irinotecan. Lack of this enzyme is known to be associated with a high incidence of severe toxicity. The objective of this study was to investigate the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28), which are associated with reduced enzyme activity and increased irinotecan toxicity, in the three main ethnic groups in Malaysia (Malays, Chinese and Indians). A total of 306 healthy unrelated volunteers were screened for UGT1A1*28, UGT1A1*6 and UGT1A1*27. Blood samples (5 ml) were obtained from each subject and DNA was extracted. PCR based methods were designed and validated for detection of UGT1A1*, UUGT1A1*27 and UUGT1A1*28. Direct DNA sequencing was performed to validate the results of randomly selected samples. Malays and Indian have two-fold higher frequency of homozygous of UGT1A1*28 (7TA/7TA) which was 8 and 8.8 per cent, respectively compared to the Chinese (4.9%). However, the distribution of UGT1A1*6 and UGT1A1*27 showed no significant differences among them. UGT1A1*27 which has not been detected in Caucasian and African American population, was found in the Malaysian Malays (3.33%) and Malaysian Chinese (2.0%). There was interethnic variability in the frequency of UGT1A1*28 in the Malaysian population. Our results suggest that genotyping of UUGT1A1*6, UGT1A1*28 and UGT1A1*27 need to be performed before patients are prescribed with irinotecan due to their high prevalence of allelic variant which could lead to adverse drug reaction.

  14. Ex vivo lung perfusion with adenosine A2A receptor agonist allows prolonged cold preservation of lungs donated after cardiac death.

    Science.gov (United States)

    Wagner, Cynthia E; Pope, Nicolas H; Charles, Eric J; Huerter, Mary E; Sharma, Ashish K; Salmon, Morgan D; Carter, Benjamin T; Stoler, Mark H; Lau, Christine L; Laubach, Victor E; Kron, Irving L

    2016-02-01

    Ex vivo lung perfusion has been successful in the assessment of marginal donor lungs, including donation after cardiac death (DCD) donor lungs. Ex vivo lung perfusion also represents a unique platform for targeted drug delivery. We sought to determine whether ischemia-reperfusion injury would be decreased after transplantation of DCD donor lungs subjected to prolonged cold preservation and treated with an adenosine A2A receptor agonist during ex vivo lung perfusion. Porcine DCD donor lungs were preserved at 4°C for 12 hours and underwent ex vivo lung perfusion for 4 hours. Left lungs were then transplanted and reperfused for 4 hours. Three groups (n = 4/group) were randomized according to treatment with the adenosine A2A receptor agonist ATL-1223 or the dimethyl sulfoxide vehicle: Infusion of dimethyl sulfoxide during ex vivo lung perfusion and reperfusion (DMSO), infusion of ATL-1223 during ex vivo lung perfusion and dimethyl sulfoxide during reperfusion (ATL-E), and infusion of ATL-1223 during ex vivo lung perfusion and reperfusion (ATL-E/R). Final Pao2/Fio2 ratios (arterial oxygen partial pressure/fraction of inspired oxygen) were determined from samples obtained from the left superior and inferior pulmonary veins. Final Pao2/Fio2 ratios in the ATL-E/R group (430.1 ± 26.4 mm Hg) were similar to final Pao2/Fio2 ratios in the ATL-E group (413.6 ± 18.8 mm Hg), but both treated groups had significantly higher final Pao2/Fio2 ratios compared with the dimethyl sulfoxide group (84.8 ± 17.7 mm Hg). Low oxygenation gradients during ex vivo lung perfusion did not preclude superior oxygenation capacity during reperfusion. After prolonged cold preservation, treatment of DCD donor lungs with an adenosine A2A receptor agonist during ex vivo lung perfusion enabled Pao2/Fio2 ratios greater than 400 mm Hg after transplantation in a preclinical porcine model. Pulmonary function during ex vivo lung perfusion was not predictive of outcomes after transplantation. Copyright

  15. Andrographolide protects liver cells from H2O2 induced cell death by upregulation of Nrf-2/HO-1 mediated via adenosine A2a receptor signalling.

    Science.gov (United States)

    Mittal, Smriti P K; Khole, Swati; Jagadish, Nidhi; Ghosh, Debjani; Gadgil, Vijay; Sinkar, Vilas; Ghaskadbi, Saroj S

    2016-11-01

    Andrographolide, principle constituent of Andrographis paniculata Nees is used in traditional medicine in Southeast Asia and is known to exhibit various biological activities. Its antioxidant activity is due to its ability to activate one of the antioxidant enzymes, heme oxygenase-1 (HO-1) which is regulated transcriptionally through Nrf-2. However, molecular mechanism underlying activation of Nrf-2/HO-1 has not yet been clearly understood. Protective effect of andrographolide against H2O2 induced cell death, reactive oxygen species and lipid peroxidation was observed in HepG2 cells. Ability of andrographolide to modulate G-protein coupled receptor (GPCR) mediated signalling was determined using in silico docking and gene expression was analyzed by qRT-PCR, confocal microscopy and western blot analysis. We clearly show that andrographolide via adenosine A2A receptor signalling leads to activation of p38 MAP kinase, resulting in upregulation of Nrf-2, its translocation to nucleus and activation of HO-1. Additionally, it activates adenylate cyclase resulting in cAMP formation which in turn activates protein kinase A leading to inhibition of GSK-3β by phosphorylation. Inactivated GSK-3β leads to retention of Nrf-2 in the nucleus leading to sustained expression of HO-1 by binding to its antioxidant response element (ARE). Thus, andrographolide probably by binding to adenosine A2a receptor activates Nrf-2 transcription and also inhibits its exclusion from the nucleus by inactivating GSK-3β, together resulting in activation of HO-1. We speculate that andrographolide can be used as a therapeutic drug to combat oxidative stress implicated in pathogenesis of various diseases such as diabetes, osteoporosis, neurodegenerative diseases etc. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Online LI-rTMS during a Visual Learning Task: Differential Impacts on Visual Circuit and Behavioral Plasticity in Adult Ephrin-A2A5-/-Mice.

    Science.gov (United States)

    Poh, Eugenia Z; Harvey, Alan R; Makowiecki, Kalina; Rodger, Jennifer

    2018-01-01

    Repetitive transcranial magnetic stimulation (rTMS) induces plasticity in normal and abnormal neural circuitries, an effect that may be influenced by intrinsic brain activity during treatment. Here, we study potential synergistic effects between low-intensity rTMS (LI-rTMS) and concurrent neural activity in promoting circuit reorganization and enhancing visual behavior. We used ephrin-A2A5 -/- mice, which are known to possess visuotopic mapping errors that are ameliorated by LI-rTMS, and assessed the impact of stimulation when mice were engaged in a visual learning task. A detachable coil was affixed to each mouse, and animals underwent 2 wk of 10-min daily training in a two-choice visual discrimination task with concurrent LI-rTMS or sham stimulation. No-task controls (+LI-rTMS/sham) were placed in the task arena without visual task training. At the end of the experiment, visuomotor tracking behavior was assessed, and corticotectal and geniculocortical pathway organization was mapped by injections of fluorescent tracers into the primary visual cortex. Consistent with previous results, LI-rTMS alone improved geniculocortical and corticotectal topography, but combining LI-rTMS with the visual learning task prevented beneficial corticotectal reorganization and had no additional effect on geniculocortical topography or visuomotor tracking performance. Unexpectedly, there was a significant increase in the total number of trials completed by task + LI-rTMS mice in the visual learning task. Comparison with wild-type mice revealed that ephrin-A2A5 -/- mice had reduced accuracy and response rates, suggesting a goal-directed behavioral deficit, which was improved by LI-rTMS. Our results suggest that concurrent brain activity during behavior interacts with LI-rTMS, altering behavior and different visual circuits in an abnormal system.

  17. Excitatory effect of the A2A adenosine receptor agonist CGS-21680 on spontaneous and K+-evoked acetylcholine release at the mouse neuromuscular junction.

    Science.gov (United States)

    Palma, A G; Muchnik, S; Losavio, A S

    2011-01-13

    The mechanism of action of the A2A adenosine receptor agonist 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680) in the facilitation of spontaneous (isotonic and hypertonic condition) and K+-evoked acetylcholine (ACh) release was investigated in the mouse diaphragm muscles. At isotonic condition, the CGS-21680-induced excitatory effect on miniature end-plate potential (MEPP) frequency was not modified in the presence of CdCl2 and in a medium free of Ca2+ (0Ca2+-EGTA), but it was abolished after buffering the rise of intracellular Ca2+ with 1,2-bis-(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetra(acetoxy-methyl) (BAPTA-AM) and when the Ca2+-ATPase inhibitor thapsigargin was used to deplete intracellular Ca2+ stores. CGS-21680 did not have a direct effect on the Ca2+-independent neurotransmitter-releasing machinery, since the modulatory effect on the hypertonic response was also occluded by BAPTA-AM and thapsigargin. CGS-21680 facilitation on K+-evoked ACh release was not altered by the P/Q-type voltage-dependent calcium channel (VDCC) blocker ω-Agatoxin IVA, but it was completely prevented by both, the L-type VDCC blocker nitrendipine (which is known to immobilize their gating charges), or thapsigargin, suggesting that the effects of CGS-21680 on L-type VDCC and thapsigargin-sensitive internal stores are associated. We found that the VDCC pore blocker Cd2+ (2 mM Ca2+ or 0Ca2+-EGTA) failed to affect the CGS-21680 effect in high K+ whereas nitrendipine in 0Ca2+-EGTA+Cd2+ occluded its action. The blockade of Ca2+ release from endoplasmic reticulum with ryanodine antagonized the facilitating effect of CGS-21680 in control and high K+ concentration. It is concluded that, at the mouse neuromuscular junction, activation of A2A receptors facilitates spontaneous and K+-evoked ACh release by an external Ca2+-independent mechanism but that involves mobilization of Ca2+ from internal stores: during spontaneous ACh release

  18. Structure-Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A2A and A3 Adenosine Receptor Ligands

    Science.gov (United States)

    Hou, Xiyan; Majik, Mahesh S.; Kim, Kyunglim; Pyee, Yuna; Lee, Yoonji; Alexander, Varughese; Chung, Hwa-Jin; Lee, Hyuk Woo; Chandra, Girish; Lee, Jin Hee; Park, Seul-gi; Choi, Won Jun; Kim, Hea Ok; Phan, Khai; Gao, Zhan-Guo; Jacobson, Kenneth A.; Choi, Sun; Lee, Sang Kook; Jeong, Lak Shin

    2011-01-01

    Truncated N6-substituted-4′-oxo- and 4′-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A2A and A3 adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA2AAR, but hydrophobic C8 substitution abolished binding at the hA2AAR. However, most of synthesized compounds displayed medium to high binding affinity at the hA3AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA2AAR agonists. C2 substitution probed geometrically through hA2AAR-docking, was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA2AAR agonist and hA3AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases. PMID:22142423

  19. METABOTROPIC GLUTAMATE TYPE 5, DOPAMINE D2 AND ADENOSINE A2A RECEPTORS FORM HIGHER-ORDER OLIGOMERS IN LIVING CELLS

    Science.gov (United States)

    Cabello, Nuria; Gandía, Jorge; Bertarelli, Daniela C. G.; Watanabe, Masahiko; Lluís, Carme; Franco, Rafael; Ferré, Sergi; Luján, Rafael; Ciruela, Francisco

    2009-01-01

    G protein-coupled receptors are known to form homo- and heteromers at the plasma membrane, but the stoichiometry of these receptor oligomers are relatively unknown. Here, by using bimolecular fluorescence complementation, we visualized for the first time the occurrence of heterodimers of metabotropic glutamate mGlu5 receptors (mGlu5R) and dopamine D2 receptors (D2R) in living cells. Furthermore, the combination of bimolecular fluorescence complementation and bioluminescence resonance energy transfer techniques, as well as the sequential resonance energy transfer (SRET) technique, allowed us to detect the occurrence receptor oligomers containing more than two protomers, mGlu5R, D2R and adenosine A2A receptor (A2AR). Interestingly, by using high-resolution immunoelectron microscopy we could confirm that the three receptors co-distribute within the extrasynaptic plasma membrane of the same dendritic spines of asymmetrical, putative glutamatergic, striatal synapses. Also, co-immunoprecipitation experiments in native tissue demonstrated the existence of an association of mGlu5R, D2R and A2AR in rat striatum homogenates. Overall, these results provide new insights into the molecular composition of G protein-coupled receptor oligomers in general and the mGlu5R/D2R/A2AR oligomer in particular, a receptor oligomer that might constitute an important target for the treatment of some neuropsychiatric disorders. PMID:19344374

  20. Role of Adenosine A2A Receptors in Modulating Synaptic Functions and Brain Levels of BDNF: a Possible Key Mechanism in the Pathophysiology of Huntington's Disease

    Directory of Open Access Journals (Sweden)

    Maria Teresa Tebano

    2010-01-01

    Full Text Available In the last few years, accumulating evidence has shown the existence of an important cross-talk between adenosine A2A receptors (A2ARs and brain-derived neurotrophic factor (BDNF. Not only are A2ARs involved in the mechanism of transactivation of BDNF receptor TrkB, they also modulate the effect of BDNF on synaptic transmission, playing a facilitatory and permissive role. The cAMP-PKA pathway, the main transduction system operated by A2ARs, is involved in such effects. Furthermore, a basal tonus of A2ARs is required to allow the regulation of BDNF physiological levels in the brain, as demonstrated by the reduced protein levels measured in A2ARs KO mice. The crucial role of adenosine A2ARs in the maintenance of synaptic functions and BDNF levels will be reviewed here and discussed in the light of possible implications for Huntington's disease therapy, in which a joint impairment of BDNF and A2ARs seems to play a pathogenetic role.

  1. 29 CFR 2550.404a-1 - Investment duties.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 9 2010-07-01 2010-07-01 false Investment duties. 2550.404a-1 Section 2550.404a-1 Labor... FIDUCIARY RESPONSIBILITY § 2550.404a-1 Investment duties. (a) In general. Section 404(a)(1)(B) of the... use in the conduct of an enterprise of a like character and with like aims. (b) Investment duties. (1...

  2. 49 CFR 178.33a-1 - Compliance.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Compliance. 178.33a-1 Section 178.33a-1 Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS SAFETY... Specifications for Inside Containers, and Linings § 178.33a-1 Compliance. (a) Required in all details. (b...

  3. Working mechanism of immunoglobulin A1 (IgA1) protease: cleavage of IgA1 antibody to Neisseria meningitidis PorA requires de novo synthesis of IgA1 Protease

    DEFF Research Database (Denmark)

    Vidarsson, G; Overbeeke, N; Stemerding, AM

    2005-01-01

    Neisseria meningitidis secretes a protease that specifically cleaves the hinge region of immunoglobulin A1 (IgA1), releasing the effector (Fc) domain of IgA1 from the antigen binding (Fab) determinants. Theoretically, the remaining Fab fragments can block pathogen receptors or toxins and still...

  4. Adenosine A1 receptors in human sleep regulation studied by electroencephalography (EEG) and positron emission tomography (PET)

    International Nuclear Information System (INIS)

    Geissler, E.

    2007-01-01

    Sleep is an essential physiological process. However, the functions of sleep and the endogenous mechanisms involved in sleep regulation are only partially understood. Convergent lines of evidence support the hypothesis that the build-up of sleep propensity during wakefulness and its decline during sleep are associated with alterations in brain adenosine levels and adenosine receptor concentrations. The non-selective A 1 and A 2A adenosine receptor antagonist caffeine stimulates alertness and is known to attenuate changes in the waking and sleep electroencephalogram (EEG) typically observed after prolonged waking. Several findings point to an important function of the adenosine A 1 receptor (A 1 AR) in the modulation of vigilance states. The A 1 AR is densely expressed in brain regions involved in sleep regulation, and pharmacological manipulations affecting the A 1 AR were shown to influence sleep propensity and sleep depth. However, an involvement of the A 2A adenosine receptor (A 2A AR) is also assumed. The distinct functions of the A 1 and A 2A receptor subtypes in sleep-wake regulation and in mediating the effects of caffeine have not been identified so far. The selective adenosine A 1 receptor antagonist, 8-cyclopentyl-3-(3- 18 Ffluoropropyl)- 1-propylxanthine ( 18 F-CPFPX), offers the opportunity to get further insights into adenosinergic mechanisms by in vivo imaging of the A 1 AR subtype with positron emission tomography (PET). The aim of this thesis was to elucidate the role of adenosine A 1 receptors in human sleep regulation, combining 18 F-CPFPX PET brain imaging and EEG recordings, the gold standard in sleep research. It was hypothesized that sleep deprivation would induce adenosine accumulation and/or changes in A 1 AR density. Thus, the question was addressed whether these effects of prolonged wakefulness can be visualized by altered 18 F-CPFPX binding. Moreover, it was investigated whether radioligand uptake might be influenced by caffeine, since

  5. Selective A2A receptor antagonist prevents microglia-mediated neuroinflammation and protects retinal ganglion cells from high intraocular pressure-induced transient ischemic injury.

    Science.gov (United States)

    Madeira, Maria H; Boia, Raquel; Elvas, Filipe; Martins, Tiago; Cunha, Rodrigo A; Ambrósio, António Francisco; Santiago, Ana Raquel

    2016-03-01

    Glaucoma is a leading cause of vision loss and blindness worldwide, characterized by chronic and progressive neuronal loss. Reactive microglial cells have been recognized as a neuropathologic feature, contributing to local inflammation and retinal neurodegeneration. In a recent in vitro work (organotypic cultures), we demonstrated that blockade of adenosine A2A receptor (A2AR) prevents the neuroinflammatory response and affords protection to retinal ganglion cells (RGCs) against exposure to elevated hydrostatic pressure (EHP), to mimic elevated intraocular pressure (IOP), the main risk factor for glaucoma development. Herein, we investigated whether a selective A2AR antagonist (SCH 58261) could modulate retinal microglia reactivity and their inflammatory response. Furthermore, we took advantage of the high IOP-induced transient ischemia (ischemia-reperfusion, I-R) animal model to evaluate the protective role of A2AR blockade in the control of retinal neuroinflammation and neurodegeneration. Primary microglial cell cultures were challenged either with lipopolysaccharide or with EHP, in the presence or absence of A2AR antagonist SCH 58261 (50 nM). In addition, I-R injury was induced in adult Wistar rats after intravitreal administration of SCH 58261 (100 nM, 5 μL). Our results showed that SCH 58261 attenuated microglia reactivity and the increased expression and release of proinflammatory cytokines. Moreover, intravitreal administration of SCH 58261 prevented I-R-induced cell death and RGC loss, by controlling microglial-mediated neuroinflammatory response. These results prompt the proposal that A2AR blockade may have great potential in the management of retinal neurodegenerative diseases characterized by microglia reactivity and RGC death, such as glaucoma and ischemic diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. The Arabidopsis UGT87A2, a stress-inducible family 1 glycosyltransferase, is involved in the plant adaptation to abiotic stresses.

    Science.gov (United States)

    Li, Pan; Li, Yan-Jie; Wang, Bo; Yu, Hui-Min; Li, Qin; Hou, Bing-Kai

    2017-04-01

    Glycosyltransferase (GT) family-1, the biggest GT family in plants, typically participates in modification of small molecules and affects many aspects during plant development. In Arabidopsis thaliana, although some UDP glycosyltransferases (UGTs) of family-1 have been functionally characterized, functions of most the UGTs remain unknown or fragmentary. Here, we report data for the Arabidopsis UGT87A2, a stress-regulated GT. We found that UGT87A2 could be dramatically induced by salinity, osmotic stress, drought and ABA. Overexpression of UGT87A2 (87A2OE) leads to accelerated germination and greening, higher survival rate as well as increased root length against abiotic stresses compared with those of wild-type (WT) plants. In addition, we observed lower water loss rate in the 87A2OE plants due to smaller stomatal apertures. The transgenic plants also showed reduced levels of H 2 O 2 and superoxide under low water status compared with those of WT plants. Consistently, function loss of UGT87A2 in ugt87a2 knockout lines resulted in opposite performances under these conditions. A transcriptome profiling revealed that 121 genes were differentially regulated upon UGT87A2 overexpression, and a large number of stress-induced genes were upregulated in UGT87A2 overexpression plants. Expression of seven genes among them were assessed by quantitative real-time polymerase chain reaction (qRT-PCR), including CPK32, CYP81F2, MYB96, DREB2A, FBS1, PUB23 and RAV2 under both control and stress treatments, and the results greatly validated our transcriptome data. Taken together, our findings support an explicit role of UGT87A2 in adaptation to abiotic stresses. © 2016 Scandinavian Plant Physiology Society.

  7. Projections of nucleus accumbens adenosine A2A receptor neurons in the mouse brain and their implications in mediating sleep-wake regulation

    Directory of Open Access Journals (Sweden)

    Jianping eZhang

    2013-12-01

    Full Text Available Adenosine A2A receptors (A2ARs in the nucleus accumbens (Acb have been demonstrated to play an important role in the arousal effect of adenosine receptor antagonist caffeine, and may be involved in physiological sleep. To better understand the functions of these receptors in sleep, projections of A2AR neurons were mapped utilizing adeno-associated virus (AAV encoding humanized Renilla green fluorescent protein (hrGFP as a tracer for long axonal pathways. The Cre-dependent AAV was injected into the core (AcbC and shell (AcbSh of the Acb in A2AR-Cre mice. Immunohistochemistry was then used to visualize hrGFP, highlighting the perikarya of the A2AR neurons in the injection sites, and their axons in projection regions. The data revealed that A2AR neurons exhibit medium-sized and either round or elliptic perikarya with their processes within the Acb. Moreover, the projections from the Acb distributed to nuclei in the forebrain, diencephalon, and brainstem. In the forebrain, A2AR neurons from all Acb sub-regions jointly projected to the ventral pallidum, the nucleus of the diagonal band, and the substantia innominata. Heavy projections from the AcbC and the ventral AcbSh, and weaker projections from the medial AcbSh, were observed in the lateral hypothalamus and lateral preoptic area. In the brainstem, the Acb projections were found in the ventral tegmental area, while AcbC and ventral AcbSh also projected to the median raphe nucleus, the dorsal raphe nucleus, and the ventrolateral periaqueductal gray. The results supply a solid base for understanding the roles of the A2AR and A2AR neurons in the Acb, especially in the regulation of sleep.

  8. Col11a1 Regulates Bone Microarchitecture during Embryonic Development

    Directory of Open Access Journals (Sweden)

    Anthony Hafez

    2015-12-01

    Full Text Available Collagen XI alpha 1 (Col11a1 is an extracellular matrix molecule required for embryonic development with a role in both nucleating the formation of fibrils and regulating the diameter of heterotypic fibrils during collagen fibrillar assembly. Although found in many different tissues throughout the vertebrate body, Col11a1 plays an essential role in endochondral ossification. To further understand the function of Col11a1 in the process of bone formation, we compared skeletal mineralization in wild-type (WT mice and Col11a1-deficient mice using X-ray microtomography (micro-CT and histology. Changes in trabecular bone microstructure were observed and are presented here. Additionally, changes to the periosteal bone collar of developing long bones were observed and resulted in an increase in thickness in the case of Col11a1-deficient mice compared to WT littermates. Vertebral bodies were incompletely formed in the absence of Col11a1. The data demonstrate that Col11a1 depletion results in alteration to newly-formed bone and is consistent with a role for Col11a1 in mineralization. These findings indicate that expression of Col11a1 in the growth plate and perichondrium is essential for trabecular bone and bone collar formation during endochondral ossification. The observed changes to mineralized tissues further define the function of Col11a1.

  9. NF-κB is activated in CD4+ iNKT cells by sickle cell disease and mediates rapid induction of adenosine A2A receptors.

    Directory of Open Access Journals (Sweden)

    Gene Lin

    Full Text Available Reperfusion injury following tissue ischemia occurs as a consequence of vaso-occlusion that is initiated by activation of invariant natural killer T (iNKT cells. Sickle cell disease (SDC results in widely disseminated microvascular ischemia and reperfusion injury as a result of vaso-occlusion by rigid and adhesive sickle red blood cells. In mice, iNKT cell activation requires NF-κB signaling and can be inhibited by the activation of anti-inflammatory adenosine A2A receptors (A2ARs. Human iNKT cells are divided into subsets of CD4+ and CD4- cells. In this study we found that human CD4+ iNKT cells, but not CD4- cells undergo rapid NF-κB activation (phosphorylation of NF-κB on p65 and induction of A2ARs (detected with a monoclonal antibody 7F6-G5-A2 during SCD painful vaso-occlusive crises. These findings indicate that SCD primarily activates the CD4+ subset of iNKT cells. Activation of NF-κB and induction of A2ARs is concordant, i.e. only CD4+ iNKT cells with activated NF-κB expressed high levels of A2ARs. iNKT cells that are not activated during pVOC express low levels of A2AR immunoreactivity. These finding suggest that A2AR transcription may be induced in CD4+ iNKT cells as a result of NF-κB activation in SCD. In order to test this hypothesis further we examined cultured human iNKT cells. In cultured cells, blockade of NF-κB with Bay 11-7082 or IKK inhibitor VII prevented rapid induction of A2AR mRNA and protein upon iNKT activation. In conclusion, NF-κB-mediated induction of A2ARs in iNKT cells may serve as a counter-regulatory mechanism to limit the extent and duration of inflammatory immune responses. As activated iNKT cells express high levels of A2ARs following their activation, they may become highly sensitive to inhibition by A2AR agonists.

  10. Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A2A-Dopamine D2 Receptor Heterotetramers and Adenylyl Cyclase

    Directory of Open Access Journals (Sweden)

    Sergi Ferré

    2018-04-01

    Full Text Available The central adenosine system and adenosine receptors play a fundamental role in the modulation of dopaminergic neurotransmission. This is mostly achieved by the strategic co-localization of different adenosine and dopamine receptor subtypes in the two populations of striatal efferent neurons, striatonigral and striatopallidal, that give rise to the direct and indirect striatal efferent pathways, respectively. With optogenetic techniques it has been possible to dissect a differential role of the direct and indirect pathways in mediating “Go” responses upon exposure to reward-related stimuli and “NoGo” responses upon exposure to non-rewarded or aversive-related stimuli, respectively, which depends on their different connecting output structures and their differential expression of dopamine and adenosine receptor subtypes. The striatopallidal neuron selectively expresses dopamine D2 receptors (D2R and adenosine A2A receptors (A2AR, and numerous experiments using multiple genetic and pharmacological in vitro, in situ and in vivo approaches, demonstrate they can form A2AR-D2R heteromers. It was initially assumed that different pharmacological interactions between dopamine and adenosine receptor ligands indicated the existence of different subpopulations of A2AR and D2R in the striatopallidal neuron. However, as elaborated in the present essay, most evidence now indicates that all interactions can be explained with a predominant population of striatal A2AR-D2R heteromers forming complexes with adenylyl cyclase subtype 5 (AC5. The A2AR-D2R heteromer has a tetrameric structure, with two homodimers, which allows not only multiple allosteric interactions between different orthosteric ligands, agonists, and antagonists, but also the canonical Gs-Gi antagonistic interaction at the level of AC5. We present a model of the function of the A2AR-D2R heterotetramer-AC5 complex, which acts as an integrative device of adenosine and dopamine signals that

  11. Blockade of adenosine A2A receptors prevents interleukin-1β-induced exacerbation of neuronal toxicity through a p38 mitogen-activated protein kinase pathway

    Directory of Open Access Journals (Sweden)

    Simões Ana

    2012-08-01

    Full Text Available Abstract Background and purpose Blockade of adenosine A2A receptors (A2AR affords robust neuroprotection in a number of brain conditions, although the mechanisms are still unknown. A likely candidate mechanism for this neuroprotection is the control of neuroinflammation, which contributes to the amplification of neurodegeneration, mainly through the abnormal release of pro-inflammatory cytokines such as interleukin(IL-1β. We investigated whether A2AR controls the signaling of IL-1β and its deleterious effects in cultured hippocampal neurons. Methods Hippocampal neuronal cultures were treated with IL-1β and/or glutamate in the presence or absence of the selective A2AR antagonist, SCH58261 (50 nmol/l. The effect of SCH58261 on the IL-1β-induced phosphorylation of the mitogen-activated protein kinases (MAPKs c-Jun N-terminal kinase (JNK and p38 was evaluated by western blotting and immunocytochemistry. The effect of SCH58261 on glutamate-induced neurodegeneration in the presence or absence of IL-1β was evaluated by nucleic acid and by propidium iodide staining, and by lactate dehydrogenase assay. Finally, the effect of A2AR blockade on glutamate-induced intracellular calcium, in the presence or absence of IL-1β, was studied using single-cell calcium imaging. Results IL-1β (10 to 100 ng/ml enhanced both JNK and p38 phosphorylation, and these effects were prevented by the IL-1 type 1 receptor antagonist IL-1Ra (5 μg/ml, in accordance with the neuronal localization of IL-1 type 1 receptors, including pre-synaptically and post-synaptically. At 100 ng/ml, IL-1β failed to affect neuronal viability but exacerbated the neurotoxicity induced by treatment with 100 μmol/l glutamate for 25 minutes (evaluated after 24 hours. It is likely that this resulted from the ability of IL-1β to enhance glutamate-induced calcium entry and late calcium deregulation, both of which were unaffected by IL-1β alone. The selective A2AR antagonist, SCH58261 (50 nmol

  12. Wind tunnel tests of the Risoe-A1-18, Risoe-A1-21 and Risoe-A1-24 airfoils

    Energy Technology Data Exchange (ETDEWEB)

    Fuglsang, P.; Dahl, K.S.; Antoniou, I.

    1999-06-01

    This report contains 2D measurements of the Risoe-A1-18, Risoe-A1-21 and Risoe-A1-24 airfoils. The aerodynamic properties were derived from pressure measurements on the airfoil surface and in the wake. The VELUX open jet wind tunnel was used having a background turbulence intensity of 1%, a flow velocity of 42 m/s and a Reynolds number of 1.6x10{sup 6}. The airfoil sections had a chord of 0.60 m and a span of 1.9 m and and plates were used to minimise 3D flow effects. The measurements comprised both static and dynamic inflow where dynamic inflow was obtained by pitching the airfoil in a harmonic motion. We tested the influence of leading edge roughness, vortex generators and Gurney flaps both individually and in combination. For smooth surface conditions, all three airfoils had the desirable properties of constant lift curve slope and low drag coefficient until the maximum lift of about 1.4 was reached. The Risoe-A1-18 airfoil had a smooth post stall whereas the Risoe-A1-21 and Risoe-A1-24 airfoils had a significant drop in the lift coefficient after stall. Test on all airfoil sections mounted with zigzag tape showed that the airfoils were insensitive to leading edge roughness. However with a drop in the maximum lift coefficient to about 1.2. Mounting of delta wing shaped vortex generators and Gurney flaps showed that there was room for a significant increase in the maximum lift coefficient, which was increased to 1.90 for Risoe-A1-24 with vortex generators located at 15% chord. The combination of vortex generators and Gurney flaps increased the maximum lift coefficient to about 2.0. (au) EFP-98. 16 tabs., 98 ills., 10 refs.

  13. Adenosine receptors in rat and human pancreatic ducts stimulate chloride transport

    DEFF Research Database (Denmark)

    Novak, Ivana; Hede, Susanne; Hansen, Mette

    2007-01-01

    adenocarcinoma lines showed that they express A(1), A(2A), A(2B), and A(3) receptors. Real-time PCR revealed relatively low messenger RNA levels of adenosine receptors compared to beta-actin; the rank order for the receptors was A(2A) > A(2B) >/= A(3) >> A(1) for rat pancreas and A(2B) > A(2A) >> A(3) >/= A(1......) for duct cell lines. Whole-cell patch-clamp recordings on rat pancreatic ducts showed that, in about half of the recordings, adenosine depolarized the membrane voltage, and this was because of the opening of Cl(-) channels. Using a Cl(-)-sensitive fluorophore and single-cell imaging on duct cell lines...

  14. Drugs affecting HbA1c levels

    Directory of Open Access Journals (Sweden)

    Ranjit Unnikrishnan

    2012-01-01

    Full Text Available Glycated hemoglobin (HbA1c is an important indicator of glycemic control in diabetes mellitus, based on which important diagnostic and therapeutic decisions are routinely made. However, there are several situations in which the level of HbA1c may not faithfully reflect the glycemic control in a given patient. Important among these is the use of certain non-diabetic medications, which can affect the HbA1c levels in different ways. This review focuses on the non-diabetic medications which can inappropriately raise or lower the HbA1c levels, and the postulated mechanisms for the same.

  15. Evidence for charged B meson decays to a1+/-(1260)pi0 and a1(0)(1260)pi+/-.

    Science.gov (United States)

    Aubert, B; Bona, M; Boutigny, D; Karyotakis, Y; Lees, J P; Poireau, V; Prudent, X; Tisserand, V; Zghiche, A; Garra Tico, J; Grauges, E; Lopez, L; Palano, A; Eigen, G; Stugu, B; Sun, L; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lopes Pegna, D; Lynch, G; Mir, L M; Orimoto, T J; Ronan, M T; Tackmann, K; Wenzel, W A; Del Amo Sanchez, P; Hawkes, C M; Watson, A T; Held, T; Koch, H; Lewandowski, B; Pelizaeus, M; Schroeder, T; Steinke, M; Walker, D; Asgeirsson, D J; Cuhadar-Donszelmann, T; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Khan, A; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Abachi, S; Buchanan, C; Foulkes, S D; Gary, J W; Liu, F; Long, O; Shen, B C; Zhang, L; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Schalk, T; Schumm, B A; Seiden, A; Wilson, M G; Winstrom, L O; Chen, E; Cheng, C H; Fang, F; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nagel, M; Nauenberg, U; Olivas, A; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Gabareen, A M; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Klose, V; Kobel, M J; Lacker, H M; Mader, W F; Nogowski, R; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Latour, E; Lombardo, V; Thiebaux, Ch; Verderi, M; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Franchini, P; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Santoro, V; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bard, D J; Dauncey, P D; Flack, R L; Nash, J A; Panduro Vazquez, W; Tibbetts, M; Behera, P K; Chai, X; Charles, M J; Mallik, U; Ziegler, V; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Lae, C K; Denig, A G; Fritsch, M; Schott, G; Arnaud, N; Béquilleux, J; Davier, M; Grosdidier, G; Höcker, A; Lepeltier, V; Le Diberder, F; Lutz, A M; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wang, W F; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Chavez, C A; Forster, I J; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; George, K A; Di Lodovico, F; Menges, W; Sacco, R; Cowan, G; Flaecher, H U; Hopkins, D A; Paramesvaran, S; Salvatore, F; Wren, A C; Brown, D N; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Salvati, E; Saremi, S; Cowan, R; Dujmic, D; Fisher, P H; Koeneke, K; Sciolla, G; Sekula, S J; Spitznagel, M; Taylor, F; Yamamoto, R K; Zhao, M; Zheng, Y; McLachlin, S E; Patel, P M; Robertson, S H; Lazzaro, A; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; De Nardo, G; Fabozzi, F; Lista, L; Monorchio, D; Sciacca, C; Baak, M A; Raven, G; Snoek, H L; Jessop, C P; Losecco, J M; Benelli, G; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Regensburger, J J; Wong, Q K; Blount, N L; Brau, J; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Gagliardi, N; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Ben-Haim, E; Briand, H; Calderini, G; Chauveau, J; David, P; Del Buono, L; de la Vaissière, Ch; Hamon, O; Leruste, Ph; Malclès, J; Ocariz, J; Perez, A; Gladney, L; Biasini, M; Covarelli, R; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Carpinelli, M; Cenci, R; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Mazur, M A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G

    2007-12-31

    We present measurements of the branching fractions for the decays B;{+/-}-->a_{1};{+/-}(1260)pi;{0} and B;{+/-}-->a_{1};{0}(1260)pi;{+/-} from a data sample of 232x10;{6} BB[over ] pairs produced in e;{+}e;{-} annihilation through the Upsilon(4S) resonance. We measure the branching fraction B(B;{+/-}-->a_{1};{+/-}(1260)pi;{0})xB(a_{1};{+/-}(1260)-->pi;{-}pi;{+}pi;{+/-})=(13.2+/-2.7+/-2.1)x10;{-6} with a significance of 4.2sigma, and the branching fraction B(B;{+/-}-->a_{1};{0}(1260)pi;{+/-})xB(a_{1};{0}(1260)-->pi;{-}pi;{+}pi;{0})=(20.4+/-4.7+/-3.4)x10;{-6} with a significance of 3.8sigma, where the first error quoted is statistical and the second is systematic.

  16. Immunoglobulin A1 protease activity in Gemella haemolysans

    DEFF Research Database (Denmark)

    Lomholt, JA; Kilian, Mogens

    2000-01-01

    The purpose of this study was to determine the occurrence and nature of immunoglobulin A1 (IgA1) protease activity in members of the genus Gemella and related taxa. Among a total of 22 Gemella strains belonging to the four species Gemella haemolysans, Gemella morbillorum, Gemella sanguinis...

  17. The A1 resonance and axial recoil approximation

    Indian Academy of Sciences (India)

    The dynamics of the formation and decay of negative ion resonance of A1 symmetry at 8.5 eV electron energy in the dissociative ... Dissociative attachment; velocity slice imaging; A1 resonance in water. 1. Introduction. The formation and .... A magnetic field of 50 gauss produced by a pair of. Helmholtz coils kept outside the ...

  18. 26 CFR 31.3121(a)-1 - Wages.

    Science.gov (United States)

    2010-04-01

    ... Contributions Act (Chapter 21, Internal Revenue Code of 1954) General Provisions § 31.3121(a)-1 Wages. (a)(1... specifically limited by the Railroad Retirement Tax Act (chapter 22 of the Internal Revenue Code) or regulation... example, to restaurant or hotel employees, or to seamen or other employees aboard vessels, since generally...

  19. Cysteine transporter SLC3A1 promotes breast cancer tumorigenesis.

    Science.gov (United States)

    Jiang, Yang; Cao, Yuan; Wang, Yongbin; Li, Wei; Liu, Xinyi; Lv, Yixuan; Li, Xiaoling; Mi, Jun

    2017-01-01

    Cysteine is an essential amino acid for infants, aged people as well as patients with metabolic disorders. Although the thiol group of cysteine side chain is active in oxidative reactions, the role of cysteine in cancer remains largely unknown. Here, we report that the expression level of the solute carrier family 3, member 1 (SLC3A1), the cysteine carrier, tightly correlated with clinical stages and patients' survival. Elevated SLC3A1 expression accelerated the cysteine uptake and the accumulation of reductive glutathione (GSH), leading to reduced reactive oxygen species (ROS). ROS increased the stability and activity of PP2Ac, resulting in decreased AKT activity. Hence, SLC3A1 activated the AKT signaling through inhibiting PP2A phosphatase activity. Consistently, overexpression of SLC3A1 enhanced tumorigenesis of breast cancer cells, whereas blocking SLC3A1 either with specific siRNA or SLC3A1 specific inhibitor sulfasalazine suppressed tumor growth and also abolished dietary NAC-promoted tumor growth. Collectively, our data demonstrate that SLC3A1 promotes cysteine uptake and determines cellular response to antioxidant N-acetylcysteine, suggesting SLC3A1 is a potential therapeutic target for breast cancer.

  20. Endovascular Treatment of Unruptured A1 Segment Aneurysms

    Science.gov (United States)

    Xiaochuan, Huo; Xiaoyun, Sun; Youxiang, Li; Ning, Guan; Wenshi, Guo; Junsheng, Luo

    2013-01-01

    Summary Aneurysms of the A1 segment of the anterior cerebral artery (A1A) are rare and challenging to treat. Less information is available regarding their management by endovascular approach. We evaluated our experience of endovascular treatment in 15 patients with unruptured A1As. We retrospectively reviewed unruptured A1As treated by embolization at our hospital. The clinical data and angiographic results were reviewed. A special technique involving shaping microcatheter tips was used for catheterization. From September 2009 to December 2012, 15 patients presenting with unruptured A1As were identified. All the patients were treated by selective embolization including five patients with balloon-assisted coiling (BAC) or stent-assisted coiling (SAC). These adjunctive techniques were used to catheterize the sac safely or to protect a branch at the neck. According to the location and direction of the aneurysm, “Z-shaped”, “S-Shaped” or “U-Shaped” microcatheter tip shaping was used for microcatheter positioning and stabilization. All patients showed an excellent clinical outcome. A complete aneurysm occlusion was obtained in all the patients. Endovascular treatment of A1As is feasible and associated with good results. Because of their location and close relationship with perforators, endovascular treatment of A1As sometimes requires the use of BAC or SAC. The microcatheter tip shaping technique is very important for coiling. Our results suggest that endovascular treatment is a suitable therapeutic option for unruptured A1As when the aneurysm size is optimal for embolization. PMID:23693042

  1. Childhood presentation of COL4A1 mutations

    NARCIS (Netherlands)

    Shah, S.; Ellard, S.; Kneen, R.; Lim, M.; Osborne, N.; Rankin, J.; Stoodley, N.; van der Knaap, M.S.; Whitney, A.; Jardine, P.

    2012-01-01

    Aim To describe the clinical and radiological features of four new families with a childhood presentation of COL4A1 mutation. Method We retrospectively reviewed the clinical presentation. Investigations included radiological findings and COL4A1 mutation analysis of the four cases. Affected family

  2. Childhood presentation of COL4A1 mutations

    NARCIS (Netherlands)

    Shah, Siddharth; Ellard, Sian; Kneen, Rachel; Lim, Ming; Osborne, Nigel; Rankin, Julia; Stoodley, Neil; van der Knaap, Marjo; Whitney, Andrea; Jardine, Philip

    2012-01-01

    To describe the clinical and radiological features of four new families with a childhood presentation of COL4A1 mutation. We retrospectively reviewed the clinical presentation. Investigations included radiological findings and COL4A1 mutation analysis of the four cases. Affected family members were

  3. Observation of B+-->a1+(1260)K0 and B0-->a1-(1260)K+.

    Science.gov (United States)

    Aubert, B; Bona, M; Boutigny, D; Karyotakis, Y; Lees, J P; Poireau, V; Prudent, X; Tisserand, V; Zghiche, A; Garra Tico, J; Grauges, E; Lopez, L; Palano, A; Pappagallo, M; Eigen, G; Stugu, B; Sun, L; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lopes Pegna, D; Lynch, G; Mir, L M; Orimoto, T J; Osipenkov, I L; Ronan, M T; Tackmann, K; Tanabe, T; Wenzel, W A; Del Amo Sanchez, P; Hawkes, C M; Watson, A T; Koch, H; Schroeder, T; Walker, D; Asgeirsson, D J; Cuhadar-Donszelmann, T; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Barrett, M; Khan, A; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Abachi, S; Buchanan, C; Foulkes, S D; Gary, J W; Liu, F; Long, O; Shen, B C; Vitug, G M; Zhang, L; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Schalk, T; Schumm, B A; Seiden, A; Wilson, M G; Winstrom, L O; Chen, E; Cheng, C H; Fang, F; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nagel, M; Nauenberg, U; Olivas, A; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Gabareen, A M; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Klose, V; Kobel, M J; Lacker, H M; Mader, W F; Nogowski, R; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Latour, E; Lombardo, V; Thiebaux, Ch; Verderi, M; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Watson, J E; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Franchini, P; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Santoro, V; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bard, D J; Dauncey, P D; Flack, R L; Nash, J A; Panduro Vazquez, W; Tibbetts, M; Behera, P K; Chai, X; Charles, M J; Mallik, U; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Lae, C K; Denig, A G; Fritsch, M; Schott, G; Arnaud, N; Béquilleux, J; D'Orazio, A; Davier, M; Grosdidier, G; Höcker, A; Lepeltier, V; Le Diberder, F; Lutz, A M; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wang, W F; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Burke, J P; Chavez, C A; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; George, K A; Di Lodovico, F; Sacco, R; Cowan, G; Flaecher, H U; Hopkins, D A; Paramesvaran, S; Salvatore, F; Wren, A C; Brown, D N; Davis, C L; Allison, J; Bailey, D; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Salvati, E; Saremi, S; Cowan, R; Dujmic, D; Fisher, P H; Koeneke, K; Sciolla, G; Spitznagel, M; Taylor, F; Yamamoto, R K; Zhao, M; Zheng, Y; McLachlin, S E; Patel, P M; Robertson, S H; Lazzaro, A; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; De Nardo, G; Fabozzi, F; Lista, L; Monorchio, D; Sciacca, C; Baak, M A; Raven, G; Snoek, H L; Jessop, C P; Knoepfel, K J; Losecco, J M; Benelli, G; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Regensburger, J J; Sekula, S J; Wong, Q K; Blount, N L; Brau, J; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Gagliardi, N; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Ben-Haim, E; Briand, H; Calderini, G; Chauveau, J; David, P; Del Buono, L; de la Vaissière, Ch; Hamon, O; Leruste, Ph; Malclès, J; Ocariz, J; Perez, A; Prendki, J; Gladney, L; Biasini, M; Covarelli, R; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Carpinelli, M; Cenci, R; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G

    2008-02-08

    We present branching fraction measurements of the decays B(+)-->a(1)(+)(1260)K(0) and B(0)-->a(1)(-)(1260)K(+) with a(1)(+/-)(1260)-->pi(-/+)pi(+/-)pi(+/-). The data sample corresponds to 383 x 10(6) BB pairs produced in e(+)e(-) annihilation through the Upsilon(4S) resonance. We measure the products of the branching fractions B(B(+)-->a(1)(+)(1260)K(0)B(a(1)(+)(1260)-->pi(-)pi(+)pi(+))=(17.4+/-2.5+/-2.2) x 10(-6) and B(B(0)-->a(1)(-)(1260)K(+)B(a(1)(-)(1260)-->pi(+)pi(-)pi(-)) = (8.2+/-1.5+/-1.2) x 10(-6). We also measure the charge asymmetries A(ch)(B(+)-->a(1)(+)(1260)K(0) = 0.12+/-0.11+/-0.02 and A(ch)(B(0)-->a(1)(-)(1260)K+) = -0.16+/-0.12+/-0.01. The first uncertainty quoted is statistical and the second is systematic.

  4. Aldehyde Dehydrogenase 7A1 (ALDH7A1) Is a Novel Enzyme Involved in Cellular Defense against Hyperosmotic Stress*

    OpenAIRE

    Brocker, Chad; Lassen, Natalie; Estey, Tia; Pappa, Aglaia; Cantore, Miriam; Orlova, Valeria V.; Chavakis, Triantafyllos; Kavanagh, Kathryn L.; Oppermann, Udo; Vasiliou, Vasilis

    2010-01-01

    Mammalian ALDH7A1 is homologous to plant ALDH7B1, an enzyme that protects against various forms of stress, such as salinity, dehydration, and osmotic stress. It is known that mutations in the human ALDH7A1 gene cause pyridoxine-dependent and folic acid-responsive seizures. Herein, we show for the first time that human ALDH7A1 protects against hyperosmotic stress by generating osmolytes and metabolizing toxic aldehydes. Human ALDH7A1 expression in Chinese hamster ovary cells attenuated osmotic...

  5. Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk

    Czech Academy of Sciences Publication Activity Database

    Campa, D.; Pastore, M.; Gentiluomo, M.; Talar-Wojnarowska, R.; Kupcinskas, J.; Malecka-Panas, E.; Neoptolemos, J. P.; Niesen, W.; Vodička, Pavel; Delle Fave, G.; Bueno-de-Mesquita, H. B.; Gazouli, M.; Pacetti, P.; Di Leo, M.; Ito, H.; Klüter, H.; Souček, P.; Corbo, V.; Yamao, K.; Hosono, S.; Kaaks, R.; Vashist, Y.; Gioffreda, D.; Strobel, O.; Shimizu, Y.; Dijk, F.; Andriulli, A.; Ivanauskas, A.; Bugert, P.; Tavano, F.; Vodičková, L.; Zambon, C.F.; Lovecek, M.; Landi, S.; Key, T. J.; Boggi, U.; Pezzilli, R.; Jamroziak, K.; Mohelníková-Duchoňová, B.; Mambrini, A.; Bambi, F.; Busch, O.; Pazienza, V.; Valente, R.; Theodoropoulos, G.E.; Hackert, T.; Capurso, G.; Cavestro, G.M.; Pasquali, C.; Basso, D.; Sperti, C.; Matsuo, K.; Büchler, M.; Khaw, K. T.; Izbicki, J.; Costello, E.; Katzke, V.; Michalski, Ch.; Stepien, A.; Rizzato, C.; Canzian, F.

    2016-01-01

    Roč. 7, č. 35 (2016), s. 57011-57020 ISSN 1949-2553 R&D Projects: GA ČR GAP301/12/1734 Institutional support: RVO:68378041 Keywords : pancreatic cancer * CDKN2A * single nucleotide polymorphisms Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.168, year: 2016

  6. Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk

    NARCIS (Netherlands)

    Campa, Daniele; Pastore, Manuela; Gentiluomo, Manuel; Talar-Wojnarowska, Renata; Kupcinskas, Juozas; Malecka-Panas, Ewa; Neoptolemos, John P.; Niesen, Willem; Vodicka, Pavel; Delle Fave, Gianfranco; Bueno-de-Mesquita, H. Bas; Gazouli, Maria; Pacetti, Paola; Di Leo, Milena; Ito, Hidemi; Klüter, Harald; Soucek, Pavel; Corbo, Vincenzo; Yamao, Kenji; Hosono, Satoyo; Kaaks, Rudolf; Vashist, Yogesh; Gioffreda, Domenica; Strobel, Oliver; Shimizu, Yasuhiro; Dijk, Frederike; Andriulli, Angelo; Ivanauskas, Audrius; Bugert, Peter; Tavano, Francesca; Vodickova, Ludmila; Zambon, Carlo Federico; Lovecek, Martin; Landi, Stefano; Key, Timothy J.; Boggi, Ugo; Pezzilli, Raffaele; Jamroziak, Krzysztof; Mohelnikova-Duchonova, Beatrice; Mambrini, Andrea; Bambi, Franco; Busch, Olivier; Pazienza, Valerio; Valente, Roberto; Theodoropoulos, George E.; Hackert, Thilo; Capurso, Gabriele; Cavestro, Giulia Martina; Pasquali, Claudio; Basso, Daniela; Sperti, Cosimo; Matsuo, Keitaro; Büchler, Markus; Khaw, Kay-Tee; Izbicki, Jakob; Costello, Eithne; Katzke, Verena; Michalski, Christoph; Stepien, Anna; Rizzato, Cosmeri; Canzian, Federico

    2016-01-01

    The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter

  7. Oxides of Nitrogen Emissions from the Testing of TF41-A-2B Engines at Naval Air Station, Lemoore, California

    Science.gov (United States)

    1987-11-01

    CRAWt ODiJ TAB 0 STATEr " T "A" per Douglas Marable .... Aircraft Environmental Support Office Naval Aviation Depot, Naval Air Station ByQ. North Island...for Research ," 2nd ed., John Wiley & Sons, Inc., New York, 1974. 6. Code of Federal Regulations, Title 40, Part 60, "Appendix B - Performance

  8. 26 CFR 31.3402(a)-1 - Requirement of withholding.

    Science.gov (United States)

    2010-04-01

    ... (for example, wages paid in stocks or bonds; see § 31.3401 (a)-1) and to pay over the tax in money. If... withholding, paying, and returning the tax and furnishing such statements rests with the employer. For...

  9. Expression of a 1-aminocyclopropane-1-carboxylate (ACC) oxidase ...

    African Journals Online (AJOL)

    Expression of a 1-aminocyclopropane-1-carboxylate (ACC) oxidase gene in peach ( Prunus persica L.) fruit in response to treatment with carbon dioxide and 1-methylcyclopropene: possible role of ethylene.

  10. Relationship between the morphology of A-1 segment of anterior ...

    African Journals Online (AJOL)

    Relationship between the morphology of A-1 segment of anterior cerebral artery and anterior communicating artery aneurysms. Wenfeng Feng, Long Zhang, Weiguang Li, Guozhong Zhang, Xiaoyan He, Gang Wang, Mingzhou Li, Songtao Qi ...

  11. Family house and studio by A1architects, Prague

    Czech Academy of Sciences Publication Activity Database

    Hnídková, Vendula

    -, č. 63 (2015), s. 61 ISSN 1573-3815 Institutional support: RVO:68378033 Keywords : Czech contemporary architecture * family house and studio * A1architects Subject RIV: AL - Art, Architecture , Cultural Heritage

  12. Metamorphosis of NPP A1, V1, V2

    International Nuclear Information System (INIS)

    Dobak, D.; Moncekova, M.

    2005-01-01

    In this book the history of construction, commissioning and exploitation of NPP A1, NPP V1 and NPP V2 in Jaslovske Bohunice is presented on documentary photos. Vicinity around of these NPPs is presented, too

  13. Pulsed Electromagnetic Fields Increased the Anti-Inflammatory Effect of A2A and A3 Adenosine Receptors in Human T/C-28a2 Chondrocytes and hFOB 1.19 Osteoblasts

    Science.gov (United States)

    Vincenzi, Fabrizio; Targa, Martina; Corciulo, Carmen; Gessi, Stefania; Merighi, Stefania; Setti, Stefania; Cadossi, Ruggero; Goldring, Mary B.; Borea, Pier Andrea; Varani, Katia

    2013-01-01

    Adenosine receptors (ARs) have an important role in the regulation of inflammation and their activation is involved in the inhibition of pro-inflammatory cytokine release. The effects of pulsed electromagnetic fields (PEMFs) on inflammation have been reported and we have demonstrated that PEMFs increased A2A and A3AR density and functionality in different cell lines. Chondrocytes and osteoblasts are two key cell types in the skeletal system that play important role in cartilage and bone metabolism representing an interesting target to study the effect of PEMFs. The primary aim of the present study was to evaluate if PEMF exposure potentiated the anti-inflammatory effect of A2A and/or A3ARs in T/C-28a2 chondrocytes and hFOB 1.19 osteoblasts. Immunofluorescence, mRNA analysis and saturation binding assays revealed that PEMF exposure up-regulated A2A and A3AR expression. A2A and A3ARs were able to modulate cAMP production and cell proliferation. The activation of A2A and A3ARs resulted in the decrease of some of the most relevant pro-inflammatory cytokine release such as interleukin (IL)-6 and IL-8, following the treatment with IL-1β as an inflammatory stimuli. In human chondrocyte and osteoblast cell lines, the inhibitory effect of A2A and A3AR stimulation on the release of prostaglandin E2 (PGE2), an important lipid inflammatory mediator, was observed. In addition, in T/C-28a2 cells, the activation of A2A or A3ARs elicited an inhibition of vascular endothelial growth factor (VEGF) secretion. In hFOB 1.19 osteoblasts, PEMF exposure determined an increase of osteoprotegerin (OPG) production. The effect of the A2A or A3AR agonists in the examined cells was enhanced in the presence of PEMFs and completely blocked by using well-known selective antagonists. These results demonstrated that PEMF exposure significantly increase the anti-inflammatory effect of A2A or A3ARs suggesting their potential therapeutic use in the therapy of inflammatory bone and joint disorders

  14. Trimester-specific reference intervals for haemoglobin A(1c) (HbA(1c)) in pregnancy.

    LENUS (Irish Health Repository)

    O'Connor, Catherine

    2011-11-26

    Abstract Background: Diabetes in pregnancy imposes additional risks to both mother and infant. These increased risks are considered to be primarily related to glycaemic control which is monitored by means of glycated haemoglobin (HbA(1c)). The correlation of HbA(1c) with clinical outcomes emphasises the need to measure HbA(1c) accurately, precisely and for correct interpretation, comparison to appropriately defined reference intervals. Since July 2010, the HbA(1c) assay in Irish laboratories is fully metrologically traceable to the IFCC standard. The objective was to establish trimester-specific reference intervals in pregnancy for IFCC standardised HbA(1c) in non-diabetic Caucasian women. Methods: The authors recruited 311 non-diabetic Caucasian pregnant (n=246) and non-pregnant women (n=65). A selective screening based on risk factors for gestational diabetes was employed. All subjects had a random plasma glucose <7.7 mmol\\/L and normal haemoglobin level. Pregnancy trimester was defined as trimester 1 (T1, n=40) up to 12 weeks +6 days, trimester 2 (T2, n=106) 13-27 weeks +6 days, trimester 3 (T3, n=100) >28 weeks to term. Results: The normal HbA(1c) reference interval for Caucasian non-pregnant women was 29-37 mmol\\/mol (Diabetes Control and Complications Trial; DCCT: 4.8%-5.5%), T1: 24-36 mmol\\/mol (DCCT: 4.3%-5.4%), T2: 25-35 mmol\\/mol (DCCT: 4.4%-5.4%) and T3: 28-39 mmol\\/mol (DCCT: 4.7%-5.7%). HbA(1c) was significantly decreased in trimesters 1 and 2 compared to non-pregnant women. Conclusions: HbA(1c) trimester-specific reference intervals are required to better inform the management of pregnancies complicated by diabetes.

  15. Retinal and nonocular abnormalities in Cyp27a1(-/-)Cyp46a1(-/-) mice with dysfunctional metabolism of cholesterol.

    Science.gov (United States)

    Saadane, Aicha; Mast, Natalia; Charvet, Casey D; Omarova, Saida; Zheng, Wenchao; Huang, Suber S; Kern, Timothy S; Peachey, Neal S; Pikuleva, Irina A

    2014-09-01

    Cholesterol elimination from nonhepatic cells involves metabolism to side-chain oxysterols, which serve as transport forms of cholesterol and bioactive molecules modulating a variety of cellular processes. Cholesterol metabolism is tissue specific, and its significance has not yet been established for the retina, where cytochromes P450 (CYP27A1 and CYP46A1) are the major cholesterol-metabolizing enzymes. We generated Cyp27a1(-/-)Cyp46a1(-/-) mice, which were lean and had normal serum cholesterol and glucose levels. These animals, however, had changes in the retinal vasculature, retina, and several nonocular organs (lungs, liver, and spleen). Changes in the retinal vasculature included structural abnormalities (retinal-choroidal anastomoses, arteriovenous shunts, increased permeability, dilation, nonperfusion, and capillary degeneration) and cholesterol deposition and oxidation in the vascular wall, which also exhibited increased adhesion of leukocytes and activation of the complement pathway. Changes in the retina included increased content of cholesterol and its metabolite, cholestanol, which were focally deposited at the apical and basal sides of the retinal pigment epithelium. Retinal macrophages of Cyp27a1(-/-)Cyp46a1(-/-) mice were activated, and oxidative stress was noted in their photoreceptor inner segments. Our findings demonstrate the importance of retinal cholesterol metabolism for maintenance of the normal retina, and suggest new targets for diseases affecting the retinal vasculature. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  16. [Microsurgical anatomy importance of A1-anterior communicating artery complex].

    Science.gov (United States)

    Monroy-Sosa, Alejandro; Pérez-Cruz, Julio César; Reyes-Soto, Gervith; Delgado-Hernández, Carlos; Macías-Duvignau, Mario Alberto; Delgado-Reyes, Luis

    2013-01-01

    The anterior cerebral artery originates from the bifurcation of the internal carotid artery lateral to the optic chiasm, then joins with its contralateral counterpart via the anterior communicating artery. A1-anterior communicating artery complex is the most frequent anatomical variants and is the major site of aneurysms between 30 to 37%. Know the anatomy microsurgical, variants anatomical and importance of complex precommunicating segment-artery anterior communicating in surgery neurological of the pathology vascular, mainly aneurysms, in Mexican population. The study was performed in 30 brains injected. Microanatomy was studied (length and diameter) of A1-anterior communicating artery complex and its variants. 60 segments A1, the average length of left side was 11.35 mm and 11.84 mm was right. The average diameter of left was 1.67 mm and the right was 1.64 mm. The average number of perforators on the left side was 7.9 and the right side was 7.5. Anterior communicating artery was found in 29 brains of the optic chiasm, its course depended on the length of the A1 segment. The average length of the segment was 2.84 mm, the average diameter was 1.41 mm and the average number of perforators was 3.27. A1-anterior communicating artery complex variants were found in 18 (60%) and the presence of two blister-like aneurysms. It is necessary to understand the A1-anterior communicating artery complex microanatomy of its variants to have a three-dimensional vision during aneurysm surgery.

  17. Neutron density optimal control of A-1 reactor analoque model

    International Nuclear Information System (INIS)

    Grof, V.

    1975-01-01

    Two applications are described of the optimal control of a reactor analog model. Both cases consider the control of neutron density. Control loops containing the on-line controlled process, the reactor of the first Czechoslovak nuclear power plant A-1, are simulated on an analog computer. Two versions of the optimal control algorithm are derived using modern control theory (Pontryagin's maximum principle, the calculus of variations, and Kalman's estimation theory), the minimum time performance index, and the quadratic performance index. The results of the optimal control analysis are compared with the A-1 reactor conventional control. (author)

  18. Characterization of SLCO5A1/OATP5A1, a solute carrier transport protein with non-classical function.

    Directory of Open Access Journals (Sweden)

    Katrin Sebastian

    Full Text Available Organic anion transporting polypeptides (OATP/SLCO have been identified to mediate the uptake of a broad range of mainly amphipathic molecules. Human OATP5A1 was found to be expressed in the epithelium of many cancerous and non-cancerous tissues throughout the body but protein characterization and functional analysis have not yet been performed. This study focused on the biochemical characterization of OATP5A1 using Xenopus laevis oocytes and Flp-In T-REx-HeLa cells providing evidence regarding a possible OATP5A1 function. SLCO5A1 is highly expressed in mature dendritic cells compared to immature dendritic cells (∼6.5-fold and SLCO5A1 expression correlates with the differentiation status of primary blood cells. A core- and complex- N-glycosylated polypeptide monomer of ∼105 kDa and ∼130 kDa could be localized in intracellular membranes and on the plasma membrane, respectively. Inducible expression of SLCO5A1 in HeLa cells led to an inhibitory effect of ∼20% after 96 h on cell proliferation. Gene expression profiling with these cells identified immunologically relevant genes (e.g. CCL20 and genes implicated in developmental processes (e.g. TGM2. A single nucleotide polymorphism leading to the exchange of amino acid 33 (L→F revealed no differences regarding protein expression and function. In conclusion, we provide evidence that OATP5A1 might be a non-classical OATP family member which is involved in biological processes that require the reorganization of the cell shape, such as differentiation and migration.

  19. PTSD and Sexual Orientation: An Examination of Criterion A1 and Non-Criterion A1 Events.

    Science.gov (United States)

    Alessi, Edward J; Meyer, Ilan H; Martin, James I

    2013-03-01

    This large-scale cross-sectional study compared posttraumatic stress disorder (PTSD) prevalence among White, Black, and Latino lesbian, gay and bisexual individuals (LGBs; n = 382) and compared them with heterosexual individuals ( n = 126). Building on previous research, we relaxed the criteria of the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV ; American Psychiatric Association, 1994), allowing non-Criterion A1 events such as ending a relationship, unemployment, homelessness, and separation from parents to qualify, and we assessed differences in PTSD prevalence between standard DSM-IV criteria and the relaxed criteria. Findings revealed that participants reporting a non-Criterion A1 event were more likely than those reporting a Criterion A1 event to have symptoms diagnosable as PTSD. There was no significant difference in either DSM-IV or relaxed Criterion A1 PTSD prevalence between lesbian and gay, and heterosexual individuals or between bisexual and heterosexual individuals. Compared with White LGBs, Black and Latino LGBs had higher prevalence of PTSD with the relaxed Criterion A1 definition, but this was statistically significant only for Latinos.

  20. 26 CFR 1.167(a)-1 - Depreciation in general.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 2 2010-04-01 2010-04-01 false Depreciation in general. 1.167(a)-1 Section 1... Depreciation in general. (a) Reasonable allowance. Section 167(a) provides that a reasonable allowance for the... the taxpayer for the production of income shall be allowed as a depreciation deduction. The allowance...

  1. Complete COL1A1 allele deletions in osteogenesis imperfecta

    NARCIS (Netherlands)

    van Dijk, Fleur S.; Huizer, Margriet; Kariminejad, Ariana; Marcelis, Carlo L.; Plomp, Astrid S.; Terhal, Paulien A.; Meijers-Heijboer, Hanne; Weiss, Marjan M.; van Rijn, Rick R.; Cobben, Jan M.; Pals, Gerard

    2010-01-01

    To identify a molecular genetic cause in patients with a clinical diagnosis of osteogenesis imperfecta (OI) type I/IV. The authors performed multiplex ligation-dependent probe amplification analysis of the COL1A1 gene in a group of 106 index patients. In four families with mild osteogenesis

  2. Complete COL1A1 allele deletions in osteogenesis imperfecta

    NARCIS (Netherlands)

    van Dijk, Fleur S.; Huizer, Margriet; Kariminejad, Ariana; Marcelis, Carlo L.; Plomp, Astrid S.; Terhal, Paulien A.; Meijers-Heijboer, Hanne; Weiss, Marjan M.; van Rijn, Rick R.; Cobben, Jan M.; Pals, Gerard

    2010-01-01

    Purpose: To identify a molecular genetic cause in patients with a clinical diagnosis of osteogenesis imperfecta (OI) type I/IV. Methods: The authors performed multiplex ligation-dependent probe amplification analysis of the COL1A1 gene in a group of 106 index patients. Results: In four families with

  3. Regulatory analysis for USI A-1, Water Hammer

    International Nuclear Information System (INIS)

    Serkiz, A.W.

    1984-03-01

    This is the staff's regulatory analysis dealing with the resolution of the Unresolved Safety Issue A-1, Water Hammer. This report contains the value-impact analysis for this issue, public comments received, and staff response, or action taken, in response to those comments. The staff's technical findings regarding water hammer in nuclear power plants are contained in NUREG-0927

  4. 17 CFR 240.14a-1 - Definitions.

    Science.gov (United States)

    2010-04-01

    ... Exchange Act of 1934 Regulation 14a: Solicitation of Proxies § 240.14a-1 Definitions. Unless the context... proxies are to be solicited or if the solicitation involves written authorizations or consents in lieu of a meeting, the earliest date they may be used to effect corporate action. (f) Proxy. The term “proxy...

  5. Circulating Apolipoprotein A1, Haptoglobin and Α2 Macroglobulin ...

    African Journals Online (AJOL)

    α2-MG), Apolipoprotein A1 (Apo-1) and Haptoglobin (HP) as non-invasive index of the presence of cirrhosis in chronic hepatitis C patients in relation to the histopathological findings. Subjects and Methods: The study was carried out on 20 ...

  6. 26 CFR 31.3231(a)-1 - Who are employers.

    Science.gov (United States)

    2010-04-01

    ... TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Railroad Retirement Tax Act (Chapter 22, Internal Revenue Code of 1954) General Provisions § 31.3231(a)-1... engaged in the mining of coal, the supplying of coal to an employer where delivery is not beyond the mine...

  7. Thickness measurement of A-1 reactor caisson tube walls

    International Nuclear Information System (INIS)

    Prepechal, J.; Sladky, J.

    1974-01-01

    The equipment is described of measuring the thickness of caisson pipes built in the Bohunice A-1 reactor. The pulse-type ultrasonic thickness gauge is based on the reflection method using the double probe. The measurement accuracy is 0.1 mm. (J.B.)

  8. Impact of corpulence parameters and haemoglobin A1c on ...

    African Journals Online (AJOL)

    We assessed the utility of body mass index (BMI), waist circumference (WC), and glycosylated haemoglobin (HbA1c) levels in metabolic control for type 2 diabetic patients. ... The apoB/apoA-I ratio was more correlated with postprandial TC/HDL and LDL-c/HDL-c ratios in men and with postprandial TG/HDL-c in women.

  9. IEA SHC Task 42/ECES Annex 29 WG A1

    DEFF Research Database (Denmark)

    Ristić, Alenka; Furbo, Simon; Moser, Christoph

    2016-01-01

    An overview on the recent results on the engineering and characterization of sorption materials, PCMs and TCMs investigated in the working group WG A1 “Engineering and processing of TES materials” of IEA SHC Task 42 / ECES Annex 29 (Task 4229) entitled “Compact Thermal Energy Storage” is presented....

  10. Synthesis, structure and luminescence properties of phosphates A1 ...

    Indian Academy of Sciences (India)

    Home; Journals; Bulletin of Materials Science; Volume 40; Issue 1. Synthesis, structure and luminescence properties of phosphates A 1 − 3 x Eu x Zr 2 (PO 4 ) 3 (A—alkali metal). ANTON KANUNOV BENOIT GLORIEUX ALBINA ORLOVA ELENA BOROVIKOVA GALINA ZAVEDEEVA. Volume 40 Issue 1 February 2017 pp 7- ...

  11. Decommissioning of the NPP A-1 heavy water management system

    International Nuclear Information System (INIS)

    Medved, J.; Rezbarik, J.; Vargovcik, L.; Vykukel, I.

    2015-01-01

    The paper deals with experience and techniques in the application of decontamination technology and remotely controlled robotic devices for the decontamination and dismantling of the heavy water management system during undergoing decommissioning process of the A-1 NPP as well as treatment of arising liquid waste All of these activities are characterized by high level of radioactivity and contamination. (authors)

  12. Brachydactyly A1: New relatives for old families?

    Indian Academy of Sciences (India)

    Unknown

    genital syndrome (Poznanski et al. 1972). Metacarpophalangeal profile was done on a family evaluated by Armour et al. (2000) who showed mild. Figure 2. IHH mutations in brachydactyly type A1. The genomic structure of the IHH gene is shown ...

  13. Relationships between hemoglobin A1c and spot glucose ...

    African Journals Online (AJOL)

    Background: Glycosylated hemoglobin, HbA1c is the most acceptable measure of chronic glycemia. It is not widely available and/or affordable in Nigeria. The mean of the monthly fasting plasma glucose (MFPG) of the preceding 3 months is often used as surrogate for assessing chronic glycemia. Objective: To determine the ...

  14. Ultraviolet-A1 irradiation therapy for systemic lupus erythematosus.

    Science.gov (United States)

    McGrath, H

    2017-10-01

    Systemic lupus erythematosus (lupus, SLE) is a chronic autoimmune disease characterized by the production of autoantibodies, which bind to antigens and are deposited within tissues to fix complement, resulting in widespread systemic inflammation. The studies presented herein are consistent with hyperpolarized, adenosine triphosphate (ATP)-deficient mitochondria being central to the disease process. These hyperpolarized mitochondria resist the depolarization required for activation-induced apoptosis. The mitochondrial ATP deficits add to this resistance to apoptosis and also reduce the macrophage energy that is needed to clear apoptotic bodies. In both cases, necrosis, the alternative pathway of cell death, results. Intracellular constituents spill into the blood and tissues, eliciting inflammatory responses directed at their removal. What results is "autoimmunity." Ultraviolet (UV)-A1 photons have the capacity to remediate this aberrancy. Exogenous exposure to low-dose, full-body, UV-A1 radiation generates singlet oxygen. Singlet oxygen has two major palliative actions in patients with lupus and the UV-A1 photons themselves have several more. Singlet oxygen depolarizes the hyperpolarized mitochondrion, triggering non-ATP-dependent apoptosis that deters necrosis. Next, singlet oxygen activates the gene encoding heme oxygenase (HO-1), a major governor of systemic homeostasis. HO-1 catalyzes the degradation of the oxidant heme into biliverdin (converted to bilirubin), Fe, and carbon monoxide (CO), the first three of these exerting powerful antioxidant effects, and in conjunction with a fourth, CO, protecting against injury to the coronary arteries, the central nervous system, and the lungs. The UV-A1 photons themselves directly attenuate disease in lupus by reducing B cell activity, preventing the suppression of cell-mediated immunity, slowing an epigenetic progression toward SLE, and ameliorating discoid and subacute cutaneous lupus. Finally, a combination of these

  15. Translation elongation factor-1A1 (eEF1A1 localizes to the spine by domain III

    Directory of Open Access Journals (Sweden)

    Sun-Jung Cho

    2012-04-01

    Full Text Available In vertebrates, there are two variants of eukaryotic peptideelongation factor 1A (eEF1A; formerly eEF-1α, eEF1A1 andeEF1A2, which have three well-conserved domains (DI, DII,and DIII. In neurons, eEF1A1 is the embryonic type, which isexpressed during embryonic development as well as the firsttwo postnatal weeks. In the present study, EGFP-tagged eEF1A1truncates were expressed in cortical neurons isolated from ratembryo (E18-19. Live cell images of transfected neurons showedthat DIII-containing EGFP-fusion proteins (EGFP-DIII, -DII-III,-DI-III formed clusters that were confined within somatodendriticdomains, while DIII-missing ones (EGFP-DI, -DII, -DI-II andcontrol EGFP were homogeneously dispersed throughout theneuron including axons. In dendrites, EGFP-DIII was targeted tothe heads of spine- and filopodia-like protrusions, where it wascolocalized with SynGAPα, a postsynaptic marker. Our dataindicate that DIII of eEF1A1 mediates formation of clusters andlocalization to spines. [BMB reports 2012; 45(4: 227-232

  16. Normal aging induces A1-like astrocyte reactivity.

    Science.gov (United States)

    Clarke, Laura E; Liddelow, Shane A; Chakraborty, Chandrani; Münch, Alexandra E; Heiman, Myriam; Barres, Ben A

    2018-02-20

    The decline of cognitive function occurs with aging, but the mechanisms responsible are unknown. Astrocytes instruct the formation, maturation, and elimination of synapses, and impairment of these functions has been implicated in many diseases. These findings raise the question of whether astrocyte dysfunction could contribute to cognitive decline in aging. We used the Bac-Trap method to perform RNA sequencing of astrocytes from different brain regions across the lifespan of the mouse. We found that astrocytes have region-specific transcriptional identities that change with age in a region-dependent manner. We validated our findings using fluorescence in situ hybridization and quantitative PCR. Detailed analysis of the differentially expressed genes in aging revealed that aged astrocytes take on a reactive phenotype of neuroinflammatory A1-like reactive astrocytes. Hippocampal and striatal astrocytes up-regulated a greater number of reactive astrocyte genes compared with cortical astrocytes. Moreover, aged brains formed many more A1 reactive astrocytes in response to the neuroinflammation inducer lipopolysaccharide. We found that the aging-induced up-regulation of reactive astrocyte genes was significantly reduced in mice lacking the microglial-secreted cytokines (IL-1α, TNF, and C1q) known to induce A1 reactive astrocyte formation, indicating that microglia promote astrocyte activation in aging. Since A1 reactive astrocytes lose the ability to carry out their normal functions, produce complement components, and release a toxic factor which kills neurons and oligodendrocytes, the aging-induced up-regulation of reactive genes by astrocytes could contribute to the cognitive decline in vulnerable brain regions in normal aging and contribute to the greater vulnerability of the aged brain to injury. Copyright © 2018 the Author(s). Published by PNAS.

  17. Annex A1: cornerstone of the five-yearly review

    CERN Multimedia

    Staff Association

    2016-01-01

    As a reminder; the purpose of the five-yearly review is to review the financial and social conditions of all CERN personnel whether employed (MPE) or associated (MPA)! In December 2015, the CERN Council approved the package proposed by the Management. Early this year, and as final act of the 2015 five-yearly review, the CERN Council may decide, if necessary and appropriate, to review the procedures defined in Annex A1 and applicable to future five-yearly reviews. At the meeting of TREF (TRipartite Employment Forum)  in early March 2016 discussions will take place between all stakeholders (representatives of Member States, Management and the Staff Association) and Council will take a decision in June 2016, on the basis of the Management's recommendations. What does Annex A1 say and where can I find it? Annex A1 (Article S V 1.02) is a part of the Staff Rules and Regulations. This annex defines: The five-yearly review of the financial and social conditions of the staff, fellows and MPA; The a...

  18. Experimental model of trigger finger through A1 pulley constriction in a human cadaveric hand: a pilot study.

    Science.gov (United States)

    Liu, Kristina J; Thomson, J Grant

    2013-10-01

    Although it can be reasonably assumed that trigger digits occur as the result of a size mismatch in the pulley-tendon system, it is unclear whether locking, histological changes, and nodule formation occur owing to an intrinsically too small pulley or an enlarged digital flexor tendon. Our purposes in this feasibility study were to (1) create a model of trigger digit by pulley constriction in nonpreserved human tissue, (2) measure the change in work of flexion as the force of pulley constriction increased, (3) compare the work of flexion between nontriggering and triggering conditions, and (4) determine whether triggering can occur at the A2, A3, and A4 pulleys under similar conditions. Using a tensiometer, we studied the work of flexion in 4 fingers (thumb, index, middle, and ring) in a human cadaveric hand. The load of flexion was measured as the A1 to A4 pulleys were incrementally constricted in order to induce triggering. Work of flexion was analyzed for differences among trial conditions. Triggering was successfully induced in all 4 digits through constriction of the A1 pulley. No triggering occurred in any of the A2, A3, or A4 pulley systems in this model. We successfully created a trigger model in a human cadaveric hand. Our results demonstrate that the A1 pulley can cause triggering from manual constriction of the pulley alone. A trigger model such as this may allow investigations of pathophysiology, and this may result in novel treatment strategies and modalities. Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

  19. Inhibitory effects of nontoxic protein volvatoxin A1 on pore-forming cardiotoxic protein volvatoxin A2 by interaction with amphipathic alpha-helix.

    Science.gov (United States)

    Wu, Pei-Tzu; Lin, Su-Chang; Hsu, Chyong-Ing; Liaw, Yen-Chywan; Lin, Jung-Yaw

    2006-07-01

    Volvatoxin A2, a pore-forming cardiotoxic protein, was isolated from the edible mushroom Volvariella volvacea. Previous studies have demonstrated that volvatoxin A consists of volvatoxin A2 and volvatoxin A1, and the hemolytic activity of volvatoxin A2 is completely abolished by volvatoxin A1 at a volvatoxin A2/volvatoxin A1 molar ratio of 2. In this study, we investigated the molecular mechanism by which volvatoxin A1 inhibits the cytotoxicity of volvatoxin A2. Volvatoxin A1 by itself was found to be nontoxic, and furthermore, it inhibited the hemolytic and cytotoxic activities of volvatoxin A2 at molar ratios of 2 or lower. Interestingly, volvatoxin A1 contains 393 amino acid residues that closely resemble a tandem repeat of volvatoxin A2. Volvatoxin A1 contains two pairs of amphipathic alpha-helices but it lacks a heparin-binding site. This suggests that volvatoxin A1 may interact with volvatoxin A2 but not with the cell membrane. By using confocal microscopy, it was demonstrated that volvatoxin A1 could not bind to the cell membrane; however, volvatoxin A1 could inhibit binding of volvatoxin A2 to the cell membrane at a molar ratio of 2. Via peptide competition assay and in conjunction with pull-down and co-pull-down experiments, we demonstrated that volvatoxin A1 and volvatoxin A2 may form a complex. Our results suggest that this occurs via the interaction of one molecule of volvatoxin A1, which contains two amphipathic alpha-helices, with two molecules of volvatoxin A2, each of which contains one amphipathic alpha-helix. Taken together, the results of this study reveal a novel mechanism by which volvatoxin A1 regulates the cytotoxicity of volvatoxin A2 via direct interaction, and potentially provide an exciting new strategy for chemotherapy.

  20. Dietary Lecithin Decreases Skeletal Muscle COL1A1 and COL3A1 Gene Expression in Finisher Gilts

    Directory of Open Access Journals (Sweden)

    Henny Akit

    2016-06-01

    Full Text Available The purpose of this study was to investigate the effect of dietary lecithin on skeletal muscle gene expression of collagen precursors and enzymes involved in collagen synthesis and degradation. Finisher gilts with an average start weight of 55.9 ± 2.22 kg were fed diets containing either 0, 4, 20 or 80 g/kg soybean lecithin prior to harvest for six weeks and the rectus abdominis muscle gene expression profile was analyzed by quantitative real-time PCR. Lecithin treatment down-regulated Type I (α1 procollagen (COL1A1 and Type III (α1 procollagen (COL3A1 mRNA expression ( p < 0.05, respectively, indicating a decrease in the precursors for collagen synthesis. The α-subunit of prolyl 4-hydroxylase (P4H mRNA expression also tended to be down-regulated ( p = 0.056, indicating a decrease in collagen synthesis. Decreased matrix metalloproteinase-1 (MMP-1 mRNA expression may reflect a positive regulatory response to the reduced collagen synthesis in muscle from the pigs fed lecithin ( p = 0.035. Lecithin had no effect on tissue inhibitor metalloproteinase-1 (TIMP-1, matrix metalloproteinase-13 (MMP-13 and lysyl oxidase mRNA expression. In conclusion, lecithin down-regulated COL1A1 and COL3A1 as well as tended to down-regulate α-subunit P4H expression. However, determination of muscle collagen content and solubility are required to support the gene functions.

  1. Value-impact analysis for USI A-1, water hammer

    International Nuclear Information System (INIS)

    Serkiz, A.W.

    1983-05-01

    The Unresolved Safety Issue (USI) A-1 deals with safety concerns related to water hammer occurrence in nucler power plants. The staff's concerns were prompted by the increasing frequency of water hammer occurrence in the mid-1970's as new plants were coming on line, and in particular, by the feedwater line rupture at Indian Point No. 2 in 1973 (attributed to water hammer induced by steam-void collapse). Principal concerns were: the potential for inadequate dynamic load design, disablement of safety systems, and the release of radioactivity. The staff's views were set forth in NUREG-0582 and water hammer was designated a USI in 1979

  2. Rotational multiphoton endoscopy with a 1 microm fiber laser system.

    Science.gov (United States)

    Liu, Gangjun; Xie, Tuqiang; Tomov, Ivan V; Su, Jianping; Yu, Lingfeng; Zhang, Jun; Tromberg, Bruce J; Chen, Zhongping

    2009-08-01

    We present multiphoton microendoscopy with a rotational probe and a 1 microm fiber-based femtosecond laser. The rotational probe is based on a double-clad photonic crystal fiber, a gradient index lens, a microprism, and a rotational microelectronicmechanical system (MEMS) motor. The MEMS motor has a diameter of 2.2 mm and can provide 360 degrees full-view rotation. The fiber laser provides ultrashort pulses with a central wavelength at 1.034 microm and a repetition rate of 50 MHz. Second-harmonic-generation images of rat-tail tendon and fish scale are demonstrated with the rotational probe-based multiphoton system.

  3. (x − a1)(x − a2)...

    Indian Academy of Sciences (India)

    has no solutions in positive integers x, m, n where m, n > 1 and y ∈ Q. We consider the equation. (x − a1)(x − a2)...(x − ak) + ... Let n be a fixed positive integer > 2 and let r be a nonzero integer which is not a perfect n-th power. .... Thus, m/(tm + 1) < C. In other words, if m is so large that m/(tm + 1) ≥ C, then there is a string of ...

  4. Study of exon 12 polymorphism of the human thromboxane synthase (CYP5A1) gene in Egyptian stroke patients

    International Nuclear Information System (INIS)

    Soliman, S.E.T.; Zaater, M.K.

    2010-01-01

    Thromboxane synthase (CYP5A1) catalyzes the conversion of prostaglandin H2 to thromboxane A2, a potent mediator of platelet aggregation, vasoconstriction and bronchoconstriction. It has been implicated in the patho-physiological process of a variety of diseases, such as atherosclerosis, myocardial infarction, stroke and asthma. On the basis of the hypothesis that variations of the CYP5A1 gene may play an important role in human diseases, we performed screening for the prevalence of exon12 polymorphism of the human Thromboxane synthase (CYP5A1) gene among Egyptian normal and stroke patients. Using sequence-specific PCR, we examined the allelic prevalence in 70 Egyptian patients with ischemic strokes and in 70 controls. In addition, we compared the CYP5A1 allelic prevalence in 30 patients with stroke recurrence despite Aspirin use, in comparison with patients who have not experienced recurrent stroke while taking Aspirin. The frequencies of the CYP5A1*9 mutant (substitution of guanine by adenine near the heme-binding catalytic domain) and of the wild-type allele were 0.197(19.7%) and 0.803 (80.3%) respectively; they did not differ significantly between stroke patients and controls. The CYP5A1*9 mutant was significantly more prevalent among stroke patients with history of previous cerebrovascular attacks; even after adjusting for the common risk factors for cardiovascular disease (odds ratio (OR)1.73, 95%, confidence interval ( CI) 1.10-2.73; p=0.017). Among stroke patients, the presence of the CYP5A1 wild type allele was more frequent among the hypertensives (OR 1.68, 95% CI, 1.01-2.79; p=0.045), and less frequent among the diabetics (OR 0.55, 95%, CI 0.36-0.84; p=0.006). Also among stroke patients, the CYP5A1*9 mutant was significantly more prevalent among those, who failed secondary Aspirin prophylaxis compared to those with successful secondary Aspirin prophylaxis (OR 1.49, 95%, CI 1.06-2.11). This study provides evidence for high prevalence of the CYP5A1*9 mutant

  5. Structural Mapping of Adenosine Receptor Mutations

    DEFF Research Database (Denmark)

    Jespers, Willem; Schiedel, Anke C; Heitman, Laura H

    2018-01-01

    The four adenosine receptors (ARs), A1, A2A, A2B, and A3, constitute a subfamily of G protein-coupled receptors (GPCRs) with exceptional foundations for structure-based ligand design. The vast amount of mutagenesis data, accumulated in the literature since the 1990s, has been recently supplemente...

  6. Welding of the A1 reactor pressure vessel

    International Nuclear Information System (INIS)

    Becka, J.

    1975-01-01

    As concerns welding, the A-1 reactor pressure vessel represents a geometrically complex unit containing 1492 welded joints. The length of welded sections varies between 10 and 620 mm. At an operating temperature of 120 degC and a pressure of 650 N/cm 2 the welded joints in the reactor core are exposed to an integral dose of 3x10 18 n/cm 2 . The chemical composition is shown for pressure vessel steel as specified by CSN 413090.9 modified by Ni, Ti and Al additions, and for the welding electrodes used. The requirements are also shown for the mechanical properties of the base and the weld metals. The technique and conditions of welding are described. No defects were found in ultrasonic testing of welded joints. (J.B.)

  7. Underwater Imaging Using a 1 × 16 CMUT Linear Array.

    Science.gov (United States)

    Zhang, Rui; Zhang, Wendong; He, Changde; Zhang, Yongmei; Song, Jinlong; Xue, Chenyang

    2016-03-01

    A 1 × 16 capacitive micro-machined ultrasonic transducer linear array was designed, fabricated, and tested for underwater imaging in the low frequency range. The linear array was fabricated using Si-SOI bonding techniques. Underwater transmission performance was tested in a water tank, and the array has a resonant frequency of 700 kHz, with pressure amplitude 182 dB (μPa·m/V) at 1 m. The -3 dB main beam width of the designed dense linear array is approximately 5 degrees. Synthetic aperture focusing technique was applied to improve the resolution of reconstructed images, with promising results. Thus, the proposed array was shown to be suitable for underwater imaging applications.

  8. Underwater Imaging Using a 1 × 16 CMUT Linear Array

    Directory of Open Access Journals (Sweden)

    Rui Zhang

    2016-03-01

    Full Text Available A 1 × 16 capacitive micro-machined ultrasonic transducer linear array was designed, fabricated, and tested for underwater imaging in the low frequency range. The linear array was fabricated using Si-SOI bonding techniques. Underwater transmission performance was tested in a water tank, and the array has a resonant frequency of 700 kHz, with pressure amplitude 182 dB (μPa·m/V at 1 m. The −3 dB main beam width of the designed dense linear array is approximately 5 degrees. Synthetic aperture focusing technique was applied to improve the resolution of reconstructed images, with promising results. Thus, the proposed array was shown to be suitable for underwater imaging applications.

  9. Wasp venom proteins: phospholipase A1 and B.

    Science.gov (United States)

    King, T P; Kochoumian, L; Joslyn, A

    1984-04-01

    Three major venom proteins from different species of wasps have been isolated and characterized. They are hyaluronidase, phospholipase, and antigen 5 of as yet unknown biochemical function. These three proteins are allergens in wasp venom-sensitive persons. The species of wasps studied, of the genus Polistes, were annularis, carolina, exclamans, fuscatus, and instabilis. Antigen 5 and phospholipase from wasp venoms were shown to be antigenically distinct from homologous proteins of yellowjacket venoms. The venom phospholipase from wasp, as well as that from yellowjacket (Vespula germanica), appears to have dual enzymatic specificities of the A1 and B types. That is, hydrolysis takes place at the 1-acyl residue of phosphatidylcholine and at the 1- or 2-acyl residue of lysophosphatidylcholine.

  10. Urethral polyp in a 1-month-old child

    International Nuclear Information System (INIS)

    Beluffi, Giampiero; Berton, Francesca; Gola, Giada; Chiari, Giorgio; Romano, Piero; Cassani, Ferdinando

    2005-01-01

    Urethral polyps are a rare finding in children, particularly in the very young. They are suspected by the presence of various clinical signs such as obstruction, voiding dysfunction and haematuria. There is an association with other urinary tract congenital anomalies. They are usually benign fibro-epithelial lesions with no tendency to recur and are treated by surgical ablation, fulguration or laser therapy. We report a 1-month-old boy with an antenatally diagnosed left ectopic pelvic kidney, postnatal urinary tract infection and no clinical signs of obstruction. Voiding cystourethrography to exclude vesico-ureteric reflux showed a trabeculated bladder and a mobile filling defect in the posterior urethra. Owing to its large size, cystotomy was necessary to remove the polyp successfully. (orig.)

  11. Urethral polyp in a 1-month-old child

    Energy Technology Data Exchange (ETDEWEB)

    Beluffi, Giampiero [Department of Radiodiagnosis, IRCCS Policlinico S. Matteo, Section of Paediatric Radiology, Piazzale Golgi, 2, I-27100, Pavia PV (Italy); Berton, Francesca; Gola, Giada [University of Pavia, IRCCS Policlinico S. Matteo, Institute of Radiology, Pavia (Italy); Chiari, Giorgio; Romano, Piero; Cassani, Ferdinando [IRCCS Policlinico S. Matteo, Division of Paediatric Surgery, Pavia (Italy)

    2005-07-01

    Urethral polyps are a rare finding in children, particularly in the very young. They are suspected by the presence of various clinical signs such as obstruction, voiding dysfunction and haematuria. There is an association with other urinary tract congenital anomalies. They are usually benign fibro-epithelial lesions with no tendency to recur and are treated by surgical ablation, fulguration or laser therapy. We report a 1-month-old boy with an antenatally diagnosed left ectopic pelvic kidney, postnatal urinary tract infection and no clinical signs of obstruction. Voiding cystourethrography to exclude vesico-ureteric reflux showed a trabeculated bladder and a mobile filling defect in the posterior urethra. Owing to its large size, cystotomy was necessary to remove the polyp successfully. (orig.)

  12. Xylitol inhibits J774A.1 macrophage adhesion in vitro

    Directory of Open Access Journals (Sweden)

    Aline Siqueira Ferreira

    2011-12-01

    Full Text Available The aim of this work was to evaluate the effect of xylitol on J774A.1 macrophage adhesion. Adhesion consisted of a three-hour interval, at room temperature, followed by washing and cell incubation at 37ºC/5% CO2/ 48h. Xylitol was used to treat the cells either before (for 24h or after the cell incubation (for 48h at 5% as final concentration in both the situations. It was found that xylitol was effective in preventing the adhesion in both the conditions in spite of the former being 100-fold greater and significant (p < 0.001. The results pointed to an important xylitol action on macrophage adhesion, which should be further investigated as an inflammatory control.

  13. Annexin A1 in primary tumors promotes melanoma dissemination.

    Science.gov (United States)

    Boudhraa, Zied; Rondepierre, Fabien; Ouchchane, Lemlih; Kintossou, Roselyne; Trzeciakiewicz, Anna; Franck, Frederic; Kanitakis, Jean; Labeille, Bruno; Joubert-Zakeyh, Juliette; Bouchon, Bernadette; Perrot, Jean Luc; Mansard, Sandrine; Papon, Janine; Dechelotte, Pierre; Chezal, Jean-Michel; Miot-Noirault, Elisabeth; Bonnet, Mathilde; D'Incan, Michel; Degoul, Françoise

    2014-10-01

    Metastatic melanoma is one of the most aggressive forms of skin cancer and has a poor prognosis. We have previously identified Annexin A1 (ANXA1) as a potential murine melanoma-spreading factor that may modulate cell invasion by binding to formyl peptide receptors (FPRs). Here, we report that (1) in a B16Bl6 spontaneous metastasis model, a siRNA-induced decrease in tumoral ANXA1 expression significantly reduced tumoral MMP2 activity and number of lung metastases; (2) in a retrospective study of 61 patients, metastasis-free survival was inversely related to ANXA1 expression levels in primary tumors (HR 3.15 [1.03-9.69], p = 0.045); (3) in human melanoma cell lines, ANXA1 level was positively correlated with in vitro invasion capacity whereas normal melanocytes contained low ANXA1 levels, and (4) the ANXA1 N-terminal peptide ANXA12-26 stimulated MMP2 activity after interaction with FPRs and significantly stimulated the in vitro invasion of melanomas by acting on FPRs. These findings identify ANXA1 as a proinvasive protein in melanoma that holds promise as a potential prognostic marker and therapeutic target.

  14. Detection of Heteromers Formed by Cannabinoid CB1, Dopamine D2, and Adenosine A2A G-Protein-Coupled Receptors by Combining Bimolecular Fluorescence Complementation and Bioluminescence Energy Transfer

    Directory of Open Access Journals (Sweden)

    Gemma Navarro

    2008-01-01

    Full Text Available Functional interactions in signaling occur between dopamine D2 (D2R and cannabinoid CB1 (CB1R receptors, between CB1R and adenosine A2A (A2AR receptors, and between D2R and A2AR. Furthermore, direct molecular interactions have been reported for the pairs CB1R-D2R, A2AR-D2R, and CB1R-A2AR. Here a combination of bimolecular fluorescence complementation and bioluminescence energy transfer techniques was used to identify the occurrence of D2R-CB1R-A2AR hetero-oligomers in living cells.

  15. Decommissioning of NPP A-1 Phase I, Jaslovske Bohunice. Documentation for application for permission to Phase II of decommissioning of NPP A-1. Schedule stage II of decommissioning of NPP A-1

    International Nuclear Information System (INIS)

    2007-04-01

    In this study documentation for application for permission to Phase II of decommissioning of NPP A-1 and the schedule stage II of decommissioning of NPP A-1 are presented. This study consists of ten appendixes.

  16. Sistema E.V.A. 1.0

    Directory of Open Access Journals (Sweden)

    Díaz Córdova, D. M.

    2003-01-01

    Full Text Available Dentro del campo del crecimiento y desarrollo, el cálculo antropométrico, es una de las herramientas más utilizadas para encontrar indicadores válidos del estado general del crecimiento biológico de una población en su interacción con los diversos factores sociales. Frente al evidente proceso de pauperización por el que viene transcurriendo el país, la evaluación del estado nutricional de la población infantil, tanto en sus aspectos poblacionales como individuales, se hace necesaria y cotidiana. Presentamos aquí un software de escritorio que permite el cálculo y la graficación de las principales variables antropométricas. El E.V.A. 1.0 (Evaluación y Visualización Antropométrica brinda también la posibilidad de almacenar los datos, de incorporar tablas de comparación (por default el sistema trae las tablas de la SAP y del NCHS, y de exportar la información al programa EPINFO y a la mayoría de las aplicaciones estándar de escritorio (planillas de cálculo, procesadores de texto, etc.. La aplicación posee también una modalidad de sugerencias de diagnóstico, con referencias bibliográficas, que puede ser de ayuda, tanto para el profesional de A.P.S. como para el investigador.

  17. Towards a 1km resolution global flood risk model

    Science.gov (United States)

    Bates, Paul; Neal, Jeff; Sampson, Chris; Smith, Andy

    2014-05-01

    Recent advances in computationally efficient numerical algorithms and new High Performance Computing architectures now make high (1-2km) resolution global hydrodynamic models a realistic proposition. However in many areas of the world the data sets and tools necessary to undertake such modelling do not currently exist. In particular, five major problems need to be resolved: (1) the best globally available terrain data (SRTM) was generated from X-band interferometric radar data which does not penetrate vegetation canopies and which has significant problems in determining ground elevations in urban areas; (2) a global river bathymetry data set does not currently exist; (3) most river channels globally are less than the smallest currently resolvable grid scale (1km) and therefore require a sub-grid treatment; (4) a means to estimate the magnitude of the T year flood at any point along the global river network does not currently exist; and (5) a large proportion of flood losses are generated by off-floodplain surface water flows which are not well represented in current hydrodynamic modelling systems. In this paper we propose solutions to each of these five issues as part of a concerted effort to develop a 1km (or better) resolution global flood hazard model. We describe the new numerical algorithms, computer architectures and computational resources used, and demonstrate solutions to the five previously intractable problems identified above. We conduct a validation study of the modelling against satellite imagery of major flooding on the Mississippi-Missouri confluence plain in the central USA before outlining a proof-of-concept regional study for SE Asia as a step towards a global scale model. For SE Asia we simulate flood hazard for ten different flood return periods over the entire Thailand, Cambodia, Vietnam, Malaysia and Laos region at 1km resolution and show that the modelling produces coherent, consistent and sensible simulations of extent and water depth.

  18. Phospholipase A1: a novel virulence factor in Trypanosoma cruzi.

    Science.gov (United States)

    Belaunzarán, María Laura; Wilkowsky, Silvina Elizabeth; Lammel, Estela María; Giménez, Guadalupe; Bott, Emanuel; Barbieri, Manuel Alejandro; de Isola, Elvira Luisa Durante

    2013-02-01

    Phospholipase A1 (PLA1) has been described in the infective stages of Trypanosoma cruzi as a membrane-bound/secreted enzyme that significantly modified host cell lipid profile with generation of second lipid messengers and concomitant activation of protein kinase C. In the present work we determined higher levels of PLA1 expression in the infective amastigotes and trypomastigotes than in the non-infective epimastigotes of lethal RA strain. In addition, we found similar expression patterns but distinct PLA1 activity levels in bloodstream trypomastigotes from Cvd and RA (lethal) and K98 (non-lethal) T. cruzi strains, obtained at their corresponding parasitemia peaks. This fact was likely due to the presence of different levels of anti-T. cruzi PLA1 antibodies in sera of infected mice, that modulated the enzyme activity. Moreover, these antibodies significantly reduced in vitro parasite invasion indicating the participation of T. cruzi PLA1 in the early events of parasite-host cell interaction. We also demonstrated the presence of lysophospholipase activity in live infective stages that could account for self-protection against the toxic lysophospholipids generated by T. cruzi PLA1 action. At the genome level, we identified at least eight putative genes that codify for T. cruzi PLA1 with high amino acid sequence variability in their amino and carboxy-terminal regions; a putative PLA1 selected gene was cloned and expressed as a recombinant protein that possessed PLA1 activity. Collectively, the results presented here point out at T. cruzi PLA1 as a novel virulence factor implicated in parasite invasion. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. A 1-D morphodynamic model of postglacial valley incision

    Science.gov (United States)

    Tunnicliffe, Jon F.; Church, Michael

    2015-11-01

    Chilliwack River is typical of many Cordilleran valley river systems that have undergone dramatic Holocene degradation of valley fills that built up over the course of Pleistocene glaciation. Downstream controls on base level, mainly blockage of valleys by glaciers, led to aggradation of significant glaciofluvial and glaciolacustrine valley fills and fan deposits, subsequently incised by fluvial action. Models of such large-scale, long-term degradation present a number of important challenges since the evolution of model parameters, such as the rate of bedload transport and grain size characteristics, are governed by the nature of the deposit. Sediment sampling in the Chilliwack Valley reveals a complex sequence of very coarse to fine textural modes. We present a 1-D numerical morphodynamic model for the river-floodplain system tailored to conditions in the valley. The model is adapted to dynamically adjust channel width to optimize sediment transporting capacity and to integrate relict valley fill material as the channel incises through valley deposits. Sensitivity to model parameters is studied using four principal criteria: profile concavity, rate of downstream grain size fining, bed surface sand content, and the timescale to equilibrium. Model results indicate that rates of abrasion and coarsening of the grain size distributions exert the strongest controls on all of the interrelated model performance criteria. While there are a number of difficulties in satisfying all model criteria simultaneously, results indicate that 1-D models of valley bottom sedimentary systems can provide a suitable framework for integrating results from sediment budget studies and chronologies of sediment evacuation established from dating.

  20. Varicella paediatric hospitalisations in Belgium: a 1-year national survey.

    Science.gov (United States)

    Blumental, Sophie; Sabbe, Martine; Lepage, Philippe

    2016-01-01

    Varicella universal vaccination (UV) has been implemented in many countries for several years. Nevertheless, varicella UV remains debated in Europe and few data are available on the real burden of infection. We assessed the burden of varicella in Belgium through analysis of hospitalised cases during a 1-year period. Data on children admitted to hospital with varicella were collected through a national network from November 2011 to October 2012. Inclusion criteria were either acute varicella or related complications up to 3 weeks after the rash. Participation of 101 hospitals was obtained, covering 97.7% of the total paediatric beds in Belgium. 552 children were included with a median age of 2.1 years. Incidence of paediatric varicella hospitalisations reached 29.5/10(5) person-years, with the highest impact among those 0-4 years old (global incidence and odds of hospitalisation: 79/10(5) person-years and 1.6/100 varicella cases, respectively). Only 14% (79/552) of the cohort had an underlying chronic condition. 65% (357/552) of children had ≥1 complication justifying their admission, 49% were bacterial superinfections and 10% neurological disorders. Only a quarter of children (141/552) received acyclovir. Incidence of complicated hospitalised cases was 19/10(5) person-years. Paediatric intensive care unit admission and surgery were required in 4% and 3% of hospitalised cases, respectively. Mortality among Belgian paediatric population was 0.5/10(6) and fatality ratio 0.2% among our cohort. Varicella demonstrated a substantial burden of disease in Belgian children, especially among the youngest. Our thorough nationwide study, run in a country without varicella UV, offers data to support varicella UV in Belgium. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  1. Application of smoothed continuous labile haemoglobin A1c reference intervals for identification of potentially spurious HbA1c results.

    Science.gov (United States)

    Loh, Tze Ping; Peng, Weng Kung; Chen, Lan; Sethi, Sunil Kumar

    2014-08-01

    We aim to develop smoothed continuous 2.5th and 97.5th percentile values for labile glycated haemoglobin A1c to glycated haemoglobin A1c (LHbA1c:HbA1c) ratio against HbA1c, and apply them on our patient population for identification of potentially spurious HbA1c measurements. The LHbA1c and HbA1c were measured using Bio-rad Variant II high-performance liquid chromatography system. We recorded the LHbA1c and HbA1c values of 1555 patients who had normal chromatograms. Using these results, the 2.5th and 97.5th percentile reference limits of the LHbA1c:HbA1c ratio were described by LHbA1c:HbA1c=-0.0072×HbA1c +0.2925 and LHbA1c:HbA1c=-0.0132×HbA1c +0.5327, respectively. When the reference intervals were applied on a separate 1000 patients, 34 and 29 of them had abnormally high and low LHbA1c:HbA1c ratios, respectively. Most of the observed high ratios were associated concurrently with elevated plasma glucose, anaemia, chronic liver and kidney diseases. A suppressed ratio was mostly associated with haemoglobin variants. Patients with heterozygous HbE or HbS variants tend to have lower LHbA1c:HbA1c ratios while the converse is true for heterozygous HbJ. The continuous LHbA1c:HbA1c ratio may be used to detect confounding factors or spurious HbA1c results, but its performance is confounded and reduced by the ambient plasma glucose. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  2. Solute carrier organic anion transporter family member 4A1 (SLCO4A1) as a prognosis marker of colorectal cancer.

    Science.gov (United States)

    Ban, Myung Jin; Ji, Sang Hee; Lee, Chi-Kyu; Bae, Sang Byung; Kim, Han Jo; Ahn, Tae Sung; Lee, Moon Soo; Baek, Moo-Jun; Jeong, Dongjun

    2017-08-01

    Solute carrier organic anion transporter family member 4A1 (SLCO4A1) is involved in the transport of various compounds, including sugars, bile salts, organic acids, metal ions, amine compounds, and estrogen. SLCO4A1 is highly expressed in several cancers and a gender bias has been observed in colorectal cancer (CRC). We investigated SLCO4A1 expression, its prognostic value in patients with CRC, and its role in CRC cell proliferation and metastasis. SLCO4A1 expression was assessed by immunohistochemistry (IHC) on specimens from 84 patients with CRC. The association of SLCO4A1 expression with clinicopathological features was examined. To confirm the biological role of SLCO4A1 in CRC, four CRC cell lines expressing SLCO4A1 were used and SLCO4A1 expression was knocked down by siRNA. Cell proliferation, MTT, migration, invasion, and semisolid agar colony formation assays were performed. SLCO4A1 was overexpressed in 32% of the CRC samples. SLCO4A1 overexpression and pathologic T stage were independent prognostic factors of decreased survival (P = 0.021). Kaplan-Meier analysis indicated a decreased cumulative survival for patients highly expressing SLCO4A1 compared to patients showing low SLCO4A1 expression (Log-rank test, P = 0.025). In cell lines, SLCO4A1 knockdown resulted in a significant decrease of viability, invasion, and migration when compared to control cells. Semisolid colony formation assay indicated that SLCO4A1-knocked down cells presented poor carcinogenic abilities compared to control cells. SLCO4A1 may be a valuable marker of poor prognostic for CRC. Furthermore, SLCO4A1 plays an important role in CRC cell proliferation, migration, invasion, and carcinogenesis.

  3. Data of evolutionary structure change: 1CE7A-1OBSA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1CE7A-1OBSA 1CE7 1OBS A A YERGDLDVTAQTTGAGYFSFITLLRDYVSSG-SFSNAIP...>1OBS A 1OBSA RLTTGADVRHE GLN CA 246 1OBS A 1OBSA...in>A 1OBSA ALYYYSTGGTQLPT ...n14> 1OBS A 1OBSA

  4. The Collection of Ice in Jet A-1 Fuel Pipes

    Science.gov (United States)

    Maloney, Thomas C.

    Ice collection and blockages in fuel systems have been of interest to the aerospace community since their discovery in the late 1950's when a B-52 crashed. A recent growth of interest was provoked by several incidents that occurred within the last few years. This study seeks to understand the underlying principles of ice growth in fuel flow systems. Tests were performed in a recirculated fuel system with a fuel tank that held approximately 115 gallons of Jet A-1 fuel and ice accumulation was observed in two removable test pipes. The setup was in an altitude chamber capable of -60 °F and the experiments involved full scale flow components. Initially, tests were done to better understand the system and variables that effected accumulation. First, initial conditions within the test pipes were varied. Next, pipe geometry, pipe surface properties, initial water content of the fuel and heat transfer from the fuel pipe were varied. As a result of the tests, observations were made about other effects involved in the study. The effects include: the result of sequentially run tests, the effect of the fuel on the freezing temperature of the entrained water, the effect of ice accumulation on pipe welds, and the effect of the test pipe entrance and exit flow conditions on ice accumulation. The results of initial tests were qualitative. Later quantitative tests were done to demonstrate the dependence of temperature, Reynolds number, and heat transfer on ice accumulation. Tests were quantified with a pressure increase across the pipe sections that was normalized by the expected theoretical initial pressure. As a result of these tests the effect of contamination in the fuel was revealed. For ease of reference, the initial tests were called "stage I" and the later tests were called "stage II". The results of stage I showed that accumulation of soft ice was greatest when a layer of hard ice had initially formed on the pipe surface. Stainless steel collected more ice than Teflon

  5. Rubimetide, humanin, and MMK1 exert anxiolytic-like activities via the formyl peptide receptor 2 in mice followed by the successive activation of DP1, A2A, and GABAA receptors.

    Science.gov (United States)

    Zhao, Hui; Sonada, Soushi; Yoshikawa, Akihiro; Ohinata, Kousaku; Yoshikawa, Masaaki

    2016-09-01

    Rubimetide (Met-Arg-Trp), which had been isolated as an antihypertensive peptide from an enzymatic digest of spinach ribulose-bisphosphate carboxylase/oxygenase (Rubisco), showed anxiolytic-like activity prostaglandin (PG) D2-dependent manner in the elevated plus-maze test after administration at a dose of 0.1mg/kg (ip.) or 1mg/kg (p.o.) in male mice of ddY strain. In this study, we found that rubimetide has weak affinities for the FPR1 and FPR2, subtypes of formyl peptide receptor (FPR). The anxiolytic-like activity of rubimetide (0.1mg/kg, ip.) was blocked by WRW4, an antagonist of FPR2, but not by Boc-FLFLF, an antagonist of FPR1, suggesting that the anxiolytic-like activity was mediated by the FPR2. Humanin, an endogenous agonist peptide of the FPR2, exerted an anxiolytic-like activity after intracerebroventricular (icv) administration, which was also blocked by WRW4. MMK1, a synthetic agonist peptide of the FPR2, also exerted anxiolytic-like activity. Thus, FPR2 proved to mediate anxiolytic-like effect as the first example of central effect exerted by FPR agonists. As well as the anxiolytic-like activity of rubimetide, that of MMK1 was blocked by BW A868C, an antagonist of the DP1-receptor. Furthermore, anxiolytic-like activity of rubimetide was blocked by SCH58251 and bicuculline, antagonists for adenosine A2A and GABAA receptors, respectively. From these results, it is concluded that the anxiolytic-like activities of rubimetide and typical agonist peptides of the FPR2 were mediated successively by the PGD2-DP1 receptor, adenosine-A2A receptor, and GABA-GABAA receptor systems downstream of the FPR2. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Effect of PlA1/A2 glycoprotein IIIa gene polymorphism on the long-term outcome after successful coronary stenting

    Directory of Open Access Journals (Sweden)

    Riddell John

    2007-11-01

    Full Text Available Abstract Aim To prospectively determine the role of platelet glycoprotein IIIa (GP IIIa gene PlA1/PlA2 polymorphism on the long-term clinical outcome in patients with coronary artery disease undergoing coronary stenting. Design and setting Prospective observational study in the University Hospital of Caen (France. Patients and methods 1 111 symptomatic consecutive Caucasian patients treated with percutaneous coronary intervention including stent implantation underwent genotyping for GP IIIa PlA1/A2. Main outcome measures Long-term clinical outcome in terms of the rate of major adverse cardiac events (MACE, ie death from any cause, non-fatal Q wave or non Q wave myocardial infarction, and need for coronary revascularisation was obtained and subsequently stratified according to the GP IIIa PlA1/A2 polymorphism. Results Three groups of patients were determined according to the GP IIIa PlA1/A2 polymorphism (71.6% had the A1/A1, 25.8% had the A1/A2 and 2.6% had the A2/A2 genotype. These three groups were comparable for all clinical characteristics including sex ratio, mean age, vascular risk factors, previous coronary events, baseline angiographic exam, indication for the percutaneous coronary intervention and drug therapy. The incidence of MACE was similar in these 3 groups of patients during a mean follow-up period of 654+/-152 days. Independent risk factors for MACE were a left ventricular ejection fraction Conclusion The GP IIIa PlA1/A2 polymorphism does not influence the clinical long-term outcome in patients with symptomatic coronary disease undergoing percutaneous coronary intervention with stent implantation.

  7. Structure-based optimisation of non-steroidal cytochrome P450 17A1 inhibitors

    DEFF Research Database (Denmark)

    Larsen, Morten; Hansen, Cecilie Hurup; Rasmussen, Tobias B.

    2017-01-01

    Five new non-steroidal inhibitors for cytochrome P450 17A1 (CYP17A1) were identified by structure-based optimisation from a recently identified selective CYP17A1 inhibitor. The compounds are nanomolar inhibitors of steroidogenesis measured in recombinant CYP17A1 and in H295R cells....

  8. Assessment of the performance of A1CNow(+) and development of an error grid analysis graph for comparative hemoglobin A1c measurements.

    Science.gov (United States)

    Jiang, Fusong; Hou, Xuhong; Lu, Jun; Zhou, Jian; Lu, Fengdi; Kan, Kai; Tang, Junling; Bao, Yuqian; Jia, Weiping

    2014-06-01

    This study investigated the performance of the A1CNow(+®) test (Bayer Diabetes Care, Sunnyvale, CA) in a large population of Chinese patients with diabetes. Hemoglobin A1c (HbA1c) levels in 1,618 Chinese patients with diabetes 10-94 years of age were measured with both the A1CNow(+) test, from a fingerstick blood sample, and the high-performance liquid chromatography (HPLC) test, using a venous blood sample, within 24 h. The reportable ranges of the HbA1c values were 4.0-13.0% (A1CNow(+)) and 4.1-16.8% (HPLC). An error grid analysis (EGA) method was developed to quantify the accuracy of the A1CNow(+) results against the HPLC reference results. The A1CNow(+) results were highly correlated with the HPLC reference results (r=0.945, P<0.01). Passing-Bablok regression analysis showed a good linear agreement between the two variables, and the linear regression equation fitted as y=-0.10+1.00x (P=0.21). The Bland-Altman difference plot presented that the mean bias of the A1CNow(+) results minus the HPLC reference results was -0.09% (P<0.001); the 95% confidence intervals for the limits of agreement were -1.28% to 1.09%, with 96.5% of the data points lying within this zone. The results of the EGA showed that 80.2% of the A1CNow(+) results were accurate, 17.7% were acceptable, 1.9% may lead to inappropriate treatment, and 0.3% may lead to severe clinical consequence. The A1CNow(+) test values demonstrated a slight negative bias from the HPLC values. The majority of A1CNow(+) test values were accurate when compared with results from the reference method.

  9. Physical interaction between the strawberry allergen Fra a 1 and an associated partner FaAP: Interaction of Fra a 1 proteins and FaAP.

    Science.gov (United States)

    Franz-Oberdorf, Katrin; Langer, Andreas; Strasser, Ralf; Isono, Erika; Ranftl, Quirin L; Wunschel, Christian; Schwab, Wilfried

    2017-10-01

    The strawberry fruit allergens Fra a 1.01E, Fra a 1.02 and Fra a 1.03 belong to the group of pathogenesis-related 10 (PR-10) proteins and are homologs of the major birch pollen Bet v 1 and apple allergen Mal d 1. Bet v 1 related proteins are the most extensively studied allergens but their physiological function in planta remains elusive. Since Mal d 1-Associated Protein has been previously identified as interaction partner of Mal d 1 we studied the binding of the orthologous Fra a 1-Associated Protein (FaAP) to Fra a 1.01E/1.02/1.03. As the C-terminal sequence of FaAP showed strong auto-activation activity in yeast 2-hybrid analysis a novel time resolved DNA-switching system was successfully applied. Fra a 1.01E, Fra a 1.02, and Fra a 1.03 bind to FaAP with K D of 4.5 ± 1.1, 15 ± 3, and 11 ± 2 nM, respectively. Fra a 1.01E forms a dimer, whereas Fra a 1.02 and Fra a 1.03 bind as monomer. The results imply that PR-10 proteins might be integrated into a protein-interaction network and FaAP binding appears to be essential for the physiological function of the Fra a 1 proteins. © 2017 Wiley Periodicals, Inc.

  10. Characterization of simvastatin acid uptake by organic anion transporting polypeptide 3A1 (OATP3A1) and influence of drug-drug interaction.

    Science.gov (United States)

    Atilano-Roque, Amandla; Joy, Melanie S

    2017-12-01

    Human organic anion transporting polypeptide 3A1 (OATP3A1) is predominately expressed in the heart. The ability of OATP3A1 to transport statins into cardiomyocytes is unknown, although other OATPs are known to mediate the uptake of statin drugs in liver. The pleiotropic effects and uptake of simvastatin acid were analyzed in primary human cardiomyocytes and HEK293 cells transfected with the OATP3A1 gene. Treatment with simvastatin acid reduced indoxyl sulfate-mediated reactive oxygen species and modulated OATP3A1 expression in cardiomyocytes and HEK293 cells transfected with the OATP3A1 gene. We observed a pH-dependent effect on OATP3A1 uptake, with more efficient simvastatin acid uptake at pH5.5 in HEK293 cells transfected with the OATP3A1 gene. The Michaelis-Menten constant (K m ) for simvastatin acid uptake by OATP3A1 was 0.017±0.002μM and the V max was 0.995±0.027fmol/min/10 5 cells. Uptake of simvastatin acid was significantly increased by known (benzylpenicillin and estrone-3-sulfate) and potential (indoxyl sulfate and cyclosporine) substrates of OATP3A1. In conclusion, the presence of OATP3A1 in cardiomyocytes suggests that this transporter may modulate the exposure of cardiac tissue to simvastatin acid due to its enrichment in cardiomyocytes. Increases in uptake of simvastatin acid by OATP3A1 when combined with OATP substrates suggest the potential for drug-drug interactions that could influence clinical outcomes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Haemoglobin J-Baltimore can be detected by HbA1c electropherogram but with underestimated HbA1c value.

    OpenAIRE

    Brunel, Valéry; Lahary, Agnes; Chagraoui, Abdeslam; Thuillez, Christian

    2016-01-01

    Glycated haemoglobin (HbA1c) is considered the gold standard for assessing diabetes compensation and treatment. In addition, fortuitous detection of haemoglobin variants during HbA1c measurement is not rare. Recently, two publications reported different conclusions on accuracy of HbA1c value using capillary electrophoresis method in presence of haemoglobin J-Baltimore (HbJ). Here we describe the fortuitous detection of unknown HbJ using capillary electrophoresis for measurement of HbA1c. ...

  12. Immunoglobulins in nasal secretions of healthy humans: structural integrity of secretory immunoglobulin A1 (IgA1) and occurrence of neutralizing antibodies to IgA1 proteases of nasal bacteria

    DEFF Research Database (Denmark)

    Kirkeby, L; Rasmussen, TT; Reinholdt, Jesper

    2000-01-01

    . Previous studies have suggested that cleavage of IgA1 in nasal secretions may be associated with the development and perpetuation of atopic disease. To clarify the potential effect of IgA1 protease-producing bacteria in the nasal cavity, we have analyzed immunoglobulin isotypes in nasal secretions of 11......). IgA1 protease-producing bacteria (Haemophilus influenzae, Streptococcus pneumoniae, or Streptococcus mitis biovar 1) were isolated from the nasal cavities of seven subjects at 2.1 x 10(3) to 7.2 x 10(6) CFU per ml of undiluted secretion, corresponding to 0.2 to 99.6% of the flora. Nevertheless, alpha......Certain bacteria, including overt pathogens as well as commensals, produce immunoglobulin A1 (IgA1) proteases. By cleaving IgA1, including secretory IgA1, in the hinge region, these enzymes may interfere with the barrier functions of mucosal IgA antibodies, as indicated by experiments in vitro...

  13. A study assessing the association of glycated hemoglobin A1C (HbA1C associated variants with HbA1C, chronic kidney disease and diabetic retinopathy in populations of Asian ancestry.

    Directory of Open Access Journals (Sweden)

    Peng Chen

    Full Text Available Glycated hemoglobin A1C (HbA1C level is used as a diagnostic marker for diabetes mellitus and a predictor of diabetes associated complications. Genome-wide association studies have identified genetic variants associated with HbA1C level. Most of these studies have been conducted in populations of European ancestry. Here we report the findings from a meta-analysis of genome-wide association studies of HbA1C levels in 6,682 non-diabetic subjects of Chinese, Malay and South Asian ancestries. We also sought to examine the associations between HbA1C associated SNPs and microvascular complications associated with diabetes mellitus, namely chronic kidney disease and retinopathy. A cluster of 6 SNPs on chromosome 17 showed an association with HbA1C which achieved genome-wide significance in the Malays but not in Chinese and Asian Indians. No other variants achieved genome-wide significance in the individual studies or in the meta-analysis. When we investigated the reproducibility of the findings that emerged from the European studies, six loci out of fifteen were found to be associated with HbA1C with effect sizes similar to those reported in the populations of European ancestry and P-value ≤ 0.05. No convincing associations with chronic kidney disease and retinopathy were identified in this study.

  14. A study assessing the association of glycated hemoglobin A1C (HbA1C) associated variants with HbA1C, chronic kidney disease and diabetic retinopathy in populations of Asian ancestry.

    Science.gov (United States)

    Chen, Peng; Ong, Rick Twee-Hee; Tay, Wan-Ting; Sim, Xueling; Ali, Mohammad; Xu, Haiyan; Suo, Chen; Liu, Jianjun; Chia, Kee-Seng; Vithana, Eranga; Young, Terri L; Aung, Tin; Lim, Wei-Yen; Khor, Chiea-Chuen; Cheng, Ching-Yu; Wong, Tien-Yin; Teo, Yik-Ying; Tai, E-Shyong

    2013-01-01

    Glycated hemoglobin A1C (HbA1C) level is used as a diagnostic marker for diabetes mellitus and a predictor of diabetes associated complications. Genome-wide association studies have identified genetic variants associated with HbA1C level. Most of these studies have been conducted in populations of European ancestry. Here we report the findings from a meta-analysis of genome-wide association studies of HbA1C levels in 6,682 non-diabetic subjects of Chinese, Malay and South Asian ancestries. We also sought to examine the associations between HbA1C associated SNPs and microvascular complications associated with diabetes mellitus, namely chronic kidney disease and retinopathy. A cluster of 6 SNPs on chromosome 17 showed an association with HbA1C which achieved genome-wide significance in the Malays but not in Chinese and Asian Indians. No other variants achieved genome-wide significance in the individual studies or in the meta-analysis. When we investigated the reproducibility of the findings that emerged from the European studies, six loci out of fifteen were found to be associated with HbA1C with effect sizes similar to those reported in the populations of European ancestry and P-value ≤ 0.05. No convincing associations with chronic kidney disease and retinopathy were identified in this study.

  15. Marked variability in hepatic expression of cytochromes CYP7A1 and CYP27A1 as compared to cerebral CYP46A1. Lessons from a dietary study with omega 3 fatty acids in hamsters.

    Science.gov (United States)

    Mast, Natalia; Shafaati, Marjan; Zaman, Wahiduz; Zheng, Wenchao; Prusak, Deborah; Wood, Thomas; Ansari, G A S; Lövgren-Sandblom, Anita; Olin, Maria; Bjorkhem, Ingemar; Pikuleva, Irina

    2010-06-01

    Two diets simulating the recommendations of the American Heart Association to increase the intake of n-3 polyunsaturated fatty acids (n-3 PUFAs) were tested on Golden Syrian hamsters and compared to the diet simulating the current estimated consumption of fat in the United States. N-3 PUFAs were evaluated for their effects on serum and brain lipids and on the three cytochrome P450 enzymes (CYPs 7A1, 27A1, and 46A1) that play key roles in cholesterol elimination from different organs. Hamsters on the highest concentration of n-3 PUFAs had a statistically significant decrease in LDL and HDL cholesterol and no change in serum total cholesterol and triglycerides levels. CYP27A1 and CYP46A1 mRNA levels were increased in the liver and brain, respectively, whereas possible effects on CYP7A1 were obscured by a marked intergroup variability at mRNA, protein, and sterol product levels. Increased levels of CYP46A1 mRNA in the brain did not lead to significant changes in the levels of lathosterol, 24S-hydroxycholesterol or cholesterol in this organ. The data obtained are discussed in relation to inconsistent effects of n-3 PUFAs on serum lipids in human trials and reported positive effects of fish oil on cognitive function. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  16. Transcriptional profiling of striatal neurons in response to single or concurrent activation of dopamine D2, adenosine A(2A) and metabotropic glutamate type 5 receptors: focus on beta-synuclein expression.

    Science.gov (United States)

    Canela, Laia; Selga, Elisabet; García-Martínez, Juan Manuel; Amaral, Olavo B; Fernández-Dueñas, Víctor; Alberch, Jordi; Canela, Enric I; Franco, Rafael; Noé, Véronique; Lluís, Carme; Ciudad, Carlos J; Ciruela, Francisco

    2012-10-25

    G protein-coupled receptor oligomerization is a concept which is changing the understanding of classical pharmacology. Both, oligomerization and functional interaction between adenosine A(2A,) dopamine D(2) and metabotropic glutamate type 5 receptors have been demonstrated in the striatum. However, the transcriptional consequences of receptors co-activation are still unexplored. We aim here to determine the changes in gene expression of striatal primary cultured neurons upon isolated or simultaneous receptor activation. Interestingly, we found that 95 genes of the total analyzed (15,866 transcripts and variants) changed their expression in response to simultaneous stimulation of all three receptors. Among these genes, we focused on the β-synuclein (β-Syn) gene (SCNB). Quantitative PCR verified the magnitude and direction of change in expression of SCNB. Since β-Syn belongs to the homologous synuclein family and may be considered a natural regulator of α-synuclein (α-Syn), it has been proposed that β-Syn might act protectively against α-Syn neuropathology. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Estrogen-regulated expression of cyp19a1a and cyp19a1b genes in swim-up fry of Labeo rohita.

    Science.gov (United States)

    Gupta, Shreyasi; Moulik, Sujata Roy; Pal, Puja; Majumder, Suravi; Das, Sumana; Guha, Payel; Juin, Subir Kumar; Panigrahi, Ashis Kumar; Mukherjee, Dilip

    2017-09-15

    P450 aromatase is the terminal enzyme in the steroidogenic pathway and catalyzes the conversion of androgens to estrogens. The expression of cyp19a1 genes in brain and gonad of Indian major carp, Labeo rohita swim-up fry was measured by quantitative real-time polymerase chain-reaction. Results demonstrated that cyp19a1b and cyp19a1a predominate in brain and gonad respectively. Treatment of fry with an aromatase inhibitor fadrozole for 6days attenuated brain cyp19a1b expression, but not cyp19a1a of gonad. Fadrozole also attenuated brain aromatase activity. Treatment with 17β-estradiol (E2) for 6days resulted in up-regulation of brain cyp19a1b transcripts in a dose- and time-dependent manner, but not cyp19a1a. Whole-body concentration of vitellogenin also increased in response to E2. Altogether, these results indicate L. rohita swim-up fry can be used to detect environmental estrogens either using vitellogenin induction or cyp19a1b gene expression. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Influence of the adenosine A1 receptor on blood pressure regulation and renin release

    DEFF Research Database (Denmark)

    Brown, Russell D.; Thorén, Peter; Steege, Andreas

    2006-01-01

    The present study was performed to investigate the role of adenosine A1 receptors in regulating blood pressure in conscious mice. Adenosine A1-receptor knockout (A1R-/-) mice and their wild-type (A1R+/+) littermates were placed on standardized normal-salt (NS), high-salt (HS), or salt-deficient (SD......) diets for a minimum of 10 days before telemetric blood pressure and urinary excretion measurements in metabolic cages. On the NS diet, daytime and nighttime mean arterial blood pressure (MAP) was 7-10 mmHg higher in A1R-/- than in A1R+/+ mice. HS diet did not affect the MAP in A1R-/- mice....... The elevated plasma renin concentrations found in the A1R-/- mice could also result in increased blood pressure. Our results confirm that adenosine, acting through the adenosine A1 receptor, plays an important role in regulating blood pressure, renin release, and sodium excretion....

  19. Cytochrome P450 1A1 (CYP1A1) protects against nonalcoholic fatty liver disease caused by Western diet containing benzo[a]pyrene in mice.

    Science.gov (United States)

    Uno, Shigeyuki; Nebert, Daniel W; Makishima, Makoto

    2018-03-01

    The Western diet contributes to nonalcoholic fatty liver disease (NAFLD) pathogenesis. Benzo[a]pyrene (BaP), a prototypical environmental pollutant produced by combustion processes, is present in charcoal-grilled meat. Cytochrome P450 1A1 (CYP1A1) metabolizes BaP, resulting in either detoxication or metabolic activation in a context-dependent manner. To elucidate a role of CYP1A1-BaP in NAFLD pathogenesis, we compared the effects of a Western diet, with or without oral BaP treatment, on the development of NAFLD in Cyp1a1(-/-) mice versus wild-type mice. A Western diet plus BaP induced lipid-droplet accumulation in liver of Cyp1a1(-/-) mice, but not wild-type mice. The hepatic steatosis observed in Cyp1a1(-/-) mice was associated with increased cholesterol, triglyceride and bile acid levels. Cyp1a1(-/-) mice fed Western diet plus BaP had changes in expression of genes involved in bile acid and lipid metabolism, and showed no increase in Cyp1a2 expression but did exhibit enhanced Cyp1b1 mRNA expression, as well as hepatic inflammation. Enhanced BaP metabolic activation, oxidative stress and inflammation may exacerbate metabolic dysfunction in liver of Cyp1a1(-/-) mice. Thus, Western diet plus BaP induces NAFLD and hepatic inflammation in Cyp1a1(-/-) mice in comparison to wild-type mice, indicating a protective role of CYP1A1 against NAFLD pathogenesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

  20. Effects of tianeptine on onset time of pentylenetetrazole-induced seizures in mice: possible role of adenosine A1 receptors.

    Science.gov (United States)

    Uzbay, Tayfun I; Kayir, Hakan; Ceyhan, Mert

    2007-02-01

    Depression is a common psychiatric problem in epileptic patients. Thus, it is important that an antidepressant agent has anticonvulsant activity. This study was organized to investigate the effects of tianeptine, an atypical antidepressant, on pentylenetetrazole (PTZ)-induced seizure in mice. A possible contribution of adenosine receptors was also evaluated. Adult male Swiss-Webster mice (25-35 g) were subjects. PTZ (80 mg/kg, i.p.) was injected to mice 30 min after tianeptine (2.5-80 mg/kg, i.p.) or saline administration. The onset times of 'first myoclonic jerk' (FMJ) and 'generalized clonic seizures' (GCS) were recorded. Duration of 600 s was taken as a cutoff time in calculation of the onset time of the seizures. To evaluate the contribution of adenosine receptors in the effect of tianeptine, a nonspecific adenosine receptor antagonist caffeine, a specific A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific A2A receptor antagonist 8-(3-chlorostyryl) caffeine (CSC) or their vehicles were administered to the mice 15 min before tianeptine (80 mg/kg) or saline treatments. Tianeptine (40 and 80 mg/kg) pretreatment significantly delayed the onset time of FMJ and GCS. Caffeine (10-60 mg/kg, i.p.) dose-dependently blocked the retarding effect of tianeptine (80 mg/kg) on the onset times of FMJ and GCS. DPCPX (20 mg/kg) but not CSC (1-8 mg/kg) blocked the effect of tianeptine (80 mg/kg) on FMJ. Our results suggest that tianeptine delayed the onset time of PTZ-induced seizures via adenosine A1 receptors in mice. Thus, this drug may be a useful choice for epileptic patients with depression.

  1. Multiple secretoglobin 1A1 genes are differentially expressed in horses

    Directory of Open Access Journals (Sweden)

    Côté Olivier

    2012-12-01

    Full Text Available Abstract Background Secretoglobin 1A1 (SCGB 1A1, also called Clara cell secretory protein, is the most abundantly secreted protein of the airway. The SCGB1A1 gene has been characterized in mammals as a single copy in the genome. However, analysis of the equine genome suggested that horses might have multiple SCGB1A1 gene copies. Non-ciliated lung epithelial cells produce SCGB 1A1 during inhalation of noxious substances to counter airway inflammation. Airway fluid and lung tissue of horses with recurrent airway obstruction (RAO, a chronic inflammatory lung disease affecting mature horses similar to environmentally induced asthma of humans, have reduced total SCGB 1A1 concentration. Herein, we investigated whether horses have distinct expressed SCGB1A1 genes; whether the transcripts are differentially expressed in tissues and in inflammatory lung disease; and whether there is cell specific protein expression in tissues. Results We identified three SCGB1A1 gene copies on equine chromosome 12, contained within a 512-kilobase region. Bioinformatic analysis showed that SCGB1A1 genes differ from each other by 8 to 10 nucleotides, and that they code for different proteins. Transcripts were detected for SCGB1A1 and SCGB1A1A, but not for SCGB1A1P. The SCGB1A1P gene had most inter-individual variability and contained a non-sense mutation in many animals, suggesting that SCGB1A1P has evolved into a pseudogene. Analysis of SCGB1A1 and SCGB1A1A sequences by endpoint-limiting dilution PCR identified a consistent difference affecting 3 bp within exon 2, which served as a gene-specific “signature”. Assessment of gene- and organ-specific expression by semiquantitative RT-PCR of 33 tissues showed strong expression of SCGB1A1 and SCGB1A1A in lung, uterus, Fallopian tube and mammary gland, which correlated with detection of SCGB 1A1 protein by immunohistochemistry. Significantly altered expression of the ratio of SCGB1A1A to SCGB1A1 was detected in RAO

  2. Prostaglandin transporter (OATP2A1/SLCO2A1) contributes to local disposition of eicosapentaenoic acid-derived PGE3.

    Science.gov (United States)

    Gose, Tomoka; Nakanishi, Takeo; Kamo, Shunsuke; Shimada, Hiroaki; Otake, Katsumasa; Tamai, Ikumi

    2016-01-01

    Eicosapentaenoic acid (EPA)-derived prostaglandin E3 (PGE3) possesses an anti-inflammatory effect; however, information for transporters that regulate its peri-cellular concentration is limited. The present study, therefore, aimed to clarify transporters involved in local disposition of PGE3. PGE3 uptake was assessed in HEK293 cells transfected with OATP2A1/SLCO2A1, OATP1B1/SLCO1B1, OATP2B1/SLCO2B1, OAT1/SLC22A6, OCT1/SLC22A1 or OCT2/SLC22A2 genes, compared with HEK293 cells transfected with plasmid vector alone (Mock). PGE3 uptake by OATP2A1-expressing HEK293 cells (HEK/2A1) was the highest and followed by HEK/1B1, while no significantly higher uptake of PGE3 than Mock cells was detected by other transporters. Saturation kinetics in PGE3 uptake by HEK/2A1 estimated the Km as 7.202 ± 0.595 μM, which was 22 times higher than that of PGE2 (Km=0.331 ± 0.131 μM). Furthermore, tissue disposition of PGE3 was examined in wild-type (WT) and Slco2a1-deficient (Slco2a1(-/-)) mice after oral administration of EPA ethyl ester (EPA-E) when they underwent intraperitoneal injection of endotoxin (e.g., lipopolysaccharide). PGE3 concentration was significantly higher in the lung, and tended to increase in the colon, stomach, and kidney of Slco2a1(-/-), compared to WT mice. Ratio of PGE2 metabolite 15-keto PGE2 over PGE2 concentration was significantly lower in the lung and colon of Slco2a1(-/-) than that of WT mice, suggesting that PGE3 metabolism is downregulated in Slco2a1(-/-) mice. In conclusion, PGE3 was found to be a substrate of OATP2A1, and local disposition of PGE3 could be regulated by OATP2A1 at least in the lung. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Haemoglobin J-Baltimore can be detected by HbA1c electropherogram but with underestimated HbA1c value.

    Science.gov (United States)

    Brunel, Valéry; Lahary, Agnčs; Chagraoui, Abdeslam; Thuillez, Christian

    2016-01-01

    Glycated haemoglobin (HbA(1c)) is considered the gold standard for assessing diabetes compensation and treatment. In addition, fortuitous detection of haemoglobin variants during HbA1c measurement is not rare. Recently, two publications reported different conclusions on accuracy of HbA(1c) value using capillary electrophoresis method in presence of haemoglobin J-Baltimore (HbJ).
Here we describe the fortuitous detection of unknown HbJ using capillary electrophoresis for measurement of HbA(1c). A patient followed for gestational diabetes in our laboratory presented unknown haemoglobin on Capillarys 2 Flex Piercing analyser which was identified as HbJ. HbJ is not associated with haematological abnormalities. High Performance Liquid Chromatography methods are known to possibly underestimate HbA(1c) value in the presence of this variant. This variant and its glycated form are clearly distinguished on electropherogram but HbJ was responsible for underestimating the true area of HbA(1c).
 Capillary electrophoresis is a good method for detecting HbJ but does not seem suitable for evaluation of HbA(1C) value in patients in presence of HbJ variant.

  4. Point-of-Care Hemoglobin A1c Testing: An Evidence-Based Analysis.

    Science.gov (United States)

    2014-01-01

    The increasing prevalence of diabetes in Ontario means that there will be growing demand for hemoglobin A1c (HbA1c) testing to monitor glycemic control for the management of this chronic disease. Testing HbA1c where patients receive their diabetes care may improve system efficiency if the results from point-of-care HbA1c testing are comparable to those from laboratory HbA1c measurements. To review the correlation between point-of-care HbA1c testing and laboratory HbA1c measurement in patients with diabetes in clinical settings. The literature search included studies published between January 2003 and June 2013. Search terms included glycohemoglobin, hemoglobin A1c, point of care, and diabetes. Studies were included if participants had diabetes; if they compared point-of-care HbA1c devices (licensed by Health Canada and available in Canada) with laboratory HbA1c measurement (reference method); if they performed point-of-care HbA1c testing using capillary blood samples (finger pricks) and laboratory HbA1c measurement using venous blood samples within 7 days; and if they reported a correlation coefficient between point-of-care HbA1c and laboratory HbA1c results. Three point-of-care HbA1c devices were reviewed in this analysis: Bayer's A1cNow+, Bio-Rad's In2it, and Siemens' DCA Vantage. Five observational studies met the inclusion criteria. The pooled results showed a positive correlation between point-of-care HbA1c testing and laboratory HbA1c measurement (correlation coefficient, 0.967; 95% confidence interval, 0.960-0.973). Outcomes were limited to the correlation coefficient, as this was a commonly reported measure of analytical performance in the literature. Results should be interpreted with caution due to risk of bias related to selection of participants, reference standards, and the multiple steps involved in POC HbA1c testing. Moderate quality evidence showed a positive correlation between point-of-care HbA1c testing and laboratory HbA1c measurement. Five

  5. The activation mechanisms of G protein-coupled receptors : the case of the adenosine A2B and HCA2/3 receptors

    NARCIS (Netherlands)

    Liu, R.

    2016-01-01

    Identifying and elucidating the functions and activation of GPCRs will provide opportunities for novel drug discovery. We confirmed that a yeast system with an extended library of G proteins is very well suited for the study of GPCR activation, G protein coupling profiles, receptor-G protein binding

  6. Self-Controlled Synthesis of Hyperbranched Poly(etherketone)s from A2 + B3 Approach in Poly(phosphoric acid)

    Science.gov (United States)

    2009-01-01

    and Soxhlet extracted with water for three days and methanol for three days, and finally freeze dried for 48 h to give 1.37 g (99.3% yield) of light...reaction mixture became dark-brown at the end of reaction. The final prod- ucts were completely worked-up in the Soxhlet extraction in water for three days

  7. Positive selection in penicillin-binding proteins 1a, 2b, and 2x from Streptococcus pneumoniae and its correlation with amoxicillin resistance development.

    Science.gov (United States)

    Stanhope, Michael J; Lefébure, Tristan; Walsh, Stacey L; Becker, Julie A; Lang, Ping; Pavinski Bitar, Paulina D; Miller, Linda A; Italia, Michael J; Amrine-Madsen, Heather

    2008-05-01

    The efficacy of beta-lactam antibiotics in Streptococcus pneumoniae has been compromised because of the development of altered penicillin-binding proteins (PBPs), however, this has been less so for amoxicillin than for penicillin. Recently, there have been a number of important methods developed to detect molecular adaptation in protein coding genes. The purpose of this study is to employ modern molecular selection approaches to predict sites under positive selection pressure in PBPs, derived from a large international S. pneumoniae collection of amoxicillin resistant and susceptible isolates, and encompassing a comparative data set of 354 pbp1a, 335 pbp2b, and 389 pbp2x gene sequences. A correspondence discriminant analysis (CDA) of positively selected pbp sites and amoxicillin MIC (minimum inhibitory concentration) values is then used to detect sites under positive selection pressure that are important in discriminating different amoxicillin MICs. Molecular adaptation was evident throughout PBP2X, with numerous positively selected sites in both the transpeptidase (TP) and C-terminal domains, strongly correlated with discriminating amoxicillin MICs. In the case of PBP1A positive selection was present in the glycosyltransfer (GT), TP and C-terminal domains. Sites within the TP domain tended to be correlated with the discrimination of low from intermediate MICs, whereas sites within the C-terminal tail, with a discrimination of intermediate from fully resistant. Most of the positively selected sites within PBP2B were in the N-terminal domain and were not correlated with amoxicillin MICs, however, several sites taken from the literature for the TP domain were strongly associated with discriminating high from intermediate level amoxicillin resistance. Many of the positively selected sites could be directly associated with functional inferences based on the crystal structures of these proteins. Our results suggest that clinical emphasis on TP domain sequences of these proteins may result in missing information relevant to antibiotic resistance development.

  8. Magnetic damping in sputter-deposited C o2MnGe Heusler compounds with A 2 ,B 2 , and L 21 orders: Experiment and theory

    Science.gov (United States)

    Shaw, Justin M.; Delczeg-Czirjak, Erna K.; Edwards, Eric R. J.; Kvashnin, Yaroslav; Thonig, Danny; Schoen, Martin A. W.; Pufall, Matt; Schneider, Michael L.; Silva, Thomas J.; Karis, Olof; Rice, Katherine P.; Eriksson, Olle; Nembach, Hans T.

    2018-03-01

    We show that very low values of the magnetic damping parameter can be achieved in sputter deposited polycrystalline films of C o2MnGe annealed at relatively low temperatures ranging from 240 °C to 400 °C. Damping values as low as 0.0014 are obtained with an intrinsic value of 0.0010 after spin-pumping contributions are considered. Of importance to most applications is the low value of inhomogeneous linewidth that yields measured linewidths of 1.8 and 5.1 mT at 10 and 40 GHz, respectively. The damping parameter monotonically decreases as the B 2 order of the films increases. This trend is reproduced and explained by ab initio calculations of the electronic structure and damping parameter. Here, the damping parameter is calculated as the structure evolves from A 2 to B 2 to L 21 orders. The largest decrease in the damping parameter occurs during the A 2 to B 2 transition as the half-metallic phase becomes established.

  9. Hydrogen sulfide inhibits A2A adenosine receptor agonist induced β-amyloid production in SH-SY5Y neuroblastoma cells via a cAMP dependent pathway.

    Directory of Open Access Journals (Sweden)

    Bhushan Vijay Nagpure

    Full Text Available Alzheimer's disease (AD is the leading cause of senile dementia in today's society. Its debilitating symptoms are manifested by disturbances in many important brain functions, which are influenced by adenosine. Hence, adenosinergic system is considered as a potential therapeutic target in AD treatment. In the present study, we found that sodium hydrosulfide (NaHS, an H2S donor, 100 µM attenuated HENECA (a selective A2A receptor agonist, 10-200 nM induced β-amyloid (1-42 (Aβ42 production in SH-SY5Y cells. NaHS also interfered with HENECA-stimulated production and post-translational modification of amyloid precursor protein (APP by inhibiting its maturation. Measurement of the C-terminal APP fragments generated from its enzymatic cleavage by β-site amyloid precursor protein cleaving enzyme 1 (BACE1 showed that NaHS did not have any significant effect on β-secretase activity. However, the direct measurements of HENECA-elevated γ-secretase activity and mRNA expressions of presenilins suggested that the suppression of Aβ42 production in NaHS pretreated cells was mediated by inhibiting γ-secretase. NaHS induced reductions were accompanied by similar decreases in intracellular cAMP levels and phosphorylation of cAMP responsive element binding protein (CREB. NaHS significantly reduced the elevated cAMP and Aβ42 production caused by forskolin (an adenylyl cyclase, AC agonist alone or forskolin in combination with IBMX (a phosphodiesterase inhibitor, but had no effect on those caused by IBMX alone. Moreover, pretreatment with NaHS significantly attenuated HENECA-elevated AC activity and mRNA expressions of various AC isoforms. These data suggest that NaHS may preferentially suppress AC activity when it was stimulated. In conclusion, H2S attenuated HENECA induced Aβ42 production in SH-SY5Y neuroblastoma cells through inhibiting γ-secretase via a cAMP dependent pathway.

  10. Fractalkine (CX3CL1) enhances hippocampal N-methyl-d-aspartate receptor (NMDAR) function via d-serine and adenosine receptor type A2 (A2AR) activity

    Science.gov (United States)

    2013-01-01

    Background N-Methyl-d-aspartate receptors (NMDARs) play fundamental roles in basic brain functions such as excitatory neurotransmission and learning and memory processes. Their function is largely regulated by factors released by glial cells, including the coagonist d-serine. We investigated whether the activation of microglial CX3CR1 induces the release of factors that modulate NMDAR functions. Methods We recorded the NMDAR component of the field excitatory postsynaptic potentials (NMDA-fEPSPs) elicited in the CA1 stratum radiatum of mouse hippocampal slices by Shaffer collateral stimulation and evaluated d-serine content in the extracellular medium of glial primary cultures by mass spectrometry analysis. Results We demonstrated that CX3CL1 increases NMDA-fEPSPs by a mechanism involving the activity of the adenosine receptor type A2 (A2AR) and the release of the NMDAR coagonist d-serine. Specifically (1) the selective A2AR blocker 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261) and the genetic ablation of A2AR prevent CX3CL1 action while the A2AR agonist 5-(6-amino-2-(phenethylthio)-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydrofuran-2-carboxamide (VT7) mimics CX3CL1 effect, and (2) the selective blocking of the NMDAR glycine (and d-serine) site by 5,7-dicholorokynurenic acid (DCKA), the enzymatic degradation of d-serine by d-amino acid oxidase (DAAO) and the saturation of the coagonist site by d-serine, all block the CX3CL1 effect. In addition, mass spectrometry analysis demonstrates that stimulation of microglia and astrocytes with CX3CL1 or VT7 increases d-serine release in the extracellular medium. Conclusions CX3CL1 transiently potentiates NMDAR function though mechanisms involving A2AR activity and the release of d-serine. PMID:23981568

  11. Adenosine A2A receptor signaling affects IL-21/IL-22 cytokines and GATA3/T-bet transcription factor expression in CD4+T cells from a BTBR T+Itpr3tf/J mouse model of autism.

    Science.gov (United States)

    Ahmad, Sheikh F; Ansari, Mushtaq A; Nadeem, Ahmed; Bakheet, Saleh A; Almutairi, Mashal M; Attia, Sabry M

    2017-10-15

    Autism is a complex heterogeneous neurodevelopmental disorder; previous studies have identified altered immune responses among individuals diagnosed with autism. An imbalance in the production of pro- and anti-inflammatory cytokines and transcription factors plays a role in neurodevelopmental behavioral and autism disorders. BTBR T + Itpr3tf/J (BTBR) mice are used as a model for autism, as they exhibit social deficits, communication deficits, and repetitive behaviors compared with C57BL/6J (B6) mice. The adenosine A2A receptor (A2AR) appears to be a potential target for the improvement of behavioral, inflammatory, immune, and neurological disorders. We investigated the effects of the A2AR antagonist SCH 5826 (SCH) and agonist CGS 21680 (CGS) on IL-21, IL-22, T-bet, T-box transcription factor (T-bet), GATA3 (GATA Binding Protein 3), and CD152 (CTLA-4) expression in BTBR mice. Our results showed that BTBR mice treated with SCH had increased CD4 + IL-21 + , CD4 + IL-22 + , CD4 + GATA3 + , and CD4 + T-bet + and decreased CD4 + CTLA-4 + expression in spleen cells compared with BTBR control mice. Moreover, CGS efficiently decreased CD4 + IL-21 + , CD4 + IL-22 + , CD4 + GATA3 + , and CD4 + T-bet + and increased CD4 + CTLA-4 production in spleen cells compared with SCH-treated and BTBR control mice. Additionally, SCH treatment significantly increased the mRNA and protein expression levels of IL-21, IL-22, GATA3, and T-bet in brain tissue compared with CGS-treated and BTBR control mice. The augmented levels of IL-21/IL-22 and GATA3/T-bet could be due to altered A2AR signaling. Our results indicate that A2AR agonists may represent a new class of compounds that can be developed for use in the treatment of autistic and neuroimmune dysfunctions. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Whole Blood Donation Affects the Interpretation of Hemoglobin A(1c)

    NARCIS (Netherlands)

    Dijkstra, Angelique; Lenters-Westra, Erna; de Kort, Wim; Bokhorst, Arlinke G.; Bilo, Henk J. G.; Slingerland, Robbert J.; Vos, Michel J.

    2017-01-01

    Introduction Several factors, including changed dynamics of erythrocyte formation and degradation, can influence the degree of hemoglobin A(1c) (HbA(1c)) formation thereby affecting its use in monitoring diabetes. This study determines the influence of whole blood donation on HbA(1c) in both

  13. Whole Blood Donation Affects the Interpretation of Hemoglobin A1c

    NARCIS (Netherlands)

    Dijkstra, Angelique; Lenters-Westra, Erna; de Kort, Wim; Bokhorst, Arlinke G.; Bilo, Henk J. G.; Slingerland, Robbert J.; Vos, Michel J.

    2017-01-01

    Several factors, including changed dynamics of erythrocyte formation and degradation, can influence the degree of hemoglobin A1c (HbA1c) formation thereby affecting its use in monitoring diabetes. This study determines the influence of whole blood donation on HbA1c in both non-diabetic blood donors

  14. 26 CFR 301.6031(a)-1 - Return of partnership income.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Return of partnership income. 301.6031(a)-1....6031(a)-1 Return of partnership income. For provisions relating to the requirement of returns of partnership income, see § 1.6031(a)-1 of this chapter. [T.D. 8841, 64 FR 61502, Nov. 12, 1999] ...

  15. Higher Pretransplantation Hemoglobin A1c Is Associated With Greater Risk of Posttransplant Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Jung-Im Shin

    2017-11-01

    Discussion: Higher pretransplantation HbA1c above 5.4% is independently associated with greater risk of PTDM among kidney transplant recipients. A continuous relationship between pretransplantation HbA1c and risk of PTDM suggests that increased risk starts at HbA1c levels well below current thresholds for prediabetes.

  16. 26 CFR 1.860A-1 - Effective dates and transition rules.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 9 2010-04-01 2010-04-01 false Effective dates and transition rules. 1.860A-1 Section 1.860A-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Real Estate Investment Trusts § 1.860A-1 Effective dates and transition...

  17. 76 FR 56637 - Airworthiness Directives; Lycoming Engines Model IO-720-A1B Reciprocating Engines

    Science.gov (United States)

    2011-09-14

    ... Airworthiness Directives; Lycoming Engines Model IO-720-A1B Reciprocating Engines AGENCY: Federal Aviation... directive (AD) for certain model IO-720-A1B Lycoming Engines reciprocating engines. This AD requires a... two Lycoming Engines model IO- 720-A1B reciprocating engines, installed on airplanes of U.S. registry...

  18. 26 CFR 1.661(a)-1 - Estates and trusts accumulating income or distributing corpus; general.

    Science.gov (United States)

    2010-04-01

    ... distributing corpus; general. 1.661(a)-1 Section 1.661(a)-1 Internal Revenue INTERNAL REVENUE SERVICE... Accumulate Income Or Which Distribute Corpus § 1.661(a)-1 Estates and trusts accumulating income or distributing corpus; general. Subpart C, part I, subchapter J, chapter 1 of the Code, is applicable to all...

  19. 17 CFR 240.15a-1 - Securities activities of OTC derivatives dealers.

    Science.gov (United States)

    2010-04-01

    ... options, forwards, futures, swap agreements, or collars involving currencies, interest or other rates... derivatives dealers. 240.15a-1 Section 240.15a-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... Under the Securities Exchange Act of 1934 Exemption of Certain Otc Derivatives Dealers § 240.15a-1...

  20. Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes

    Science.gov (United States)

    Ginés, Silvia; Hillion, Joëlle; Torvinen, Maria; Le Crom, Stèphane; Casadó, Vicent; Canela, Enric I.; Rondin, Sofia; Lew, Jow Y.; Watson, Stanley; Zoli, Michele; Agnati, Luigi Francesco; Vernier, Philippe; Lluis, Carmen; Ferré, Sergi; Fuxe, Kjell; Franco, Rafael

    2000-01-01

    The possible molecular basis for the previously described antagonistic interactions between adenosine A1 receptors (A1R) and dopamine D1 receptors (D1R) in the brain have been studied in mouse fibroblast Ltk− cells cotransfected with human A1R and D1R cDNAs or with human A1R and dopamine D2 receptor (long-form) (D2R) cDNAs and in cortical neurons in culture. A1R and D1R, but not A1R and D2R, were found to coimmunoprecipitate in cotransfected fibroblasts. This selective A1R/D1R heteromerization disappeared after pretreatment with the D1R agonist, but not after combined pretreatment with D1R and A1R agonists. A high degree of A1R and D1R colocalization, demonstrated in double immunofluorescence experiments with confocal laser microscopy, was found in both cotransfected fibroblast cells and cortical neurons in culture. On the other hand, a low degree of A1R and D2R colocalization was observed in cotransfected fibroblasts. Pretreatment with the A1R agonist caused coclustering (coaggregation) of A1R and D1R, which was blocked by combined pretreatment with the D1R and A1R agonists in both fibroblast cells and in cortical neurons in culture. Combined pretreatment with D1R and A1R agonists, but not with either one alone, substantially reduced the D1R agonist-induced accumulation of cAMP. The A1R/D1R heteromerization may be one molecular basis for the demonstrated antagonistic modulation of A1R of D1R receptor signaling in the brain. The persistence of A1R/D1R heteromerization seems to be essential for the blockade of A1R agonist-induced A1R/D1R coclustering and for the desensitization of the D1R agonist-induced cAMP accumulation seen on combined pretreatment with D1R and A1R agonists, which indicates a potential role of A1R/D1R heteromers also in desensitization mechanisms and receptor trafficking. PMID:10890919

  1. The structure of an E. coli tRNAfMet A1-U72 variant shows an unusual conformation of the A1-U72 base pair.

    Science.gov (United States)

    Monestier, Auriane; Aleksandrov, Alexey; Coureux, Pierre-Damien; Panvert, Michel; Mechulam, Yves; Schmitt, Emmanuelle

    2017-05-01

    Translation initiation in eukaryotes and archaea involves a methionylated initiator tRNA delivered to the ribosome in a ternary complex with e/aIF2 and GTP. Eukaryotic and archaeal initiator tRNAs contain a highly conserved A 1 -U 72 base pair at the top of the acceptor stem. The importance of this base pair to discriminate initiator tRNAs from elongator tRNAs has been established previously using genetics and biochemistry. However, no structural data illustrating how the A 1 -U 72 base pair participates in the accurate selection of the initiator tRNAs by the translation initiation systems are available. Here, we describe the crystal structure of a mutant E. coli initiator tRNA f Met A 1 -U 72 , aminoacylated with methionine, in which the C 1 :A 72 mismatch at the end of the tRNA acceptor stem has been changed to an A 1 -U 72 base pair. Sequence alignments show that the mutant E. coli tRNA is a good mimic of archaeal initiator tRNAs. The crystal structure, determined at 2.8 Å resolution, shows that the A 1 -U 72 pair adopts an unusual arrangement. A 1 is in a syn conformation and forms a single H-bond interaction with U 72 This interaction requires protonation of the N1 atom of A 1 Moreover, the 5' phosphoryl group folds back into the major groove of the acceptor stem and interacts with the N7 atom of G 2 A possible role of this unusual geometry of the A 1 -U 72 pair in the recognition of the initiator tRNA by its partners during eukaryotic and archaeal translation initiation is discussed. © 2017 Monestier et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

  2. Rat olfactory bulb and epithelium UDP-glucuronosyltransferase 2A1 (UGT2A1) expression: in situ mRNA localization and quantitative analysis.

    Science.gov (United States)

    Heydel, J; Leclerc, S; Bernard, P; Pelczar, H; Gradinaru, D; Magdalou, J; Minn, A; Artur, Y; Goudonnet, H

    2001-05-20

    UDP-glucuronosyltransferases (UGTs) form a multigenic family of enzymes involved in the biotransformation and elimination of numerous endo- and xenobiotic compounds. Beside the diverse UGT isoforms present in the liver as well as in other tissues, the UGT2A1 isoform, also called olfactory UGT, was initially thought to be expressed in the nasal epithelium only. In this work, we demonstrate the UGT2A1 mRNA expression in the olfactory bulb, using in situ hybridization and quantitative reverse transcription-polymerase chain reaction (RT-PCR) techniques. Within the epithelium, UGT2A1 mRNA is mainly found in the sustentacular cells and to a lesser extent in Bowman's gland cells. Moreover, in situ hybrization staining reveals UGT2A1 mRNA expression in the olfactory sensory neuron nuclei. Neuronal localization of UGT2A1 mRNA within the olfactory bulb is mainly found in the deeper granular cells. The development of the quantitative multistandard RT-PCR method firstly required characterization of the mouse Ugt2A1 cDNA by rapid amplification of cDNA ends (RACE)-PCR. UGT2A1 mRNA levels appear quantitatively six-fold lower in the olfactory bulb than in the epithelium, in both the rat and mouse. The expression of UGT2A1 in the olfactory bulb, which directly connects the nasal epithelium to the brain, emphasizes the potential role of this enzyme in the protection of the brain against airborne hazardous chemicals.

  3. Diagnosis of diabetes mellitus using HbA1c in Asians: relationship between HbA1c and retinopathy in a multiethnic Asian population.

    Science.gov (United States)

    Sabanayagam, Charumathi; Khoo, Eric Y H; Lye, Weng Kit; Ikram, M Kamran; Lamoureux, Ecosse L; Cheng, Ching Yu; Tan, Maudrene L S; Salim, Agus; Lee, Jeannette; Lim, Su-Chi; Tavintharan, Subramaniam; Thai, Ah-Chuan; Heng, Derrick; Ma, Stefan; Tai, E Shyong; Wong, Tien Y

    2015-02-01

    Hemoglobin A1c (HbA1c) ≥ 6.5% (47.5 mmol/mol) has recently been included as a criterion for the diagnosis of diabetes mellitus. It is unclear whether this criterion is appropriate in Asians. To examine the relationship between HbA1c and diabetes-specific moderate retinopathy in Asian ethnic groups. Four independent population-based cross-sectional studies (2004-2011) in Singapore representing the three major Asian ethnic groups (n = 13 170 adults aged ≥ 25 y: Chinese, 5834; Malays, 3596; and Indians, 3740). Moderate retinopathy was assessed from digital retinal photographs and defined as a level >43 using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Sensitivity, specificity, positive and negative predictive values, and the area under the receiver operating characteristic curve for detecting moderate retinopathy were compared across ethnic groups at different HbA1c cut-points. HbA1c levels were higher in Indians and Malays compared to Chinese (P retinopathy below HbA1c retinopathy was lower in Chinese subjects compared to Indians and Malays (75.8 vs 86.0 and 85.3%), but specificity (89.7 vs 71.9 and 76.3%) was higher; however, positive predictive value and negative predictive value were similar among Chinese, Indians, and Malays (10.5, 12.3, 12.4%; and 99.6, 99.1, 99.2%, respectively). The AUCs were similar across all three ethnic groups (0.861, 0.851, and 0.853). Our study supports the use of HbA1c for diagnosing diabetes in Asians. Despite some interethnic variation in the relationship of HbA1c and retinopathy, a cut-point of 6.5% performs reasonably well in the three major Asian ethnic groups.

  4. Comparison of four variants of a major allergen in hazelnut (Corylus avellana) Cor a 1.04 with the major hazel pollen allergen Cor a 1.01

    DEFF Research Database (Denmark)

    Lüttkopf, D; Müller, U; Skov, P S

    2002-01-01

    -blind placebo-controlled food challenges (DBPCFC) in a multicenter study. Total RNA was isolated from immature hazelnuts and transcribed into cDNA. Full length coding DNA obtained by PCR-strategy was subcloned into pTYB11 vector and expressed in E. coli ER2566 cells. Native non-fusion target proteins were...... purified by DTT-induced self-cleavage of the intein-tagged N-terminal fusion proteins. IgE reactivity of the recombinant allergens was tested by enzyme allergosorbent test (EAST), EAST-inhibition, immunoblot-inhibition and histamine release assays. Four recombinant allergens were produced showing deduced...... amino acid sequence identities among each other of 97-99%, and were considered as variants Cor a 1.0401 (GenBank Accession no.: AF136945), Cor a 1.0402 (AF323973), Cor a 1.0403 (AF323974) and Cor a 1.0404 (AF323975). Cor a 1.0402 and 03 only differed in a C4S exchange. Cor a 1.0404 had a unique proline...

  5. Silencing of NRF2 Reduces the Expression of ALDH1A1 and ALDH3A1 and Sensitizes to 5-FU in Pancreatic Cancer Cells

    Directory of Open Access Journals (Sweden)

    Hong-Quan Duong

    2017-07-01

    Full Text Available Pancreatic cancer remains an intractable cancer with a poor five-year survival rate, which requires new therapeutic modalities based on the biology of pancreatic oncogenesis. Nuclear factor E2 related factor-2 (NRF2, a key cytoprotective nuclear transcription factor, regulates antioxidant production, reduction, detoxification and drug efflux proteins. It also plays an essential role in cell homeostasis, cell proliferation and resistance to chemotherapy. We aimed to evaluate the possibility that modulation of NRF2 expression could be effective in the treatment of pancreatic cancer cells. We investigated whether the depletion of NRF2 by using small interfering RNAs (siRNAs is effective in the expression of biomarkers of pancreatic cancer stemness such as aldehyde dehydrogenase 1 family, member A1 (ALDH1A1 and aldehyde dehydrogenase 3 family, member A1 (ALDH3A1. NRF2 knockdown markedly reduced the expression of NRF2 and glutamate-cysteine ligase catalytic subunit (GCLC in cell lines established from pancreatic cancers. NRF2 silencing also decreased the ALDH1A1 and ALDH3A1 expression. Furthermore, this NRF2 depletion enhanced the antiproliferative effects of the chemotherapeutic agent, 5-fluorouracil (5-FU in pancreatic cancer cells.

  6. Relationship of HbA1c variability, absolute changes in HbA1c, and all-cause mortality in type 2 diabetes

    DEFF Research Database (Denmark)

    Skriver, Mette Vinther; Sandbæk, Annelli; Kristensen, Jette Kolding

    2015-01-01

    OBJECTIVE: We assessed the relationship of mortality with glycated hemoglobin (HbA1c) variability and with absolute change in HbA1c. DESIGN: A population-based prospective observational study with a median follow-up time of 6 years. METHODS: Based on a validated algorithm, 11 205 Danish individuals...... with type 2 diabetes during 2001-2006 were identified from public data files, with at least three HbA1c measurements: one index measure, one closing measure 22-26 months later, and one measurement in-between. Medium index HbA1c was 7.3%, median age was 63.9 years, and 48% were women. HbA1c variability...... was defined as the mean absolute residual around the line connecting index value with closing value. Cox proportional hazard models with restricted cubic splines were used, with all-cause mortality as the outcome. RESULTS: Variability between 0 and 0.5 HbA1c percentage point was not associated with mortality...

  7. Retinal and Nonocular Abnormalities in Cyp27a1−/−Cyp46a1−/− Mice with Dysfunctional Metabolism of Cholesterol

    Science.gov (United States)

    Saadane, Aicha; Mast, Natalia; Charvet, Casey D.; Omarova, Saida; Zheng, Wenchao; Huang, Suber S.; Kern, Timothy S.; Peachey, Neal S.; Pikuleva, Irina A.

    2015-01-01

    Cholesterol elimination from nonhepatic cells involves metabolism to side-chain oxysterols, which serve as transport forms of cholesterol and bioactive molecules modulating a variety of cellular processes. Cholesterol metabolism is tissue specific, and its significance has not yet been established for the retina, where cytochromes P450 (CYP27A1 and CYP46A1) are the major cholesterol-metabolizing enzymes. We generated Cyp27a1−/−Cyp46a1−/− mice, which were lean and had normal serum cholesterol and glucose levels. These animals, however, had changes in the retinal vasculature, retina, and several nonocular organs (lungs, liver, and spleen). Changes in the retinal vasculature included structural abnormalities (retinal-choroidal anastomoses, arteriovenous shunts, increased permeability, dilation, nonperfusion, and capillary degeneration) and cholesterol deposition and oxidation in the vascular wall, which also exhibited increased adhesion of leukocytes and activation of the complement pathway. Changes in the retina included increased content of cholesterol and its metabolite, cholestanol, which were focally deposited at the apical and basal sides of the retinal pigment epithelium. Retinal macrophages of Cyp27a1−/−Cyp46a1−/− mice were activated, and oxidative stress was noted in their photoreceptor inner segments. Our findings demonstrate the importance of retinal cholesterol metabolism for maintenance of the normal retina, and suggest new targets for diseases affecting the retinal vasculature. PMID:25065682

  8. Ethnic differences in the prevalence of polymorphisms in CYP7A1, CYP7B1 AND CYP27A1 enzymes involved in cholesterol metabolism

    Directory of Open Access Journals (Sweden)

    Vera Dias

    2011-01-01

    Full Text Available It is well known that drug disposition and response are greatly determined by the activities of drug metabolizing enzymes, which are polymorphic. Some of these polymorphisms are clinically relevant and presented an ethnic-dependent pattern of distribution. The characterization of the genetic distribution of different populations allows the selection of therapeutic options in accordance with the genetic background, with the objective to avoid adverse reactions and inefficacy of the treatment. In this work, we studied selected genetic polymorphisms in drug metabolizing enzymes in three different ethnic groups - Portugal, Mozambique and Colombia. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP genotyping methods were developed for drug metabolizing enzymes, namely, cholesterol 7α-hydroxylase (CYP7A1 (−203A>C, −346C>T, −496C>T, N233S, G347S, sterol 27-hydroxylase (CYP27A1 (R164W, A169V, D273N, V400A and oxysterol 7α-hydroxylase (CYP7B1 (−116C>G, R324H, 1774C>T to characterize the allelic distribution of these polymorphisms among three different ethnic/geographic origins. A total of 12 CYP7A1, CYP27A1 and CYP7B1 genetic variants were genotyped in a sample of 92 Portuguese, 151 Mozambican and 91 Colombian subjects. The variants N233S in CYP7A1 and 1774C>T in CYP7B1 were not detected in any population studied. The promoter polymorphisms in CYP7A1 (−203A>C, −346C>T, −496C>T had high frequency in the three ethnic groups. G347S (CYP7A1, R164W, A169V and V400A (CYP27A1 were present in a low frequency but with a similar distribution in the three ethnic groups. Significant differences were observed for D273N (CYP27A1, −346C>T (CYP7A1, −116C>G and R324H (CYP7B1Our results demonstrate a high variability of drug metabolizing enzymes between the different populations analyzed, indicating that at least some of these polymorphisms are ethnic specific.

  9. Ethnic differences in the prevalence of polymorphisms in CYP7A1, CYP7B1 AND CYP27A1 enzymes involved in cholesterol metabolism.

    Science.gov (United States)

    Dias, Vera; Ribeiro, V

    2011-07-01

    It is well known that drug disposition and response are greatly determined by the activities of drug metabolizing enzymes, which are polymorphic. Some of these polymorphisms are clinically relevant and presented an ethnic-dependent pattern of distribution. The characterization of the genetic distribution of different populations allows the selection of therapeutic options in accordance with the genetic background, with the objective to avoid adverse reactions and inefficacy of the treatment. In this work, we studied selected genetic polymorphisms in drug metabolizing enzymes in three different ethnic groups - Portugal, Mozambique and Colombia. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) genotyping methods were developed for drug metabolizing enzymes, namely, cholesterol 7α-hydroxylase (CYP7A1) (-203A>C, -346C>T, -496C>T, N233S, G347S), sterol 27-hydroxylase (CYP27A1) (R164W, A169V, D273N, V400A) and oxysterol 7α-hydroxylase (CYP7B1) (-116C>G, R324H, 1774C>T) to characterize the allelic distribution of these polymorphisms among three different ethnic/geographic origins. A total of 12 CYP7A1, CYP27A1 and CYP7B1 genetic variants were genotyped in a sample of 92 Portuguese, 151 Mozambican and 91 Colombian subjects. The variants N233S in CYP7A1 and 1774C>T in CYP7B1 were not detected in any population studied. The promoter polymorphisms in CYP7A1 (-203A>C, -346C>T, -496C>T) had high frequency in the three ethnic groups. G347S (CYP7A1), R164W, A169V and V400A (CYP27A1) were present in a low frequency but with a similar distribution in the three ethnic groups. Significant differences were observed for D273N (CYP27A1), -346C>T (CYP7A1), -116C>G and R324H (CYP7B1)Our results demonstrate a high variability of drug metabolizing enzymes between the different populations analyzed, indicating that at least some of these polymorphisms are ethnic specific.

  10. Recovery sleep after extended wakefulness restores elevated A1adenosine receptor availability in the human brain.

    Science.gov (United States)

    Elmenhorst, David; Elmenhorst, Eva-Maria; Hennecke, Eva; Kroll, Tina; Matusch, Andreas; Aeschbach, Daniel; Bauer, Andreas

    2017-04-18

    Adenosine and functional A 1 adenosine receptor (A 1 AR) availability are supposed to mediate sleep-wake regulation and cognitive performance. We hypothesized that cerebral A 1 AR availability after an extended wake period decreases to a well-rested state after recovery sleep. [ 18 F]CPFPX positron emission tomography was used to quantify A 1 AR availability in 15 healthy male adults after 52 h of sleep deprivation and following 14 h of recovery sleep. Data were additionally compared with A 1 AR values after 8 h of baseline sleep from an earlier dataset. Polysomnography, cognitive performance, and sleepiness were monitored. Recovery from sleep deprivation was associated with a decrease in A 1 AR availability in several brain regions, ranging from 11% (insula) to 14% (striatum). A 1 AR availabilities after recovery did not differ from baseline sleep in the control group. The degree of performance impairment, sleepiness, and homeostatic sleep-pressure response to sleep deprivation correlated negatively with the decrease in A 1 AR availability. Sleep deprivation resulted in a higher A 1 AR availability in the human brain. The increase that was observed after 52 h of wakefulness was restored to control levels during a 14-h recovery sleep episode. Individuals with a large increase in A 1 AR availability were more resilient to sleep-loss effects than those with a subtle increase. This pattern implies that differences in endogenous adenosine and A 1 AR availability might be causal for individual responses to sleep loss.

  11. Development of a PCR-based tool for detecting immunologically relevant Alt a 1 and Alt a 1 homologue coding sequences.

    Science.gov (United States)

    Gabriel, M F; Postigo, I; Gutiérrez-Rodríguez, A; Suñén, E; Tomaz, C T; Martínez, J

    2015-08-01

    Alt a 1 has been recognized as the most important allergen produced by the Pleosporaceae family and is a risk factor for asthma development and/or exacerbation. The aim of this study was to develop a detection tool that is highly specific for species that produced airborne Alt a 1. Based on the highly conserved internal nucleotide region of the several Alt a 1 sequences that are available in GenBank, a pair of primers (Alta1CF/Alta1CR) was designed. A set of primers used by other authors for the production of recombinant Alt a 1 (A21F/A21R) was also tested. The molecular analyses were based on the polymerase chain reaction (PCR) amplification and sequencing of the cDNA that was obtained from thirteen common fungal species. The PCR system that utilized Alta1CF/Alta1CR was highly specific, sensitive, and was able to detect an amplicon of approximately 180 bp from Alt a 1 and Alt a 1-like encoding genes from A. alternata, A. tenuissima, A. infectoria, U. botrytis, and S. botryosum. In contrast, the A21F/A21R primers were specific for the very close taxonomically related species A. alternata and A. tenuissima. Thus, this rapid, sensitive, and specific detection tool can be used to assess Alt a 1 exposure levels and to inform the implementation of the appropriate public health measures. © The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  12. Features of the retinal environment which affect the activities and product profile of cholesterol-metabolizing cytochromes P450 CYP27A1 and CYP11A1.

    Science.gov (United States)

    Heo, Gun-Young; Liao, Wei-Li; Turko, Illarion V; Pikuleva, Irina A

    2012-02-15

    The retina is the sensory organ in the back of the eye which absorbs and converts light to electrochemical impulses transferred to the brain. Herein, we studied how retinal environment affects enzyme-mediated cholesterol removal. We focused on two mitochondrial cytochrome P450 enzymes, CYPs 27A1 and 11A1, which catalyze the first steps in metabolism of cholesterol in the retina and other tissues. Phospholipids (PL) from mitochondria of bovine neural retina, retinal pigment epithelium, liver and adrenal cortex were isolated and compared for the effect on kinetic properties of purified recombinant CYPs in the reconstituted system in vitro. The four studied tissues were also evaluated for the mitochondrial PL and cholesterol content and levels of CYPs 27A1, 11A1 and their redox partners. The data obtained were used for modeling the retinal environment in the in vitro enzyme assays in which we detected the P450 metabolites, 22R-hydroxycholesterol and 5-cholestenoic acid, unexpectedly found by us in the retina in our previous studies. The effect of the by-product of the visual cycle pyridinium bis-retinoid A2E on kinetics of CYP27A1-mediated cholesterol metabolism was also investigated. The results provide insight into the retina's regulation of the enzyme-mediated cholesterol removal. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Point-of-Care Hemoglobin A1c Testing: A Budget Impact Analysis.

    Science.gov (United States)

    Chadee, A; Blackhouse, G; Goeree, R

    2014-01-01

    The increasing prevalence of diabetes in Ontario means that there will be growing demand for hemoglobin A1c (HbA1c) testing to monitor glycemic control as part of managing this chronic disease. Testing HbA1c where patients receive their diabetes care may improve system efficiency if the results from point-of-care HbA1c testing are comparable to those from laboratory HbA1c measurements. To estimate the budget impact of point-of-care HbA1c testing to replace laboratory HbA1c measurement for monitoring glycemic control in patients with diabetes in 2013/2014. This analysis compared the average testing cost of 3 point-of-care HbA1c devices licensed by Health Canada and available on the market in Canada (Bayer's A1cNow+, Siemens's DCA Vantage, and Bio Rad's In2it), with that of the laboratory HbA1c reference method. The cost difference between point-of-care HbA1c testing and laboratory HbA1c measurement was calculated. Costs and the corresponding range of net impact were estimated in sensitivity analyses. The total annual costs of laboratory HbA1c measurement and point-of-care HbA1c testing for 2013/2014 were $91.5 million and $86.8 million, respectively. Replacing all laboratory HbA1c measurements with point-of-care HbA1c testing would save approximately $4.7 million over the next year. Savings could be realized by the health care system at each level that point-of-care HbA1c testing is substituted for laboratory HbA1c measurement. If physician fees were excluded from the analysis, the health care system would incur a net impact from using point-of-care HbA1c testing instead of laboratory A1c measurement. Point-of-care HbA1c technology is already in use in the Ontario health care system, but the current uptake is unclear. Knowing the adoption rate and market share of point-of-care HbA1c technology would allow for a more accurate estimate of budget impact. Replacing laboratory HbA1c measurement with point-of-care HbA1c testing or using point-of-care HbA1c testing in

  14. Phylogenetic relationships among Perissodactyla: secretoglobin 1A1 gene duplication and triplication in the Equidae family.

    Science.gov (United States)

    Côté, Olivier; Viel, Laurent; Bienzle, Dorothee

    2013-12-01

    Secretoglobin family 1A member 1 (SCGB 1A1) is a small anti-inflammatory and immunomodulatory protein that is abundantly secreted in airway surface fluids. We recently reported the existence of three distinct SCGB1A1 genes in the domestic horse genome as opposed to the single gene copy consensus present in other mammals. The origin of SCGB1A1 gene triplication and the evolutionary relationship of the three genes amongst Equidae family members are unknown. For this study, SCGB1A1 genomic data were collected from various Equus individuals including E. caballus, E. przewalskii, E. asinus, E. grevyi, and E. quagga. Three SCGB1A1 genes in E. przewalskii, two SCGB1A1 genes in E. asinus, and a single SCGB1A1 gene in E. grevyi and E. quagga were identified. Sequence analysis revealed that the non-synonymous nucleotide substitutions between the different equid genes coded for 17 amino acid changes. Most of these changes localized to the SCGB 1A1 central cavity that binds hydrophobic ligands, suggesting that this area of SCGB 1A1 evolved to accommodate diverse molecular interactions. Three-dimensional modeling of the proteins revealed that the size of the SCGB 1A1 central cavity is larger than that of SCGB 1A1A. Altogether, these findings suggest that evolution of the SCGB1A1 gene may parallel the separation of caballine and non-caballine species amongst Equidae, and may indicate an expansion of function for SCGB1A1 gene products. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Impact of Mean Cell Hemoglobin on Hb A1c-Defined Glycemia Status.

    Science.gov (United States)

    Rodriguez-Segade, Santiago; Garcia, Javier Rodriguez; García-López, José M; Gude, Francisco; Casanueva, Felipe F; Rs-Alonso, Santiago; Camiña, Félix

    2016-12-01

    Several hematological alterations are associated with altered hemoglobin A 1c (Hb A 1c ). However, there have been no reports of their influence on the rates of exceeding standard Hb A 1c thresholds by patients for whom Hb A 1c determination is requested in clinical practice. The initial data set included the first profiles (complete blood counts, Hb A 1c , fasting glucose, and renal and hepatic parameters) of all adult patients for whom such a profile was requested between 2008 and 2013 inclusive. After appropriate exclusions, 21844 patients remained in the study. Linear and logistic regression models were adjusted for demographic, hematological, and biochemical variables excluded from the predictors. Mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV) correlated negatively with Hb A 1c . Fasting glucose, MCH, and age emerged as predictors of Hb A 1c in a stepwise regression that discarded sex, hemoglobin, MCV, mean corpuscular hemoglobin concentration (MCHC), serum creatinine, and liver disease. Mean Hb A 1c in MCH interdecile intervals fell from 6.8% (51 mmol/mol) in the lowest (≤27.5 pg) to 6.0% (43 mmol/mol) in the highest (>32.5 pg), with similar results for MCV. After adjustment for fasting glucose and other correlates of Hb A 1c , a 1 pg increase in MCH reduced the odds of Hb A 1c -defined dysglycemia, diabetes and poor glycemia control by 10%-14%. For at least 25% of patients, low or high MCH or MCV levels are associated with increased risk of an erroneous Hb A 1c -based identification of glycemia status. Although causality has not been demonstrated, these parameters should be taken into account in interpreting Hb A 1c levels in clinical practice. © 2016 American Association for Clinical Chemistry.

  16. Marked change in the balance between CYP27A1 and CYP46A1 mediated elimination of cholesterol during differentiation of human neuronal cells.

    Science.gov (United States)

    Milagre, Inês; Olin, Maria; Nunes, Maria João; Moutinho, Miguel; Lövgren-Sandblom, Anita; Gama, Maria João; Björkhem, Ingemar; Rodrigues, Elsa

    2012-01-01

    Cholesterol metabolism in the brain is distinct from that in other tissues due to the fact that cholesterol itself is unable to pass across the blood-brain barrier. Elimination of brain cholesterol is mainly dependent on a neuronal-specific cytochrome P450, CYP46A1, catalyzing the conversion of cholesterol into 24(S)-hydroxycholesterol (24OHC), which is able to pass the blood-brain barrier. A suitable model for studying this elimination from human neuronal cells has not been described previously. It is shown here that differentiated Ntera2/clone D1 (NT2) cells express the key genes involved in brain cholesterol homeostasis including CYP46A1, and that the expression profiles of the genes observed during neuronal differentiation are those expected to occur in vivo. Thus there was a decrease in the mRNA levels corresponding to cholesterol synthesis enzymes and a marked increase in the mRNA level of CYP46A1. The latter increase was associated with increased levels of CYP46A1 protein and increased production of 24OHC. The magnitude of the secretion of 24OHC from the differentiated NT2 cells into the medium was similar to that expected to occur under in vivo conditions. An alternative to elimination of cholesterol by the CYP46A1 mechanism is elimination by CYP27A1, and the product of this enzyme, 27-hydroxycholesterol (27OHC), is also known to pass the blood-brain barrier. The CYP27A1 protein level decreased during the differentiation of the NT2 cells in parallel with decreased production of 27OHC. The ratio between 24OHC and 27OHC in the medium from the cultured cells increased, by a factor of 13, during the differentiation process. The results suggest that progenitor cells eliminate cholesterol in the form of 27OHC while neurogenesis induces a change to the CYP46A1 dependent pathway. Furthermore this study demonstrates that differentiated NT2 cells are suitable for studies of cholesterol homeostasis in human neurons. Copyright © 2011 Elsevier Ltd. All rights reserved.

  17. Gambaran Populasi Golongan Darah Subgroup A (A1, A2 di PMI Kulon Progo

    Directory of Open Access Journals (Sweden)

    Hieronymus Rayi Prasetya

    2017-08-01

    Full Text Available Subgroup A1 and A2 are the most important in the blood group A. Subgroup A1 has the A antigen more than A2 subgroup, the A2 subgroup can cause misidentification of blood group due to poor A antigen and genetic variation possessed. Misidentification of the blood group will increase the risk of transfusion reactions. This research aims to describe the A1 and A2 subgroup population in Kulon Progo district. This study was conducted with a cross sectional sampling technique. The sample in this study were taken from donors of blood group A in Kulon Progo Red Cross. Identification of A1 and A2 subgroup is done by using lectin (Dolichos biflorus extract. The result of the examination of 53 samples showed that 96,2% was A1 subgroup and 3,8% was A2 subgroup. Key words : Subgroup A1, Subgroup A2, Population, Kulon Progo

  18. Serial changes in plasma annexin A1 and cortisol levels in sepsis patients.

    Science.gov (United States)

    Tsai, Wen-Hui; Li, I-Ting; Yu, Yuan-Bin; Hsu, Hui-Chi; Shih, Chung-Hung

    2014-02-28

    Annexin A1 (AnxA1), originally identified as a glucocorticoid-regulated protein, is an impor- tant endogenous anti-inflammatory mediator during the resolution phase of inflammation, and its cir- culating level has been rarely studied in sepsis patients. Glucocorticoid has been extensively used in treating patients with sepsis. However, it is unclear whether endogenous cortisol or exogenous glucocor- ticoid contributes to the regulation of AnxA1 levels in peripheral blood of sepsis patients. The aim of this study was to investigate: [1] serial changes over time in the plasma levels of AnxA1 and cortisol in sepsis patients; and [2] prognostic value of AnxA1 level in the survival of sepsis patients. Fifty-eight adult sepsis patients admitted to an intensive care unit (ICU) were enrolled. The plasma levels of cortisol and AnxA1 were determined by specific enzyme-link immunosorbent assay. Results show that the median daily levels of cortisol at the 1st, 3rd, 5th and 7th day after admission to ICU were signifi- cantly elevated over the cortisol level of the control subjects. However, the AnxA1 level was elevated in only thirty-three patients (56%) over the observation period. There was no significant correlation between cortisol levels and AnxA1 levels. Further analysis indicated that steroid treatment resulted in significant elevation of the cortisol level over time, but did not affect the AnxA1 level. AnxA1 levels were also not statistically different between surviving and non-surviving patients. In conclusions, the circu- lating level of AnxA1 is elevated in a subgroup of sepsis patients, and the AnxA1 level does not correlate with the cortisol level in the peripheral blood of sepsis patients.

  19. Cyclin A1 is a transcriptional target of PITX2 and overexpressed in papillary thyroid carcinoma.

    Science.gov (United States)

    Liu, Yan; Huang, Yue; Zhu, Guo-Zhang

    2013-12-01

    Physiological expression of cyclin A1, a unique cell cycle regulator essential for spermatogenesis, is predominantly restricted in male germ cells. Outstandingly, previous studies have also demonstrated the abnormal expression of cyclin A1 in various human tumors. How male germ cell-specific cyclin A1 is transcriptionally activated in tumor cells, however, is elusive. To begin to understand the molecular mechanisms governing the ectopic expression of cyclin A1, we searched for transcription factors and cis-regulatory DNA elements. We found that overexpression of PITX2, a paired-like homeodomain transcription factor and a downstream effector of Wnt/β-catenin signaling, resulted in upregulation of cyclin A1 in HEK293 cells and TPC-1 thyroid cancer cells. On the other hand, PITX2 knockdown in TPC-1 cells caused reduced cyclin A1. Promoter reporter assays with a series of deletion constructs determined that the DNA element from -102 to -96 bp of the cyclin A1 promoter is responsible for PITX2-induced gene expression. The result of chromatin immunoprecipitation revealed the occupancy of PITX2 on the cyclin A1 promoter. Taken together, these findings demonstrate that cyclin A1 is a transcriptional target of PITX2. Consistently, our immunohistochemistry result showed up-regulation of cyclin A1 in human papillary thyroid carcinoma, where overexpressed PITX2 has been endorsed in our recent report. Thus, our study provides new evidence on the regulation of cyclin A1 gene expression and offers a PITX2-cycin A1 pathway for cell cycle regulation.

  20. Aldehyde dehydrogenase 1A1 circumscribes high invasive glioma cells and predicts poor prognosis

    Science.gov (United States)

    Xu, Sen-Lin; Liu, Sha; Cui, Wei; Shi, Yu; Liu, Qin; Duan, Jiang-Jie; Yu, Shi-Cang; Zhang, Xia; Cui, You-Hong; Kung, Hsiang-Fu; Bian, Xiu-Wu

    2015-01-01

    Glioma is the most aggressive brain tumor with high invasiveness and poor prognosis. More reliable, sensitive and practical biomarkers to reveal glioma high invasiveness remain to be explored for the guidance of therapy. We herein evaluated the diagnostic and prognostic value of aldehyde dehydrogenase 1A1 (ALDH1A1) in the glioma specimens from 237 patients, and found that ADLH1A1 was frequently overexpressed in the high-grade glioma (WHO grade III-IV) as compared to the low-grade glioma (WHO grade I-II) patients. The tumor cells with ALDH1A1 expression were more abundant in the region between tumor and the borderline of adjacent tissue as compared to the central part of the tumor. ALDH1A1 overexpression was associated with poor differentiation and dismal prognosis. Notably, the overall and disease-free survivals of the patients who had ALDH1A1+ tumor cells sparsely located in the adjacent tissue were much worse. Furthermore, ALDH1A1 expression was correlated with the “classical-like” (CL) subtype as we examined GBM specimens from 72 patients. Multivariate Cox regression analysis revealed that ALDH1A1 was an independent marker for glioma patients’ outcome. Mechanistically, both in vitro and in vivo studies revealed that ALDH1A1+ cells isolated from either a glioblastoma cell line U251 or primary glioblastoma cells displayed significant invasiveness, clonogenicity, and proliferation as compared to ALDH1A1- cells, due to increased levels of mRNA and protein for matrix metalloproteinase 2, 7 and 9 (MMP2, MMP7 and MMP9). These results indicate that ALDH1A1+ cells contribute to the progression of glioma including invasion, proliferation and poor prognosis, and suggest that targeting ALDH1A1 may have important implications for the treatment of highly invasive glioma. PMID:26101711

  1. Proresolving protein Annexin A1: The role in type 2 diabetes mellitus and obesity.

    Science.gov (United States)

    Pietrani, Nathalia T; Ferreira, Cláudia N; Rodrigues, Kathryna F; Perucci, Luiza O; Carneiro, Fernanda S; Bosco, Adriana A; Oliveira, Marina C; Pereira, Solange S; Teixeira, Antônio L; Alvarez-Leite, Jacqueline I; Ferreira, Adaliene V; Sousa, Lirlândia P; Gomes, Karina B

    2018-04-17

    Annexin A1 (AnxA1) is a protein involved in inflammation resolution that might be altered in obesity-associated type 2 diabetes mellitus (DM), which is a chronic inflammatory disease. The aim of this study was to evaluate AnxA1 serum levels in individuals with and without DM stratified according to the body mass index (BMI), and the dynamic of AnxA1 expression in adipose tissue from humans with obesity and non-obesity. Serum samples were obtained from 41 patients with DM (lean, overweight and obese) and 40 controls, and adipose tissue samples were obtained from 16 individuals with obesity (with or without DM), and 15 controls. DM patients showed similar AnxA1 serum levels when compared to controls. However, when the individuals were stratified according to BMI, AnxA1 levels were higher in individuals with obesity than lean or overweight, and in overweight compared to lean individuals. Moreover, AnxA1 was correlated positively with IL-6 levels. AnxA1 levels were also positively correlated with BMI, waist circumference and waist-to-hip ratio. Furthermore, higher levels of cleaved AnxA1 were observed in adipose tissue from individuals with obesity, independently of DM status. Enhanced levels of AnxA1 in serum of individuals with obesity suggest an attempt to counter-regulate the systemic inflammation process in this disease. However, the higher levels of cleaved AnxA1 in the adipose tissue of individuals with obesity could compromise its anti-inflammatory and proresolving actions, locally. Considering our data, AnxA1 cleavage in the adipose tissue, despite increased serum levels of this protein, and consequently the failure in inflammation resolution, suggests an important pathophysiological mechanism involved in inflammatory status observed in obesity. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  2. Drugs and Scaffold That Inhibit Cytochrome P450 27A1 In Vitro and In Vivo.

    Science.gov (United States)

    Lam, Morrie; Mast, Natalia; Pikuleva, Irina A

    2018-02-01

    Cytochrome P450 27A1 (CYP27A1) is a ubiquitous enzyme that hydroxylates cholesterol and other sterols. Complete CYP27A1 deficiency owing to genetic mutations is detrimental to human health, whereas 50% of activity retention is not and does not affect the whole body cholesterol levels. CYP27A1 is considered a potential therapeutic target in breast cancer and age-related neurodegenerative diseases; however, CYP27A1 inhibition should be ≤50%. Herein, 131 pharmaceuticals were tested for their effect on CYP27A1-mediated cholesterol 27-hydroxylation by in vitro enzyme assay. Of them, 14 drugs inhibited CYP27A1 by ≥75% and were evaluated for in vitro binding to the enzyme active site and for inhibition constants. All drugs except one (dasatinib) elicited a spectral response in CYP27A1 and had K i values for cholesterol 27-hydroxylation either in the submicromolar (clevidipine, delavirdine, etravirine, felodipine, nicardipine, nilotinib, and sorafenib) or low micromolar range (abiratone, candesartan, celecoxib, dasatinib, nilvadipine, nimodipine, and regorafenib). Clevidipine, felodipine, nicardipine, nilvadipine, and nimodipine have the same 1,4-dihydropyridine scaffold and are indicated for hypertension. We used two of these antihypertensives (felodipine and nilvadipine) for administration to mice at a 1-mg/kg of body weight dose, daily, for 7 days. Mouse 27-hydroxycholesterol levels in the plasma, brain, and liver were reduced, whereas tissue levels of total cholesterol were unchanged. Structure-activity relationships within the 1,4-dihydropyridine scaffold were investigated, and features important for CY27A1 inhibition were identified. We confirmed our previous finding that CYP27A1 is a druggable enzyme and found additional drugs as well as the scaffold with potential for partial CYP27A1 inhibition in humans. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  3. FoxA1 as a lineage-specific oncogene in luminal type breast cancer

    International Nuclear Information System (INIS)

    Yamaguchi, Noritaka; Ito, Emi; Azuma, Sakura; Honma, Reiko; Yanagisawa, Yuka; Nishikawa, Akira; Kawamura, Mika; Imai, Jun-ichi

    2008-01-01

    The forkhead transcription factor FoxA1 is thought to be involved in mammary tumorigenesis. However, the precise role of FoxA1 in breast cancer development is controversial. We examined expression of FoxA1 in 35 human breast cancer cell lines and compared it with that of ErbB2, a marker of poor prognosis in breast cancer. We found that FoxA1 is expressed at high levels in all ErbB2-positive cell lines and a subset of ErbB2-negative cell lines. Down-regulation of FoxA1 by RNA interference significantly suppressed proliferation of ErbB2-negative and FoxA1-positive breast cancer cell lines. Down-regulation of FoxA1 also enhanced the toxic effect of Herceptin on ErbB2-positive cell lines through induction of apoptosis. Taken together with previous data that FoxA1 is a marker of luminal cells in mammary gland, our present results suggest that FoxA1 plays an important role as a lineage-specific oncogene in proliferation of cancer cells derived from mammary luminal cells

  4. Falsely decreased HbA1c in a type 2 diabetic patient treated with dapsone.

    Science.gov (United States)

    Lai, Ying-Chuen; Wang, Chou-Shiang; Wang, Yi-Ching; Hsu, Yu-Ling; Chuang, Lee-Ming

    2012-02-01

    Glycated hemoglobin A1c (HbA1c) is an important indicator of glycemic control. The current recommendation for glycemic control based on HbA1c values has been widely accepted. However, HbA1c values depend on the lifespan of erythrocytes and the assay methods used. Here, we report the case of a patient with type 2 diabetes with unusual falling of HbA1c due to interference from dapsone treatment for leukocytoclastic vasculitis. He was a 52-year-old man, who was diagnosed with type 2 diabetes mellitus 5 years previously and who had been treated in our hospital in the past 3 years. Glycemia was controlled by sulfonylurea and metformin. During the 3-years follow-up period, HbA1c dropped significantly during the addition of dapsone treatment, although plasma glucose levels remained stable. HbA1c levels were raised after discontinuation of dapsone. With rechallenge of dapsone usage, HbA1c decreased again. We conclude that dapsone may be the cause of artificially low HbA1c. Other measurements to monitor glycemic control should be considered when dapsone is used for the treatment of concurrent disorders, such as autoimmune disease and pneumocystis jiroveci pneumonia. Copyright © 2012. Published by Elsevier B.V.

  5. Conundrum of elevated HbA1C and hypoglycemia-a rare cause.

    Science.gov (United States)

    Nanda, Sudip; Sharma, Shree Gopal; Bhatt, Surya Prakash; Pamula, John; Arastu, Mohammad I

    2008-05-01

    A white diabetic patient on insulin therapy presented with recurrent hypoglycemia despite very high glycosylated hemoglobin (HbA1c) values. Hemoglobin (Hb) variants, chemically modified Hb, and abnormalities of red cell turnover cause errors in HbA1c measurement. Widely prevalent Hb variants affecting HbA1c estimation include HbS and HbC in African Americans, HbE in southeast Asians, and carbamyl-Hb in uremic patients. In addition, there are at least 893 other Hb variants as of 2005, many of which affect HbA1c estimation. HbA1c values are also affected by methodology of estimation. Our patient had HbJ, which is rare amongst whites. The relationship between HbA1c values and mean plasma glucose allows estimation of expected HbA1c. Significant discrepancy between expected and measured HbA1c should be evaluated. Considering Hb variants, evaluating for the same and estimating HbA1c with the appropriate method under such circumstances are described. Numerous new or rare Hb variants will be diagnosed if suspicion is appropriately entertained.

  6. HbA1c, fasting plasma glucose and the prediction of diabetes

    DEFF Research Database (Denmark)

    Soulimane, Soraya; Simon, Dominique; Shaw, Jonathan

    2012-01-01

    With diabetes defined by HbA1c≥6.5% and/or FPG≥7.0mmol/l and/or diabetes treatment, we investigated HbA1c and fasting plasma glucose (FPG) thresholds/change-points above which the incidence of diabetes increases.......With diabetes defined by HbA1c≥6.5% and/or FPG≥7.0mmol/l and/or diabetes treatment, we investigated HbA1c and fasting plasma glucose (FPG) thresholds/change-points above which the incidence of diabetes increases....

  7. Falsely decreased HbA1c in a type 2 diabetic patient treated with dapsone

    Directory of Open Access Journals (Sweden)

    Ying-Chuen Lai

    2012-02-01

    Full Text Available Glycated hemoglobin A1c (HbA1c is an important indicator of glycemic control. The current recommendation for glycemic control based on HbA1c values has been widely accepted. However, HbA1c values depend on the lifespan of erythrocytes and the assay methods used. Here, we report the case of a patient with type 2 diabetes with unusual falling of HbA1c due to interference from dapsone treatment for leukocytoclastic vasculitis. He was a 52-year-old man, who was diagnosed with type 2 diabetes mellitus 5 years previously and who had been treated in our hospital in the past 3 years. Glycemia was controlled by sulfonylurea and metformin. During the 3-years follow-up period, HbA1c dropped significantly during the addition of dapsone treatment, although plasma glucose levels remained stable. HbA1c levels were raised after discontinuation of dapsone. With rechallenge of dapsone usage, HbA1c decreased again. We conclude that dapsone may be the cause of artificially low HbA1c. Other measurements to monitor glycemic control should be considered when dapsone is used for the treatment of concurrent disorders, such as autoimmune disease and pneumocystis jiroveci pneumonia.

  8. Expression and localization of sterol 27-hydroxylase (CYP27A1) in monkey retina

    OpenAIRE

    Lee, Jung Wha; Fuda, Hirotoshi; Javitt, Norman B.; Strott, Charles A.; Rodriguez, Ignacio R.

    2006-01-01

    Sterol 27-hydroxylase (CYP27A1) is a mitochondrial P-450 enzyme with broad substrate specificity for C27 sterols including 7-ketocholesterol (7kCh). CYP27A1 is widely expressed in human tissues but has not been previously demonstrated in the retina. In this study, we examined the expression and localization of CYP27A1 in the monkey retina where it localized mainly to the photoreceptor inner segments. CYP27A1 was also observed in Müller cells with faint immuno staining detected in the RPE and ...

  9. Determination of CYP27a1 in biological samples using nano liquid chromatography mass spectrometry

    OpenAIRE

    Sæterdal, Kristina Erikstad

    2016-01-01

    The cytochrome P450 enzyme, CYP27a1, converts cholesterol into 27-hydroxycholesterol, and both the metabolite and the enzyme are associated with breast cancer, promoting proliferation and metastasis. CYP27A1 is enriched in cancer tissues, and the amount of CYP27a1 correlates to tumor grade. Hence, CYP27a1 is a potential biomarker, and a method for determination and quantification is needed. Antibody assays shows limited performance, and therefore the goal of this work was to develop a nano li...

  10. Hepatic caveolin-1 is enhanced in Cyp27a1/ApoE double knockout mice

    OpenAIRE

    Escher, Geneviève; Zurkinden, Line; Mistry, H; Mansour, Y; Rohrbach, B; Vogt, Bruno

    2016-01-01

    Sterol 27?hydroxylase (CYP27A1) is involved in bile acid synthesis and cholesterol homoeostasis. Cyp27a1 (?/?)/Apolipoprotein E (?/?) double knockout mice (DKO) fed a western diet failed to develop atherosclerosis. Caveolin?1 (CAV?1), the main component of caveolae, is associated with lipid homoeostasis and has regulatory roles in vascular diseases. We hypothesized that liver CAV?1 would contribute to the athero?protective mechanism in DKO mice. Cyp27a1 (+/+)/ApoE (?/?) (ApoE KO), Cyp27a1 (+/...

  11. Anti-nociceptive properties of the xanthine oxidase inhibitor allopurinol in mice: role of A1 adenosine receptors

    Science.gov (United States)

    Schmidt, AP; Böhmer, AE; Antunes, C; Schallenberger, C; Porciúncula, LO; Elisabetsky, E; Lara, DR; Souza, DO

    2009-01-01

    Background and purpose Allopurinol is a potent inhibitor of the enzyme xanthine oxidase, used primarily in the treatment of hyperuricemia and gout. It is well known that purines exert multiple effects on pain transmission. We hypothesized that the inhibition of xanthine oxidase by allopurinol, thereby reducing purine degradation, could be a valid strategy to enhance purinergic activity. The aim of this study was to investigate the anti-nociceptive profile of allopurinol on chemical and thermal pain models in mice. Experimental approach Mice received an intraperitoneal (i.p.) injection of vehicle (Tween 10%) or allopurinol (10–400 mg kg−1). Anti-nociceptive effects were measured with intraplantar capsaicin, intraplantar glutamate, tail-flick or hot-plate tests. Key results Allopurinol presented dose-dependent anti-nociceptive effects in all models. The opioid antagonist naloxone did not affect these anti-nociceptive effects. The non-selective adenosine-receptor antagonist caffeine and the selective A1 adenosine-receptor antagonist, DPCPX, but not the selective A2A adenosine-receptor antagonist, SCH58261, completely prevented allopurinol-induced anti-nociception. No obvious motor deficits were produced by allopurinol, at doses up to 200 mg kg−1. Allopurinol also caused an increase in cerebrospinal fluid levels of purines, including the nucleosides adenosine and guanosine, and decreased cerebrospinal fluid concentration of uric acid. Conclusions and implications Allopurinol-induced anti-nociception may be related to adenosine accumulation. Allopurinol is an old and extensively used compound and seems to be well tolerated with no obvious central nervous system toxic effects at high doses. This drug may be useful to treat pain syndromes in humans. PMID:19133997

  12. Comparison of four variants of a major allergen in hazelnut (Corylus avellana) Cor a 1.04 with the major hazel pollen allergen Cor a 1.01

    DEFF Research Database (Denmark)

    Lüttkopf, D; Müller, U; Skov, P S

    2002-01-01

    -blind placebo-controlled food challenges (DBPCFC) in a multicenter study. Total RNA was isolated from immature hazelnuts and transcribed into cDNA. Full length coding DNA obtained by PCR-strategy was subcloned into pTYB11 vector and expressed in E. coli ER2566 cells. Native non-fusion target proteins were...... purified by DTT-induced self-cleavage of the intein-tagged N-terminal fusion proteins. IgE reactivity of the recombinant allergens was tested by enzyme allergosorbent test (EAST), EAST-inhibition, immunoblot-inhibition and histamine release assays. Four recombinant allergens were produced showing deduced...... residue in position 99. Surprisingly, only 63% identity was revealed with hazel pollen Cor a 1. EAST with 43 sera of patients with positive DBPCFC to hazelnut indicated IgE reactivity to Cor a 1.0401 in 95% of the sera, to Cor a 1.0402 in 93%, to Cor a 1.0403 in 91%, and in only 74% of the sera...

  13. Prostaglandins A1, A2 and 19-hydroxy A1; their actions on smooth muscle and their inactivation on passage through the pulmonary and hepatic portal vascular beds

    Science.gov (United States)

    Horton, E. W.; Jones, R. L.

    1969-01-01

    1. Prostaglandins A1, A2 and 19-hydroxy A1 have qualitatively similar actions to prostaglandin E1 on smooth muscle. 2. The prostaglandins A have little activity on gastrointestinal, respiratory and reproductive smooth muscle but are potent depressors of the systemic arterial blood pressure of the dog, cat and rabbit. 3. Our experiments support the view that the depressor action of the prostaglandins E and A is due to a direct dilator action on many peripheral vascular beds and not due to changes in nervous tone to these beds. 4. A single passage through the pulmonary circulation of the cat or dog causes substantial loss of the vasodilator activity of prostaglandin E1 but little if any loss of the vasodilator activity of the prostaglandins A. 5. A single passage through the hepatic portal circulation of the cat causes substantial loss of the vasodilator activity of prostaglandins E1, A1 and A2. 6. The cat blood pressure and rat fundal strip would be a suitable combination for the parallel biological assay of the prostaglandins A1 and A2. ImagesFIG. 5 PMID:5348473

  14. Ischaemic heart disease, Type 1 diabetes, and cow milk A1 beta-casein.

    Science.gov (United States)

    Laugesen, Murray; Elliott, Robert

    2003-01-24

    To test the correlation of per capita A1 beta-casein (A1/capita) and milk protein with: 1) ischaemic heart disease (IHD) mortality; 2) Type 1 (insulin-dependent) diabetes mellitus (DM-1) incidence. A1/capita was estimated as the product of per capita cow milk and cream supply and its A1 beta-casein content (A1/beta) (calculated from herd tests and breed distribution, or from tests of commercial milk), then tested for correlation with: 1) IHD five years later in 1980, 1985, 1990 and 1995, in 20 countries which spent at least US $1000 (purchasing power parities) per capita in 1995 on healthcare; 2) DM-1 at age 0-14 years in 1990-4 (51 were surveyed by WHO DiaMond Project; 19 had A1 data). For comparison, we also correlated 77 food, and 110 nutritive supply FAO (Food and Agriculture Organization)-based measures, against IHD and DM-1. For IHD, cow milk proteins (A1/capita, r = 0.76, p milk protein r = 0.60, p = 0.005) had stronger positive correlations with IHD five years later, than fat supply variables, such as the atherogenic index (r = 0.50), and myristic, the 14-carbon saturated fat (r = 0.48, p cholesterol (r = 0.42); saturated fat (r = 0.37); and total dairy fat (r = 0.31) were not significant for IHD in 1995. Across the 20 countries, a 1% change in A1/capita in 1990 was associated with a 0.57% change in IHD in 1995. A1/capita correlations were stronger for male than female mortality. On multiple regression of A1/capita and other food supply variables in 1990, only A1/capita was significantly correlated with IHD in 1995. DM-1 was correlated with supply of: A1/capita in milk and cream (r = 0.92, p milk and cream protein excluding cheese (r = 0.68, p milk and cream (r = 0.47, p milk beta-casein. DM-1 incidence at 0-4, 5-9 and 10-14 years was equally correlated (r = 0.80, 0.81, 0.81 respectively) with milk protein supply. A 1% change in A1/capita was associated with a 1.3% change in DM-1 in the same direction. Cow A1 beta-casein per capita supply in milk and cream

  15. Proteomic analysis reveals the enhancement of human serum apolipoprotein A-1(APO A-1) in individuals infected with multiple dengue virus serotypes.

    Science.gov (United States)

    Manchala, Nageswar Reddy; Dungdung, Ranjeet; Pilankatta, Rajendra

    2017-10-01

    Human serum protein profiling of the individual infected with multiple dengue virus serotypes for identifying the potential biomarkers and to investigate the cause for the severity of dengue virus infection. Dengue virus NS1-positive serum samples were pooled into two groups (S2 and S3) based on the molecular serotyping and number of heterotypic infections. The pooled serum samples were subjected to two-dimensional gel electrophoresis (2DGE) to identify the differentially expressed proteins. The peptide masses of upregulated protein were detected by matrix-assisted laser desorption-ionisation time-of-flight MALDI-TOF mass spectrometry and analysed by MASCOT search engine. The results were compared with the control group (S1). The commonly upregulated protein was validated by quantitative ELISA and compared with control as well as single serotypic infected samples. Based on 2DGE, total thirteen proteins were differentially upregulated in S2 and S3 groups as compared to control. Some of the upregulated proteins were involved in mediating the complement activation of immune response. The apolipoprotein A-1 (APO A-1) was upregulated in S2 and S3 groups. Upon validation, APO A-1 levels were increased in line with the number of heterotypic infection of dengue viruses. Heterotypic infection of dengue viruses upregulate the serum proteins involved in the complement pathway in the early phase of infection. There was a significant increase in the level of APO A-1 in three different serotypic infections of dengue virus as compared to control. Further, the role of APO-A1 can be explored in elucidating the mechanism of dengue pathogenesis. © 2017 John Wiley & Sons Ltd.

  16. Prostaglandin Transporter (PGT/SLCO2A1 Protects the Lung from Bleomycin-Induced Fibrosis.

    Directory of Open Access Journals (Sweden)

    Takeo Nakanishi

    Full Text Available Prostaglandin (PG E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1. The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI and II (ATII epithelial cells, and electron-microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT C57BL/6 mice. PGE2 uptake activity was abrogated in ATI-like cells from Slco2a1-deficient (Slco2a1-/- mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE2 concentrations in lung tissues were lower in Slco2a1-/- than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg or vehicle (phosphate buffered saline was intratracheally injected into WT and Slco2a1-/- mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in Slco2a1-/- than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE2 levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of Slco2a1-/- mice. Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC δ along with a modest activation of Smad3 in lung from Slco2a1-/- mice, suggesting a role of PKCδ associated with TGF-β signaling in aggravated fibrosis in BLM-treated Slco2a1-/- mice. In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.

  17. Prostaglandin Transporter (PGT/SLCO2A1) Protects the Lung from Bleomycin-Induced Fibrosis.

    Science.gov (United States)

    Nakanishi, Takeo; Hasegawa, Yoshitaka; Mimura, Reo; Wakayama, Tomohiko; Uetoko, Yuka; Komori, Hisakazu; Akanuma, Shin-Ichi; Hosoya, Ken-Ichi; Tamai, Ikumi

    2015-01-01

    Prostaglandin (PG) E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1). The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM)-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI) and II (ATII) epithelial cells, and electron-microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT) C57BL/6 mice. PGE2 uptake activity was abrogated in ATI-like cells from Slco2a1-deficient (Slco2a1-/-) mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE2 concentrations in lung tissues were lower in Slco2a1-/- than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg) or vehicle (phosphate buffered saline) was intratracheally injected into WT and Slco2a1-/- mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in Slco2a1-/- than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE2 levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of Slco2a1-/- mice. Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC) δ along with a modest activation of Smad3 in lung from Slco2a1-/- mice, suggesting a role of PKCδ associated with TGF-β signaling in aggravated fibrosis in BLM-treated Slco2a1-/- mice. In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.

  18. The clinical application of UGT1A1 pharmacogenetic testing: Gene-environment interactions

    Directory of Open Access Journals (Sweden)

    Marques Sara

    2010-04-01

    Full Text Available Abstract Over the past decade, the number of pharmacogenetic tests has increased considerably, allowing for the development of our knowledge of their clinical application. The uridine diphosphate glucuronosyltransferase 1A1 gene (UGT1A1 assay is an example of a pharmacogenetic test. Numerous variants have been found in UGT1A1, the main conjugating enzyme of bilirubin and drugs such as the anticancer drug irinotecan. Recently, the US Food and Drug Administration (FDA recommended testing for the presence of UGT1A1*28, an allele correlated with decreased transcriptional activity, to predict patients at risk of irinotecan toxicity. The administration of other drugs -- such as inhibitors of the UGT1A1 enzyme -- can clinically mimic the *28 phenotype, whereas inducers of UGT1A1 can increase the glucuronidation rate of the enzyme. The *28 polymorphism is not present in all ethnicities at a similar frequency, which suggests that it is important to study different populations to determine the clinical relevance of testing for UGT1A1*28 and to identify other clinically relevant UGT1A1 variants. Environmental factors such as lifestyle can also affect UGT1A1 activity. This review is a critical analysis of studies on drugs that can be affected by the presence of UGT1A1*28, the distribution of this polymorphism around the globe, distinct variants that may be clinically significant in African and Asian populations and how lifestyle can affect treatment outcomes that depend on UGT1A1 activity.

  19. Epigenetic Regulation of Vitamin D 24-Hydroxylase/CYP24A1 in Human Prostate Cancer

    Science.gov (United States)

    Luo, Wei; Karpf, Adam R.; Deeb, Kristin K.; Muindi, Josephia R.; Morrison, Carl D.; Johnson, Candace S.; Trump, Donald L.

    2010-01-01

    Calcitriol, a regulator of calcium homeostasis with antitumor properties, is degraded by the product of the CYP24A1 gene which is downregulated in human prostate cancer by unknown mechanisms. We found that CYP24A1 expression is inversely correlated with promoter DNA methylation in prostate cancer cell lines. Treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) activates CYP24A1 expression in prostate cancer cells. In vitro methylation of the CYP24A1 promoter represses its promoter activity. Furthermore, inhibition of histone deacetylases by trichostatin A (TSA) enhances the expression of CYP24A1 in prostate cancer cells. ChIP-qPCR reveals that specific histone modifications are associated with the CYP24A1 promoter region. Treatment with TSA increases H3K9ac and H3K4me2 and simultaneously decreases H3K9me2 at the CYP24A1 promoter. ChIP-qPCR assay reveals that treatment with DAC and TSA increases the recruitment of VDR to the CYP24A1 promoter. RT-PCR analysis of paired human prostate samples reveals that CYP24A1 expression is down-regulated in prostate malignant lesions compared to adjacent histologically benign lesions. Bisulfite pyrosequencing shows that CYP24A1 gene is hypermethylated in malignant lesions compared to matched benign lesions. Our findings indicate that repression of CYP24A1 gene expression in human prostate cancer cells is mediated in part by promoter DNA methylation and repressive histone modifications. PMID:20587525

  20. MAGE-A1 promotes melanoma proliferation and migration through C-JUN activation

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Dong [Department of Dermatology, General Hospital of People' s Liberation Army, Beijing 100853 (China); The 309th Hospital of China People' s Liberation Army, Beijing 100091 (China); Wang, Junyun; Ding, Nan [CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Li, Yongjun; Yang, Yaran [CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101 (China); Fang, Xiangdong, E-mail: fangxd@big.ac.cn [CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101 (China); Zhao, Hua, E-mail: luckhua301@163.com [Department of Dermatology, General Hospital of People' s Liberation Army, Beijing 100853 (China)

    2016-05-13

    MAGE-A1 belongs to the chromosome X-clustered genes of cancer-testis antigen family and is normally expressed in the human germ line but is also overexpressed in various tumors. Previous studies of MAGE-A1 in melanoma mainly focused on methylation changes or its role in immunotherapy, however, its biological functions in melanoma have remained unknown. In order to determine the role of MAGE-A1 in melanoma growth and metastasis, we manipulated melanoma cell lines with overexpression and knockdown of MAGE-A1. Integration of cell proliferation assays, transwell migration and invasion assays, and RNA-Seq analysis revealed that up-regulation of MAGE-A1 dramatically promoted proliferation, migration, and invasion of human melanoma cell lines in vitro, while down-regulation of MAGE-A1 inhibited those characteristics associated with tumor cells. Furthermore, transcriptome sequencing revealed that MAGE-A1 exerts its tumor promoting activity by activating p-C-JUN directly or through ERK-MAPK signaling pathways. Based on our findings, we propose that MAGE-A1 may be a potential therapeutic target for melanoma patients. - Highlights: • MAGE-A1 promotes proliferation and clone formation in melanoma cell lines. • MAGE-A1 enhances tumor cell migration and invasion in melanoma cell lines. • Network including C-JUN, IL8, and ARHGAP29 play critical role in malignant melanoma. • Oncogenic MAGE-A1 increases p-C-JUN levels, possibly via ERK-MAPK signaling pathway.

  1. Bifunctional role of ephrin A1-Eph system in stimulating cell proliferation and protecting cells from cell death through the attenuation of ER stress and inflammatory responses in bovine mammary epithelial cells.

    Science.gov (United States)

    Kang, Minkyung; Jeong, Wooyoung; Bae, Hyocheol; Lim, Whasun; Bazer, Fuller W; Song, Gwonhwa

    2018-03-01

    Structural and functional development of the mammary gland is constant in the mammary gland life cycle. Eph receptors and their ligands, ephrins, control events through cell-to-cell interactions during embryonic development, and adult tissue homeostasis; however, little information on participation of ephrin A1, a representative ligand of the Eph receptor, in the development and function of normal mammary glands is known. In this study, we demonstrated functional effects of the ephrin A1-Eph system and mechanisms of its action on bovine mammary epithelial (MAC-T) cells. The in vitro cultured MAC-T cells expressed the ephrin A1 ligand and EphA1, A2, A4, A7, and A8 among the eight members of the Eph A family. Our results revealed that ephrin A1 induced MAC-T cell cycle progression and stimulated cell proliferation with abundant expression of nucleic PCNA and cyclin D1 proteins. Additionally, ephrin A1 induced activation of intracellular signaling molecules involved in PI3 K/AKT and MAPK signaling, and the proliferation-stimulating effect of ephrin A1 was mediated by activation of these pathways. Furthermore, ephrin A1 influenced expression and activation of various ER stress-related proteins and protected MAC-T cells from stress-induced cell death. Finally, ephrin A1 alleviated LPS-induced cell death through down-regulation of inflammatory cytokines. In conclusion, the results of this study suggest that the Eph A-ephrin A1 system is a positive factor in the increase and maintenance of epithelial cells in mammary glands of cows; the signaling system contributes to development, remodeling, and functionality of normal mammary glands and could overcome mastitis in cows and other mammals. © 2017 Wiley Periodicals, Inc.

  2. A novel CYP1A1 gene polymorphism and the risk of head and neck ...

    African Journals Online (AJOL)

    Several polymorphisms in the CYP1A1 locus have been identified and their genotypes appear to exhibit population frequencies that depend on ethnicity. In this study, we assessed the role of CYP1A1 genotype in 388 head and neck cancer patients in Pakistani population via a case-control study. Polymerase chain reaction ...

  3. Annexin A1 and A2: roles in retrograde trafficking of Shiga toxin.

    Science.gov (United States)

    Tcatchoff, Lionel; Andersson, Sofia; Utskarpen, Audrun; Klokk, Tove Irene; Skånland, Sigrid S; Pust, Sascha; Gerke, Volker; Sandvig, Kirsten

    2012-01-01

    Annexins constitute a family of calcium and membrane binding proteins. As annexin A1 and A2 have previously been linked to various membrane trafficking events, we initiated this study to investigate the role of these annexins in the uptake and intracellular transport of the bacterial Shiga toxin (Stx) and the plant toxin ricin. Once endocytosed, both toxins are retrogradely transported from endosomes to the Golgi apparatus and the endoplasmic reticulum before being targeted to the cytosol where they inhibit protein synthesis. This study was performed to obtain new information both about toxin transport and the function of annexin A1 and annexin A2. Our data show that depletion of annexin A1 or A2 alters the retrograde transport of Stx but not ricin, without affecting toxin binding or internalization. Knockdown of annexin A1 increases Golgi transport of Stx, whereas knockdown of annexin A2 slightly decreases the same transport step. Interestingly, annexin A1 was found in proximity to cytoplasmic phospholipase A2 (cPLA(2)), and the basal as well as the increased Golgi transport of Stx upon annexin A1 knockdown is dependent on cPLA(2) activity. In conclusion, annexin A1 and A2 have different roles in Stx transport to the trans-Golgi network. The most prominent role is played by annexin A1 which normally works as a negative regulator of retrograde transport from the endosomes to the Golgi network, most likely by complex formation and inhibition of cPLA(2).

  4. In vitro determination of hemoglobin A1c for diabetes diagnosis and management: technology update

    Directory of Open Access Journals (Sweden)

    English E

    2014-07-01

    Full Text Available Emma English,1 Elise T Milosevich,1 W Garry John2 1School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, United Kingdom; 2Department of Clinical Biochemistry, Norfolk and Norwich University Hospital, Norwich, United Kingdom Abstract: It is fascinating to consider the analytical improvements that have occurred since glycated hemoglobin was first used in routine clinical laboratories for diabetes monitoring around 1977; at that time methods displayed poor precision, there were no calibrators or material with assayed values for quality control purposes. This review outlines the major improvements in hemoglobin A1c (HbA1c measurement that have occurred since its introduction, and reflects on the increased importance of this hemoglobin fraction in the monitoring of glycemic control. The use of HbA1c as a diagnostic tool is discussed in addition to its use in monitoring the patient with diabetes; the biochemistry of HbA1c formation is described, and how these changes to the hemoglobin molecule have been used to develop methods to measure this fraction. Standardization of HbA1c is described in detail; the development of the IFCC Reference Measurement Procedure for HbA1c has enabled global standardization to be achieved which has allowed global targets to be set for glycemic control and diagnosis. The importance of factors that may interfere in the measurement of HbA1c are highlighted. Keywords: glycated hemoglobin, HbA1c, IFCC

  5. Cytochrome P450, CYP93A1, as a defense marker in soybean

    Science.gov (United States)

    CYP93A1 is a cytochrome P450 that is involved in the synthesis of the phytoalexin glyceollin in soybean (Glycine max L. Merr). The gene encoding CYP93A1 has been used as a defense marker in soybean cell cultures, however, little is known regarding how this gene is expressed in the intact plant. To f...

  6. Hb A1c Separation by High Performance Liquid Chromatography in Hemoglobinopathies

    Directory of Open Access Journals (Sweden)

    Vani Chandrashekar

    2016-01-01

    Full Text Available Hb A1c measurement is subject to interference by hemoglobin traits and this is dependent on the method used for determination. In this paper we studied the difference between Hb A1c measured by HPLC in hemoglobin traits and normal chromatograms. We also studied the correlation of Hb A1c with age. Hemoglobin analysis was carried out by high performance liquid chromatography. Spearman’s rank correlation was used to study correlation between A1c levels and age. Mann-Whitney U test was used to study the difference in Hb A1c between patients with normal hemoglobin and hemoglobin traits. A total of 431 patients were studied. There was positive correlation with age in patients with normal chromatograms only. No correlation was seen in Hb E trait or beta thalassemia trait. No significant difference in Hb A1c of patients with normal chromatograms and patients with hemoglobin traits was seen. There is no interference by abnormal hemoglobin in the detection of A1c by high performance liquid chromatography. This method cannot be used for detection of A1c in compound heterozygous and homozygous disorders.

  7. Multicentre evaluation of the Tosoh HbA1c G8 analyser

    NARCIS (Netherlands)

    Chapelle, Jean-Paul; Teixeira, Jelda; Maisin, Diane; Assink, Hans; Barla, Gerhard; Stroobants, An K.; Delzenne, Barend; van den Eshof, Wouter

    2010-01-01

    We report a Dutch-Belgian multicentre evaluation of the Tosoh HLC-723G8 glycohaemoglobin analyser, an ion-exchange HPLC instrument for the separation and quantification of haemoglobin A1c (HbA1c) in whole blood. We evaluated the analytical performances of the Tosoh G8 analyser and compared the

  8. Production of the Allergenic Protein Alt a 1 by Alternaria Isolates from Working Environments

    Directory of Open Access Journals (Sweden)

    Justyna Skóra

    2015-02-01

    Full Text Available The aim of the study was to evaluate the ability of Alternaria isolates from workplaces to produce Alt a 1 allergenic protein, and to analyze whether technical materials (cellulose, compost, leather present within the working environment stimulate or inhibit Alt a 1 production (ELISA test. Studies included identification of the isolated molds by nucleotide sequences analyzing of the ITS1/ITS2 regions, actin, calmodulin and Alt a 1 genes. It has been shown that Alternaria molds are significant part of microbiocenosis in the archive, museum, library, composting plant and tannery (14%–16% frequency in the air. The presence of the gene encoding the Alt a 1 protein has been detected for the strains: Alternaria alternata, A. lini, A. limoniasperae A. nobilis and A. tenuissima. Environmental strains produced Alt a 1 at higher concentrations (1.103–6.528 ng/mL than a ATCC strain (0.551–0.975 ng/mL. It has been shown that the homogenization of the mycelium and the use of ultrafiltration allow a considerable increase of Alt a 1 concentration. Variations in the production of Alt a 1 protein, depend on the strain and extraction methods. These studies revealed no impact of the technical material from the workplaces on the production of Alt a 1 protein.

  9. The UGT1A1*28 allele and disease in childhood

    DEFF Research Database (Denmark)

    Petersen, Jesper Padkær

    2014-01-01

    at identificere studiepopulationerne. Genotyper blev bestemt ud fra PKU kort i den Danske Neonatale Screenings Biobank. Resultater: Ingen association blev vist for UGT1A1*28 genotyper og ALL hos børn. Ingen association blev vist for UGT1A1*28 genotyper og ekstrem neonatal hyperbilirubinæmi. I den præterme kohorte...

  10. 26 CFR 1.381(a)-1 - General rule relating to carryovers in certain corporate acquisitions.

    Science.gov (United States)

    2010-04-01

    ... corporate acquisitions. 1.381(a)-1 Section 1.381(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT...)-1 General rule relating to carryovers in certain corporate acquisitions. (a) Allowance of carryovers... requirements of section 354(b)(1)(A) and (B) are satisfied; and (v) A mere change in identity, form, or place...

  11. Data of evolutionary structure change: 1A1SA-2ATCA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1A1SA-2ATCA 1A1S 2ATC A A VVSLAGRDLLCLQDYTAEEIWTILETAKMFKIWQKIGKP...entryChain> 2ATC A 2ATCA TEFSGNVP...entryChain> 2ATC A 2ATCA MVGDLKYG...ntryChain> 2ATC A 2ATCA ALAKFDGNR...VID> 3 2ATC A 2ATCA

  12. Elevated third-trimester haemoglobin A(1c) predicts preterm delivery in type 1 diabetes

    DEFF Research Database (Denmark)

    Ekbom, Pia; Damm, Peter; Feldt-Rasmussen, Bo

    2008-01-01

    The prevalence of preterm delivery is considerably elevated in women with type 1 diabetes. The aim of the study was to evaluate haemoglobin A(1c) (HbA(1c)) as a predictor of preterm delivery. Two hundred thirteen consecutive pregnant women with type 1 diabetes and normal urinary albumin excretion...

  13. High maternal HbA1c is associated with overweight in neonates

    DEFF Research Database (Denmark)

    Mikkelsen, Maria R.; Nielsen, Sigrid Bruun; Stage, E

    2011-01-01

    The aims of this study were to determine the prevalence of women with gestational diabetes mellitus (GDM) not obtaining HbA1c within the normal range (= 5.6%) before delivery and to examine whether elevated HbA1c values are associated with an increased risk of large for gestational age (LGA) infa...

  14. REDUCTION OF ADENOSINE-A1-RECEPTORS IN THE PERFORANT PATHWAY TERMINAL ZONE IN ALZHEIMER HIPPOCAMPUS

    NARCIS (Netherlands)

    JAARSMA, D; SEBENS, JB; KORF, J

    1991-01-01

    The cells of origin of the perforant pathway are destroyed in Alzheimer's disease (AD). In rat the adenosine A1-receptors are specifically localized on the perforant path terminals in the molecular layer of the dentate gyrus. In the present study the density of A1-receptors in the hippocampus of

  15. Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures

    DEFF Research Database (Denmark)

    Carvill, Gemma L; McMahon, Jacinta M; Schneider, Amy

    2015-01-01

    GAT-1, encoded by SLC6A1, is one of the major gamma-aminobutyric acid (GABA) transporters in the brain and is responsible for re-uptake of GABA from the synapse. In this study, targeted resequencing of 644 individuals with epileptic encephalopathies led to the identification of six SLC6A1 mutatio...

  16. Clinical Significance of UGT1A1 Genetic Analysis in Chinese Neonates with Severe Hyperbilirubinemia

    Directory of Open Access Journals (Sweden)

    Hui Yang

    2016-08-01

    Conclusion: Besides G6PD-deficiency screening, UGT1A1 genetic analysis, and especially the UGT1A1*6(c.211G>A, p.Arg71Gly polymorphism detection, may be taken into consideration for early diagnosis and treatment of severe hyperbilirubinemic newborns in southern China.

  17. High maternal HbA1c is associated with overweight in neonates

    DEFF Research Database (Denmark)

    Mikkelsen, Maria R.; Nielsen, Sigrid Bruun; Stage, E

    2011-01-01

    The aims of this study were to determine the prevalence of women with gestational diabetes mellitus (GDM) not obtaining HbA1c within the normal range (= 5.6%) before delivery and to examine whether elevated HbA1c values are associated with an increased risk of large for gestational age (LGA...

  18. The role of SLC2A1 in early onset and childhood absence epilepsies

    DEFF Research Database (Denmark)

    Muhle, Hiltrud; Helbig, Ingo; Frøslev, Tobias Guldberg

    2013-01-01

    Early Onset Absence Epilepsy constitutes an Idiopathic Generalized Epilepsy with absences starting before the age of four years. Mutations in SLC2A1, encoding the glucose transporter, account for approximately 10% of EOAE cases. The role of SLC2A1 mutations in absence epilepsies with a later onse...

  19. Lipid and liver abnormalities in haemoglobin A1c-defined prediabetes and type 2 diabetes

    DEFF Research Database (Denmark)

    Calanna, S; Scicali, R; Di Pino, A

    2014-01-01

    , higher blood pressure and triglycerides levels, higher FLI, increased prevalence of and more severe hepatic steatosis, higher BARD score, and higher total body muscle mass. Moreover, HbA1c was correlated with BMI, HOMA-IR, triglycerides, HDL cholesterol, AST, and ALT. CONCLUSIONS: Subjects with HbA1c...

  20. 26 CFR 1.691(a)-1 - Income in respect of a decedent.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Income in respect of a decedent. 1.691(a)-1...) INCOME TAX (CONTINUED) INCOME TAXES Income in Respect of Decedents § 1.691(a)-1 Income in respect of a... to the extent that such amounts constitute “income in respect of a decedent”; (2) the taxable effect...

  1. Production of the Allergenic Protein Alt a 1 by Alternaria Isolates from Working Environments

    Science.gov (United States)

    Skóra, Justyna; Otlewska, Anna; Gutarowska, Beata; Leszczyńska, Joanna; Majak, Iwona; Stępień, Łukasz

    2015-01-01

    The aim of the study was to evaluate the ability of Alternaria isolates from workplaces to produce Alt a 1 allergenic protein, and to analyze whether technical materials (cellulose, compost, leather) present within the working environment stimulate or inhibit Alt a 1 production (ELISA test). Studies included identification of the isolated molds by nucleotide sequences analyzing of the ITS1/ITS2 regions, actin, calmodulin and Alt a 1 genes. It has been shown that Alternaria molds are significant part of microbiocenosis in the archive, museum, library, composting plant and tannery (14%–16% frequency in the air). The presence of the gene encoding the Alt a 1 protein has been detected for the strains: Alternaria alternata, A. lini, A. limoniasperae A. nobilis and A. tenuissima. Environmental strains produced Alt a 1 at higher concentrations (1.103–6.528 ng/mL) than a ATCC strain (0.551–0.975 ng/mL). It has been shown that the homogenization of the mycelium and the use of ultrafiltration allow a considerable increase of Alt a 1 concentration. Variations in the production of Alt a 1 protein, depend on the strain and extraction methods. These studies revealed no impact of the technical material from the workplaces on the production of Alt a 1 protein. PMID:25689994

  2. The SWITCH study (sensing with insulin pump therapy to control HbA(1c))

    DEFF Research Database (Denmark)

    Conget, Ignacio; Battelino, Tadej; Giménez, Marga

    2011-01-01

    injections. However, there is still a proportion of subjects using continuous subcutaneous insulin infusion in whom goals for metabolic control are far from achieved or benefits of this type of insulin therapy are transient. The SWITCH (Sensing With Insulin pump Therapy to Control HbA(1c) [hemoglobin A1c...

  3. A genetic variant in COL11A1 is functionally associated with lumbar ...

    Indian Academy of Sciences (India)

    This study aimed to explore whether the genetic variant of COL11A1 is functionally associated with the development of lumbar disc herniation (LDH) in Chinese population. SNP rs1676486 of COL11A1 was genotyped in 647 patients and 532 healthy controls. The differences of genotype and allele distributions between ...

  4. Production of the allergenic protein Alt a 1 by Alternaria isolates from working environments.

    Science.gov (United States)

    Skóra, Justyna; Otlewska, Anna; Gutarowska, Beata; Leszczyńska, Joanna; Majak, Iwona; Stępień, Łukasz

    2015-02-16

    The aim of the study was to evaluate the ability of Alternaria isolates from workplaces to produce Alt a 1 allergenic protein, and to analyze whether technical materials (cellulose, compost, leather) present within the working environment stimulate or inhibit Alt a 1 production (ELISA test). Studies included identification of the isolated molds by nucleotide sequences analyzing of the ITS1/ITS2 regions, actin, calmodulin and Alt a 1 genes. It has been shown that Alternaria molds are significant part of microbiocenosis in the archive, museum, library, composting plant and tannery (14%-16% frequency in the air). The presence of the gene encoding the Alt a 1 protein has been detected for the strains: Alternaria alternata, A. lini, A. limoniasperae A. nobilis and A. tenuissima. Environmental strains produced Alt a 1 at higher concentrations (1.103-6.528 ng/mL) than a ATCC strain (0.551-0.975 ng/mL). It has been shown that the homogenization of the mycelium and the use of ultrafiltration allow a considerable increase of Alt a 1 concentration. Variations in the production of Alt a 1 protein, depend on the strain and extraction methods. These studies revealed no impact of the technical material from the workplaces on the production of Alt a 1 protein.

  5. Association of ATP-binding cassette transporter-A1 polymorphism ...

    Indian Academy of Sciences (India)

    [Halalkhor S., Mesbah-Namin S. A., Daneshpour M. S., Hedayati M. and Azizi F. 2011 Association of ATP-binding cassette transporter-A1 polymorphism with apolipoprotein AI level in Tehranian population. J. Genet. 90, 129–132 ]. Introduction. The ATP-binding cassette transporter-A1 (ABCA1) plays a crucial role in reverse ...

  6. Novel COL4A1 mutations cause cerebral small vessel disease by haploinsufficiency

    NARCIS (Netherlands)

    Lemmens, R.; Maugeri, A.; Niessen, H.W.M.; Goris, A.; Tousseyn, T.; Demaerel, P.; Corveleyn, A.; Robberecht, W.; van der Knaap, M.S.; Thijs, V.N.; Zwijnenburg, P.J.G.

    2013-01-01

    Mutations in COL4A1 have been identified in families with hereditary small vessel disease of the brain presumably due to a dominant-negative mechanism. Here, we report on two novel mutations in COL4A1 in two families with porencephaly, intracerebral hemorrhage and severe white matter disease caused

  7. 17 CFR 275.204A-1 - Investment adviser codes of ethics.

    Science.gov (United States)

    2010-04-01

    ... ethics. 275.204A-1 Section 275.204A-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... codes of ethics. (a) Adoption of code of ethics. If you are an investment adviser registered or required... enforce a written code of ethics that, at a minimum, includes: (1) A standard (or standards) of business...

  8. A genetic variant in COL11A1 is functionally associated with lumbar ...

    Indian Academy of Sciences (India)

    WENJUN LIU

    2017-12-14

    Dec 14, 2017 ... Abstract. This study aimed to explore whether the genetic variant of COL11A1 is functionally associated with the development of lumbar disc herniation (LDH) in Chinese population. SNP rs1676486 of COL11A1 was genotyped in 647 patients and 532 healthy controls. The differences of genotype and ...

  9. 17 CFR 240.11a-1 - Regulation of floor trading.

    Science.gov (United States)

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Regulation of floor trading... Securities Exchange Act of 1934 Adoption of Floor Trading Regulation (rule 11a-1) § 240.11a-1 Regulation of floor trading. (a) No member of a national securities exchange, while on the floor of such exchange...

  10. Allosteric Modulation of SULT2A1 by Celecoxib and Nimesulide: Computational Analyses

    OpenAIRE

    Yalcin, Emine Bihter; Struzik, Scott M.; King, Roberta S.

    2008-01-01

    We used protein-ligand docking and minimization to identify celecoxib as an allosteric modulator of SULT2A1-catalyzed estradiol sulfonation. Subsequent to celecoxib docking and complex minimization, conformational changes in SULT2A1 allowed estradiol docking to an alternative binding region with predicted preference for 17β-OH-E2 sulfonation over 3-OH-E2 sulfonation.

  11. Non-ribose ligands for the human adenosine A1 receptor

    NARCIS (Netherlands)

    Klaasse, Elisabeth Cornelia

    2008-01-01

    This thesis describes new, non-ribose ligands for the human Adenosine A1 Receptor (hA1R). An introduction to the four adenosine receptors subtypes, their history and cloning, occurrence, functioning, trafficking and therapeutic potential is given in Chapter 1. The process of desensitization and

  12. Intestinal bacterium-derived cyp27a1 prevents colon cancer cell apoptosis.

    Science.gov (United States)

    Ji, Yan-Chao; Liu, Chang; Zhang, Xia; Zhang, Cheng-Sen; Wang, Dong; Zhang, Yan

    2016-01-01

    The pathogenesis of metastasis of colon cancer (Cca) is to be further investigated. The dysfunction of apoptotic mechanism plays a role in the cancer cell over growth. This study tests a hypothesis by which intestinal bacterium-derived cyp27a1 prevents apoptosis in colon cancer cells. In this study, the levels of cyp27a1 in human stool samples were assessed by enzyme-linked immunosorbent assay. The apoptosis of Cca cells was observed by flow cytometry. The expression of cyp27a1 was assessed by real time RT-PCR and Western blotting. We observed higher levels of cyp27a1 in the stool samples of Cca patients than that from healthy subjects. Cca colon epithelial biopsy contained high levels of cyp27a1 protein, but not the cyp27a1 mRNA. Cyp27a1 prevented Cca cell apoptosis induced by vitamin D3. In conclusion, intestinal bacterium-derived cyp27a1 facilitates Cca survival by inhibiting Cca cell apoptosis.

  13. CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer.

    Science.gov (United States)

    Alfaqih, Mahmoud A; Nelson, Erik R; Liu, Wen; Safi, Rachid; Jasper, Jeffery S; Macias, Everardo; Geradts, Joseph; Thompson, J Will; Dubois, Laura G; Freeman, Michael R; Chang, Ching-Yi; Chi, Jen-Tsan; McDonnell, Donald P; Freedland, Stephen J

    2017-04-01

    In this study, we used a bioinformatic approach to identify genes whose expression is dysregulated in human prostate cancers. One of the most dramatically downregulated genes identified encodes CYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis. Importantly, lower CYP27A1 transcript levels were associated with shorter disease-free survival and higher tumor grade. Loss of CYP27A1 in prostate cancer was confirmed at the protein level by immunostaining for CYP27A1 in annotated tissue microarrays. Restoration of CYP27A1 expression in cells where its gene was silenced attenuated their growth in vitro and in tumor xenografts. Studies performed in vitro revealed that treatment of prostate cancer cells with 27-hydroxycholesterol (27HC), an enzymatic product of CYP27A1, reduced cellular cholesterol content in prostate cancer cell lines by inhibiting the activation of sterol regulatory-element binding protein 2 and downregulating low-density lipoprotein receptor expression. Our findings suggest that CYP27A1 is a critical cellular cholesterol sensor in prostate cells and that dysregulation of the CYP27A1/27HC axis contributes significantly to prostate cancer pathogenesis. Cancer Res; 77(7); 1662-73. ©2017 AACR . ©2017 American Association for Cancer Research.

  14. HtrA1 expression associated with the occurrence and development of esophageal cancer

    Directory of Open Access Journals (Sweden)

    Yu Youtao

    2012-08-01

    Full Text Available Abstract Background The purposes of this study were to measure both the mRNA and protein expression levels of high-temperature requirement serine peptidase 1 (HtrA1 in human esophageal cancer tissues and their adjacent, comparatively normal esophageal tissues. Methods The expression levels of HtrA1 mRNA and protein in both tissue types were measured by semi-quantitative RT-PCR (reverse transcription-polymerase chain reaction and Western blotting. The clinical and pathological correlation between HtrA1 expression levels and the occurrence and development of esophageal cancer was analyzed. Results The expression levels of HtrA1 mRNA and protein in esophageal carcinoma were significantly lower than the levels expressed in their adjacent normal esophageal tissue (p p p p  Conclusions HtrA1 expression is associated with the occurrence and development of esophageal cancer.

  15. Pathology of experimental infection by Pasteurella multocida serotype A: 1 in buffalo calves.

    Science.gov (United States)

    Praveena, P E; Periasamy, S; Kumar, A A; Singh, N

    2014-11-01

    Pasteurella multocida serotype A:3 has been mostly implicated in pneumonic pasteurellosis in ruminants. In contrast, our previous studies have reported that both serotypes A:1 and A:3 were responsible for respiratory diseases in cattle and buffaloes. However, the pathology and pathogenesis of P. multocida serotype A:1 (Pm A:1) infection have not been studied in ruminants. In the present study, 12- to 15-week-old buffalo calves (Bubalus bubalis) infected by Pm A:1 had fibrinous and suppurative bronchopneumonia with focal areas of coagulation necrosis typical of pneumonic pasteurellosis. For the first time, this study reports the lung pathology and pathogenecity of Pm A:1 infection in calves. © The Author(s) 2014.

  16. Evaluation of P availability from Fe and A1 labelled (32P) phosphates

    International Nuclear Information System (INIS)

    Bittencourt, V.S.

    1975-07-01

    Synthetically Fe and A1 labelled phosphates ( 32 P) show a certain amount of available P to the plants when applied to Sao Paulo State soils. This availability decreases from considered amorphous A1-phosphate (A1-P sub(am)) to A1 phosphate with a certain cristalinity grade (A1-P sub(cr)) and than from this to Fe-P sub(am) followed by Fe-P sub(cr), and it is influenced by both the soil characteristics and mainly by the iron constituents of the samples. In this way, one can not expect that the 0,05 N 2 H SO 4 and the CHANG and JACKSON (1957a) solutions can define properly the available P of these soils. The addition of lime to the soils do not drive to a better P absorption by the plants and its effects are dubious

  17. Study on the DNA-protein crosslinks induced by chromium (VI) in SPC-A1

    Science.gov (United States)

    Liu, Yanqun; Ding, Jianjun; Lu, Xiongbing; You, Hao

    2018-01-01

    Objective: This study was designed to investigate the effect of chromium (VI) on DNA-protein crosslinks (DPC) of SPC-A1 cells. Methods: We exposed SPC-A1 cells were cultured in 1640 medium and treated with the SPC-A1 cells in vitro to different concentrations of Hexavalent chromium Cr(VI) for 2h, the KC1-SDS precipitation assay were used to measure the DNA-protein cross-linking effect. Results: All the different concentrations of Cr(VI) could cause the increase of DPC coefficient in SPC-A1 cells. But this effect was not significant (P>0.05) at low concentrations; while in high concentration Cr(VI) induced SPC-A1 cells could produce DNA-protein cross-linking effect significantly (PDNA-protein crosslink.

  18. Trajectories of HbA1c levels in children and youth with type 1 diabetes.

    Directory of Open Access Journals (Sweden)

    Orit Pinhas-Hamiel

    Full Text Available To illustrate the distribution of Hemoglobin A1c (HbA1c levels according to age and gender among children, adolescents and youth with type 1 diabetes (T1DM.Consecutive HbA1c measurements of 349 patients, aged 2 to 30 years with T1DM were obtained from 1995 through 2010. Measurement from patients diagnosed with celiac disease (n = 20, eating disorders (n = 41 and hemoglobinopathy (n = 1 were excluded. The study sample comprised 4815 measurements of HbA1c from 287 patients. Regression percentiles of HbA1c were calculated as a function of age and gender by the quantile regression method using the SAS procedure QUANTREG.Crude percentiles of HbA1c as a function of age and gender, and the modeled curves produced using quantile regression showed good concordance. The curves show a decline in HbA1c levels from age 2 to 4 years at each percentile. Thereafter, there is a gradual increase during the prepubertal years with a peak at ages 12 to 14 years. HbA1c levels subsequently decline to the lowest values in the third decade. Curves of females and males followed closely, with females having HbA1c levels about 0.1% (1.1 mmol/mol higher in the 25th 50th and 75th percentiles.We constructed age-specific distribution curves for HbA1c levels for patients with T1DM. These percentiles may be used to demonstrate the individual patient's measurements longitudinally compared with age-matched patients.

  19. Trajectories of HbA1c levels in children and youth with type 1 diabetes.

    Science.gov (United States)

    Pinhas-Hamiel, Orit; Hamiel, Uri; Boyko, Valentina; Graph-Barel, Chana; Reichman, Brian; Lerner-Geva, Liat

    2014-01-01

    To illustrate the distribution of Hemoglobin A1c (HbA1c) levels according to age and gender among children, adolescents and youth with type 1 diabetes (T1DM). Consecutive HbA1c measurements of 349 patients, aged 2 to 30 years with T1DM were obtained from 1995 through 2010. Measurement from patients diagnosed with celiac disease (n = 20), eating disorders (n = 41) and hemoglobinopathy (n = 1) were excluded. The study sample comprised 4815 measurements of HbA1c from 287 patients. Regression percentiles of HbA1c were calculated as a function of age and gender by the quantile regression method using the SAS procedure QUANTREG. Crude percentiles of HbA1c as a function of age and gender, and the modeled curves produced using quantile regression showed good concordance. The curves show a decline in HbA1c levels from age 2 to 4 years at each percentile. Thereafter, there is a gradual increase during the prepubertal years with a peak at ages 12 to 14 years. HbA1c levels subsequently decline to the lowest values in the third decade. Curves of females and males followed closely, with females having HbA1c levels about 0.1% (1.1 mmol/mol) higher in the 25th 50th and 75th percentiles. We constructed age-specific distribution curves for HbA1c levels for patients with T1DM. These percentiles may be used to demonstrate the individual patient's measurements longitudinally compared with age-matched patients.

  20. Subgenotype A1 of HBV--tracing human migrations in and out of Africa.

    Science.gov (United States)

    Kramvis, Anna; Paraskevis, Dimitrios

    2013-01-01

    HBV subgenotype A1 is the dominant genotype A strain in Africa, with molecular characteristics differentiating it from A2, which prevails elsewhere. Outside Africa, A1 is confined to areas with migration history from Africa, including India and Latin America. The aim of this study was to reconstruct A1 phylogeny on a spatial scale in order to determine whether A1 can be used to track human migrations. A phylogenetic comparison of A1 was established using neighbour-joining analysis of complete genomes, and the Bayesian method, implemented in BEAST, was performed on the S region of isolates from 22 countries. Migration events were estimated by ancestral state reconstruction using the criterion of parsimony. From the tree reconstruction, nucleotide divergence calculations and migration analysis, it was evident that Africa was the source of dispersal of A1 globally, and its dispersal to Asia and Latin America occurred at a similar time period. Strains from South Africa were the most divergent, clustering in both the African and Asian/American clades and a South African subclade was the origin of A1. The effect of the 9th to 19th century trade and slave routes on the dispersal of A1 was evident and certain unexpected findings, such as the co-clustering of Somalian and Latin American strains, and the dispersal of A1 from India to Haiti, correlated with historical evidence. Phylogeographic analyses of subgenotype A1 can be used to trace human migrations in and out of Africa and the plausible sites of origin and migration routes are presented.

  1. Transverse anatomic landmarks for the A1 pulley of the thumb.

    Science.gov (United States)

    Hazani, Ron; Elston, Josh; Wilhelmi, Bradon J

    2011-12-01

    Triggering of the thumb is a common entity resulting in pain and disability. Operative management requires accurate knowledge of the pulley system for proper release of the A1 pulley. The purpose of this study was to predict the location of the A1 pulley with surface anatomic landmarks while avoiding injury to the neurovascular bundles and the critical oblique pulley. Thirteen fresh cadaveric thumbs were dissected while the volar digital creases of the thumb served as our potential anatomic landmarks for the A1 pulley. These included the distal crease and the two identifiable proximal creases. Measurements from the proximal edge of the A1 pulley to the surface landmarks were obtained. The pulley system was also inspected for variability, and the length of the A1 pulley was measured. Of the three volar creases in the thumb, the proximal-proximal crease (PPC) corresponded anatomically to the A1 pulley and demonstrated minimal variability compared to the other landmarks. It measured 0.10 ± 0.15 cm distal to the proximal edge of the A1 pulley. The average length of the thumb A1 pulley measured 0.61 ± 0.17 cm. Therefore, the distal edge of the A1 pulley is predicted to be located 0.51 cm distal to the PPC. Hand surface landmarks can be used reliably to predict the location of the thumb A1 pulley, thus avoiding injury to adjacent structures such as the critical oblique pulley.

  2. Monitoring HIV-infected Patients with Diabetes: Hemoglobin A1c, Fructosamine, or Glucose?

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    So-Young Kim

    2014-01-01

    Full Text Available Background Published studies report inappropriately low hemoglobin A1C (HbA1c values that underestimate glycemia in HIV patients. Methods We reviewed the charts of all HIV patients with diabetes mellitus (DM at our clinic. Fifty-nine patients had HbA1c data, of whom 26 patients also had fructosamine data. We compared the most recent HbA1c to finger-stick (FS glucose averaged over three months, and fructosamine to FS averaged over six weeks. Predicted average glucose (pAG was calculated as reported by Nathan et al: pAG (mg/dL = 28.7 × A1C% – 46.7. Data were analyzed using the Statistical Analysis System (SAS and Kruskal–Wallis test. Results HbA1c values underestimated (UE actual average glucose (aAG in 19% of these patients and overestimated (OE aAG in 27%. HbA1c estimated aAG within the established range in only 54% of the patients. There were no statistical differences in the types of HIV medication used in patients with UE, OE, or accurately estimated (AE glycemia. A Spearman correlation coefficient between HbA1c and aAG was r = 0.53 ( P < 0.0001. Correlation between fructosamine and aAG was r = 0.47 ( P = 0.016. Conclusions The correlations between HbA1c and aAG and between fructosamine and aAG were weaker than expected, and fructosamine was not more accurate than HbA1c.

  3. Aldehyde Dehydrogenase 1A1: Friend or Foe to Female Metabolism?

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    Jennifer M. Petrosino

    2014-03-01

    Full Text Available In this review, we summarize recent advances in understanding vitamin A-dependent regulation of sex-specific differences in metabolic diseases, inflammation, and certain cancers. We focus on the characterization of the aldehyde dehydrogenase-1 family of enzymes (ALDH1A1, ALDH1A2, ALDH1A3 that catalyze conversion of retinaldehyde to retinoic acid. Additionally, we propose a “horizontal transfer of signaling” from estrogen to retinoids through the action of ALDH1A1. Although estrogen does not directly influence expression of Aldh1a1, it has the ability to suppress Aldh1a2 and Aldh1a3, thereby establishing a female-specific mechanism for retinoic acid generation in target tissues. ALDH1A1 regulates adipogenesis, abdominal fat formation, glucose tolerance, and suppression of thermogenesis in adipocytes; in B cells, ALDH1A1 plays a protective role by inducing oncogene suppressors Rara and Pparg. Considering the conflicting responses of Aldh1a1 in a multitude of physiological processes, only tissue-specific regulation of Aldh1a1 can result in therapeutic effects. We have shown through successful implantation of tissue-specific Aldh1a1−/− preadipocytes that thermogenesis can be induced in wild-type adipose tissues to resolve diet-induced visceral obesity in females. We will briefly discuss the emerging role of ALDH1A1 in multiple myeloma, the regulation of reproduction, and immune responses, and conclude by discussing the role of ALDH1A1 in future therapeutic applications.

  4. Carrier-bound Alt a 1 peptides without allergenic activity for vaccination against Alternaria alternata allergy

    Science.gov (United States)

    Twaroch, T. E.; Focke, M.; Fleischmann, K.; Balic, N.; Lupinek, C.; Blatt, K.; Ferrara, R.; Mari, A.; Ebner, C.; Valent, P.; Spitzauer, S.; Swoboda, I.; Valenta, R.

    2017-01-01

    Background The mould Alternaria alternata is a major elicitor of allergic asthma. Diagnosis and specific immunotherapy (SIT) of Alternaria allergy are often limited by the insufficient quality of natural mould extracts. Objective To investigate whether recombinant Alt a 1 can be used for reliable diagnosis of Alternaria alternata allergy and to develop a safe, non-allergenic vaccine for SIT of Alternaria allergy. Methods The qualitative sensitization profile of 80 Alternaria-allergic patients from Austria and Italy was investigated using an allergen micro-array and the amount of Alternaria-specific IgE directed to rAlt a 1 was quantified by ImmunoCAP measurements. Peptides spanning regions of predicted high surface accessibility of Alt a 1 were synthesized and tested for IgE reactivity and allergenic activity, using sera and basophils from allergic patients. Carrier-bound peptides were studied for their ability to induce IgG antibodies in rabbits which recognize Alt a 1 and inhibit allergic patients’ IgE reactivity to Alt a 1. Results rAlt a 1 allowed diagnosis of Alternaria allergy in all tested patients, bound the vast majority (i.e. >95%) of Alternaria-specific IgE and elicited basophil activation already at a concentration of 0.1 ng/mL. Four non-allergenic peptides were synthesized which, after coupling to the carrier protein keyhole limpet hemocyanin, induced Alt a 1-specific IgG and inhibited allergic patients’ IgE binding to Alt a 1. Conclusions and clinical relevance rAlt a 1 is a highly allergenic molecule allowing sensitive diagnosis of Alternaria allergy. Carrier-bound non-allergenic Alt a 1 peptides are candidates for safe SIT of Alternaria allergy. PMID:22909168

  5. CYP24A1 Expression Inversely Correlates with Melanoma Progression: Clinic-Pathological Studies

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    Anna A. Brożyna

    2014-10-01

    Full Text Available The major role of 24-hydroxylase (CYP24A1 is to maintain 1,25-dihydroxyvitamin D3 (1,25(OH2D3 homeostasis. Recently, it has been discovered that CYP24A1 also catalyses the hydroxylation of 20(OHD3, producing dihydroxy-derivatives that show very effective antitumorigenic activities. Previously we showed a negative correlation of vitamin D receptor (VDR and CYP27B1 expression with progression, aggressiveness and overall or disease-free survivals of skin melanomas. Therefore, we analyzed CYP24A1 expression in relation to clinicopathomorphological features of nevi, skin melanomas and metastases. In melanocytic tumors, the level of CYP24A1 was higher than in the normal epidermis. The statistically highest mean CYP24A1 level was found in nevi and early stage melanomas. With melanoma progression, CYP24A1 levels decreased and in advanced stages were comparable to the normal epidermis and metastases. Furthermore, the CYP24A1 expression positively correlated with VDR and CYP27B1, and negatively correlated with mitotic activity. Lower CYP24A1 levels correlated with the presence of ulceration, necrosis, nodular type and amelanotic phenotypes. Moreover, a lack of detectable CYP24A1 expression was related to shorter overall and disease-free survival. In conclusion, the local vitamin D endocrine system affects melanoma behavior and an elevated level of CYP24A1 appears to have an important impact on the formation of melanocytic nevi and melanomagenesis, or progression, at early stages of tumor development.

  6. Screening of the COL2A1 mutation in idiopathic osteonecrosis of the femoral head.

    Science.gov (United States)

    Sakamoto, Yuma; Yamamoto, Takuaki; Miyake, Noriko; Matsumoto, Naomichi; Iida, Aritoshi; Nakashima, Yasuharu; Iwamoto, Yukihide; Ikegawa, Shiro

    2017-04-01

    Idiopathic osteonecrosis of the femoral head (idiopathic ONFH) is an ischemic disorder resulting in necrosis of the subchondral bone of the femoral head. COL2A1 mutations, including c.3508G>A, have been reported to be involved in its etiology. However, the etiological role of COL2A1 mutations in idiopathic ONFH remains controversial, because the pathology of idiopathic ONFH is ischemic necrosis, not epiphyseal dysplasia usually seen in the diseases caused by COL2A1 mutations. The purpose of this study is to examine whether COL2A1 mutations have causal relation with idiopathic ONFH or not. We recruited 1,451 Japanese patients with idiopathic ONFH, including steroid-, alcohol-, and neither steroid nor alcohol-associated (neither-associated) ONFH. The diagnosis was based on the criteria of the Japanese Research Committee on idiopathic ONFH of the Ministry of Health, Labour and Welfare. By whole-exome sequencing, entire COL2A1 coding regions and flanking introns were analyzed in 49 neither-associated ONFH patients. In addition, the c.3508G>A mutation of COL2A1 was checked in all idiopathic ONFH patients using the invader assay. Whole-exome sequencing did not detect any COL2A1 mutations in the 49 patients. The c.3508G>A mutation was not found in any of the 1,451 patients. In conclusion, COL2A1 is unlikely to cause idiopathic ONFH. Epiphyseal dysplasia of the femoral head caused by COL2A1 mutations may radiographically mimic idiopathic ONFH. COL2A1 mutations should prompt clinical re-evaluation of the patient's phenotype. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:768-774, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  7. Impact of 27-hydroxylase (CYP27A1) and 27-hydroxycholesterol in breast cancer.

    Science.gov (United States)

    Kimbung, Siker; Chang, Ching-Yi; Bendahl, Pär-Ola; Dubois, Laura; Thompson, J Will; McDonnell, Donald P; Borgquist, Signe

    2017-07-01

    The impact of systemic 27-hydroxycholesterol (27HC) and intratumoral CYP27A1 expression on pathobiology and clinical response to statins in breast cancer needs clarification. 27HC is an oxysterol produced from cholesterol by the monooxygenase CYP27A1, which regulates intracellular cholesterol homeostasis. 27HC also acts as an endogenous selective estrogen receptor (ER) modulator capable of increasing breast cancer growth and metastasis. 27HC levels can be modulated by statins or direct inhibition of CYP27A1, thereby attenuating its pro-tumorigenic activities. Herein, the effect of statins on serum 27HC and tumor-specific CYP27A1 expression was evaluated in 42 breast cancer patients treated with atorvastatin within a phase II clinical trial. Further, the associations between CYP27A1 expression with other primary tumor pathological features and clinical outcomes were studied in two additional independent cohorts. Statin treatment effectively decreased serum 27HC and deregulated CYP27A1 expression in tumors. However, these changes were not associated with anti-proliferative responses to statin treatment. CYP27A1 was heterogeneously expressed among primary tumors, with high expression significantly associated with high tumor grade, ER negativity and basal-like subtype. High CYP27A1 expression was independently prognostic for longer recurrence-free and overall survival. Importantly, the beneficial effect of high CYP27A1 in ER-positive breast cancer seemed limited to women aged ≤50 years. These results establish a link between CYP27A1 and breast cancer pathobiology and prognosis and propose that the efficacy of statins in reducing serum lipids does not directly translate to anti-proliferative effects in tumors. Changes in other undetermined serum or tumor factors suggestively mediate the anti-proliferative effects of statins in breast cancer. © 2017 The authors.

  8. Annexin A1 is elevated in patients with COPD and affects lung fibroblast function

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    Lai TW

    2018-02-01

    Full Text Available Tianwen Lai,1,* Yanyu Li,1,* Zongjiong Mai,2 Xiaoxia Wen,1 Yingying Lv,1 Zhanqing Xie,3 Quanchao Lv,1 Min Chen,1 Dong Wu,1 Bin Wu1 1Department of Respiratory and Critical Care Medicine, 2Department of Oncology, 3Department of Thoracic Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, People’s Republic of China *These authors contributed equally to this work Purpose: Fibrosis in peripheral airways is responsible for airflow limitation in chronic obstructive pulmonary disease (COPD. Annexin A1 modulates several key biological events during inflammation. However, little is known about its role in airway fibrosis in COPD. We investigated whether levels of Annexin A1 were upregulated in patients with COPD, and whether it promoted airway fibrosis.Methods: We quantified serum Annexin A1 levels in never-smokers (n=12, smokers without COPD (n=11, and smokers with COPD (n=22. Correlations between Annexin A1 expression and clinical indicators (eg, lung function were assessed. In vitro, human bronchial epithelial (HBE cells were exposed to cigarette smoke extract (CSE and Annexin A1 expression was assessed. Primary human lung fibroblasts were isolated from patients with COPD and effects of Annexin A1 on fibrotic deposition of lung fibroblasts were evaluated.Results: Serum Annexin A1 was significantly higher in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD guidelines stage III or IV than in those with GOLD stages I or II (12.8±0.8 ng/mL versus 9.8±0.7 ng/mL; p=0.016. Annexin A1 expression was negatively associated with airflow obstruction (forced expiratory volume in one second % predicted; r=−0.72, p<0.001. In vitro, Annexin A1 was significantly increased in CSE-exposed HBE cells in a time- and concentration-dependent manner. Annexin A1 promoted lung fibroblasts proliferation, migration, differentiation, and collagen deposition via the ERK1/2 and p38 mitogen-activated protein kinase pathways

  9. The relationship between the incidence of adhesive capsulitis and hemoglobin A1c.

    Science.gov (United States)

    Chan, Justin H; Ho, Bryant S; Alvi, Hasham M; Saltzman, Matthew D; Marra, Guido

    2017-10-01

    Previous studies have shown no correlation between adhesive capsulitis and hemoglobin A 1c (HbA 1c ). However, HbA 1c is only a measure of short-term blood sugar control. We created a previously nonvalidated variable, cumulative HbA 1c , that uses HbA 1c values over time to estimate the total disease burden a single individual experiences over a period. In this study, we aimed to evaluate whether a correlation exists between cumulative HbA 1c levels in diabetic patients and the prevalence of frozen shoulder. We hypothesized that poor long-term glucose control would be correlated with increased incidence of adhesive capsulitis. A retrospective analysis at a single institution was performed. Data from all patients from a single institution with any HbA 1c values were collected. A total of 24,417 patients met the inclusion criteria. A variable was created establishing the cumulative magnitude of abnormal HbA 1c values over time, termed "cumulative HbA 1c ." Logistic regression analysis was performed to determine whether long-term glucose control was predictive of the development of adhesive capsulitis. Cumulative HbA 1c was positively associated with adhesive capsulitis (7.6 × 10 -5 ) (ie, odds ratio of 1.000076). The effect size of cumulative HbA 1c on adhesive capsulitis was significant; for each unit of time that the HbA 1c level was greater than 7, there was a 2.77% increase in the risk of adhesive capsulitis. Cumulative HbA 1c was associated with an increased incidence of adhesive capsulitis. This finding suggests that the effects of diabetes that predispose patients to the development of adhesive capsulitis are dose dependent. Patients with worse blood sugar control over a longer period are at an increased risk of the development of adhesive capsulitis. Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

  10. Association Between Preoperative Hemoglobin A1c Levels, Postoperative Hyperglycemia, and Readmissions Following Gastrointestinal Surgery.

    Science.gov (United States)

    Jones, Caroline E; Graham, Laura A; Morris, Melanie S; Richman, Joshua S; Hollis, Robert H; Wahl, Tyler S; Copeland, Laurel A; Burns, Edith A; Itani, Kamal M F; Hawn, Mary T

    2017-11-01

    Preoperative hyperglycemia is associated with adverse postoperative outcomes among patients who undergo surgery. Whether preoperative hemoglobin A1c (HbA1c) or postoperative glucose levels are more useful in predicting adverse events following surgery is uncertain in the current literature. To examine the use of preoperative HbA1c and early postoperative glucose levels for predicting postoperative complications and readmission. In this observational cohort study, inpatient gastrointestinal surgical procedures performed at 117 Veterans Affairs hospitals from 2007 to 2014 were identified, and cases of known infection within 3 days before surgery were excluded. Preoperative HbA1c levels were examined as a continuous and categorical variable (6.5%). A logistic regression modeled postoperative complications and readmissions with the closest preoperative HbA1c within 90 days and the highest postoperative glucose levels within 48 hours of undergoing surgery. Postoperative complications and 30-day unplanned readmission following discharge. Of 21 541 participants, 1193 (5.5%) were women, and the mean (SD) age was 63.7 (10.6) years. The cohort included 23 094 operations with measurements of preoperative HbA1c levels and postoperative glucose levels. The complication and 30-day readmission rates were 27.2% and 14.7%, respectively. In logistic regression models adjusting for HbA1c, postoperative glucose levels, postoperative insulin use, diabetes, body mass index (calculated as weight in kilograms divided by height in meters squared), and other patient and procedural factors, peak postoperative glucose levels of more than 250 mg/dL were associated with increased 30-day readmissions (odds ratio, 1.18; 95% CI, 0.99-1.41; P = .07). By contrast, a preoperative HbA1c of more than 6.5% was associated with decreased 30-day readmissions (odds ratio, 0.85; 95% CI, 0.74-0.96; P = .01). As preoperative HbA1c increased, the frequency of 48-hour postoperative glucose checks

  11. Complex formation and functional interaction between adenosine A1 receptor and type-1 metabotropic glutamate receptor

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    Yuji Kamikubo

    2015-07-01

    Full Text Available The adenosine A1 receptor (A1R is a G protein-coupled receptor (GPCR for adenosine, a ubiquitous neuromodulator, and thus regulates neuronal excitability, as well as arousal and sensitivity to pain. In addition, we have previously described a new mode of action for A1R: in cerebellar Purkinje cells, its activation attenuates neuronal responses to glutamate, as mediated by the type-1 metabotropic glutamate receptor (mGluR1. mGluR1 is also a GPCR, and elicits such responses as long-term depression of the postsynaptic response to glutamate, a cellular basis for cerebellar motor learning. Here, we explore in greater detail the interaction between A1R and mGluR1 using non-neuronal cells. Co-immunoprecipitation and Förster resonance energy transfer (FRET analysis reveal that A1R and mGluR1 form a complex. Furthermore, we found that mGluR1 activation inhibits A1R signaling, as measured by changes in intracellular cAMP. These findings demonstrate that A1R and mGluR1 have the intrinsic ability to form a heteromeric complex and mutually modulate signaling. This interaction may represent a new form of intriguing GPCR-mediated cellular responses.

  12. Changing from glucose to HbA1c for diabetes diagnosis

    DEFF Research Database (Denmark)

    Nielsen, Aneta Aleksandra; Petersen, Per Hyltoft; Green, Anders

    2014-01-01

    BACKGROUND: In Denmark, the use of HbA1c in the diagnosis of diabetes was adopted from March 2012. We evaluated the change in the number of diabetes cases diagnosed by haemoglobin A1c (HbA1c) versus fasting venous plasma glucose (FPG), and estimated the influence of analytical variation and bias...... on the HbA1c-based prevalence of diabetes. METHODS: The study population constituted 4239 individuals not known to have diabetes randomly selected from all inhabitants aged 25-75 years in the former County of Vejle, Denmark. The number of undiagnosed patients with diabetes in the study population using FPG...... or HbA1c as the diagnostic criterion was estimated. Furthermore, changes in the analytical bias and coefficient of variation (CV) for HbA1c analysis were simulated and the effect on the number of diabetes cases was observed. RESULTS: Changing the diagnostic test from FPG to HbA1c reduced the number...

  13. Characterisation of a flavonoid ligand of the fungal protein Alt a 1.

    Science.gov (United States)

    Garrido-Arandia, María; Silva-Navas, Javier; Ramírez-Castillejo, Carmen; Cubells-Baeza, Nuria; Gómez-Casado, Cristina; Barber, Domingo; Pozo, Juan C; Melendi, Pablo G; Pacios, Luis F; Díaz-Perales, Araceli

    2016-09-16

    Spores of pathogenic fungi are virtually ubiquitous and cause human disease and severe losses in crops. The endophytic fungi Alternaria species produce host-selective phytotoxins. Alt a 1 is a strongly allergenic protein found in A. alternata that causes severe asthma. Despite the well-established pathogenicity of Alt a 1, the molecular mechanisms underlying its action and physiological function remain largely unknown. To gain insight into the role played by this protein in the pathogenicity of the fungus, we studied production of Alt a 1 and its activity in spores. We found that Alt a 1 accumulates inside spores and that its release with a ligand is pH-dependent, with optimum production in the 5.0-6.5 interval. The Alt a 1 ligand was identified as a methylated flavonoid that inhibits plant root growth and detoxifies reactive oxygen species. We also found that Alt a 1 changes its oligomerization state depending on the pH of the surrounding medium and that these changes facilitate the release of the ligand. Based on these results, we propose that release of Alt a 1 should be a pathogenic target in approaches used to block plant defenses and consequently to favor fungal entry into the plant.

  14. Identification of a novel signaling pathway and its relevance for GluA1 recycling.

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    Guiscard Seebohm

    Full Text Available We previously showed that the serum- and glucocorticoid-inducible kinase 3 (SGK3 increases the AMPA-type glutamate receptor GluA1 protein in the plasma membrane. The activation of AMPA receptors by NMDA-type glutamate receptors eventually leads to postsynaptic neuronal plasticity. Here, we show that SGK3 mRNA is upregulated in the hippocampus of new-born wild type Wistar rats after NMDA receptor activation. We further demonstrate in the Xenopus oocyte expression system that delivery of GluA1 protein to the plasma membrane depends on the small GTPase RAB11. This RAB-dependent GluA1 trafficking requires phosphorylation and activation of phosphoinositol-3-phosphate-5-kinase (PIKfyve and the generation of PI(3,5P(2. In line with this mechanism we could show PIKfyve mRNA expression in the hippocampus of wild type C57/BL6 mice and phosphorylation of PIKfyve by SGK3. Incubation of hippocampal slices with the PIKfyve inhibitor YM201636 revealed reduced CA1 basal synaptic activity. Furthermore, treatment of primary hippocampal neurons with YM201636 altered the GluA1 expression pattern towards reduced synaptic expression of GluA1. Our findings demonstrate for the first time an involvement of PIKfyve and PI(3,5P(2 in NMDA receptor-triggered synaptic GluA1 trafficking. This new regulatory pathway of GluA1 may contribute to synaptic plasticity and memory.

  15. Novel COL4A1 mutations cause cerebral small vessel disease by haploinsufficiency.

    Science.gov (United States)

    Lemmens, Robin; Maugeri, Alessandra; Niessen, Hans W M; Goris, An; Tousseyn, Thomas; Demaerel, Philippe; Corveleyn, Anniek; Robberecht, Wim; van der Knaap, Marjo S; Thijs, Vincent N; Zwijnenburg, Petra J G

    2013-01-15

    Mutations in COL4A1 have been identified in families with hereditary small vessel disease of the brain presumably due to a dominant-negative mechanism. Here, we report on two novel mutations in COL4A1 in two families with porencephaly, intracerebral hemorrhage and severe white matter disease caused by haploinsufficiency. Two families with various clinical presentations of cerebral microangiopathy and autosomal dominant inheritance were examined. Clinical, neuroradiological and genetic investigations were performed. Electron microscopy of the skin was also performed. In one of the families, sequence analysis revealed a one base deletion, c.2085del, leading to a frameshift and a premature stopcodon, p.(Gly696fs). In the other family, a splice site mutation was identified, c.2194-1G>A, which most likely leads to skipping of an exon with a frameshift and premature termination as a result. In fibroblasts of affected individuals from both the families, nonsense-mediated decay (NMD) of the mutant COL4A1 messenger RNAs (mRNAs) and a clear reduction of COL4A1 protein expression were demonstrated, indicating haploinsufficiency of COL4A1. Moreover, thickening of the capillary basement membrane in the skin was documented, similar to reports in patients with COL4A1 missense mutations. These findings suggest haploinsufficiency, a different mechanism from the commonly assumed dominant-negative effect, for COL4A1 mutations as a cause of (antenatal) intracerebral hemorrhage and white matter disease.

  16. CYP1A1 messenger RNA levels in placental tissue as a biomarker of environmental exposure.

    Science.gov (United States)

    Whyatt, R M; Garte, S J; Cosma, G; Bell, D A; Jedrychowski, W; Wahrendorf, J; Randall, M C; Cooper, T B; Ottman, R; Tang, D

    1995-03-01

    The human CYP1A1 gene codes for an inducible enzyme system involved in biotransformation of certain xenobiotics, including polycyclic aromatic hydrocarbons; some of the metabolites are carcinogenic and mutagenic. Effects of environmental exposures (smoking, air pollution, and diet) on CYP1A1 gene induction in placental tissue and the modulation of induction by the CYP1A1 MspI RFLP were evaluated in two groups from Poland: 70 mother-child pairs from Krakow, a city with elevated air pollution; and 90 pairs from Limanowa, a less polluted area. Compared to placentas from nonsmoking women, CYP1A1 mRNA levels were significantly increased in placentas from current smokers (P meat, cheese, and fish (P < 0.01). The CYP1A1 MspI RFLP was not a significant determinant of CYP1A1 mRNA levels after controlling for smoking and other variables. Human placenta provides a readily available and responsive system that can serve as a model for evaluating environmental and genetic determinants of CYP1A1 induction.

  17. Altered expression of cyclin A 1 in muscle of patients with facioscapulohumeral muscle dystrophy (FSHD-1.

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    Anna Pakula

    Full Text Available OBJECTIVES: Cyclin A1 regulates cell cycle activity and proliferation in somatic and germ-line cells. Its expression increases in G1/S phase and reaches a maximum in G2 and M phases. Altered cyclin A1 expression might contribute to clinical symptoms in facioscapulohumeral muscular dystrophy (FSHD. METHODS: Muscle biopsies were taken from the Vastus lateralis muscle for cDNA microarray, RT-PCR, immunohistochemistry and Western blot analyses to assess RNA and protein expression of cyclin A1 in human muscle cell lines and muscle tissue. Muscle fibers diameter was calculated on cryosections to test for hypertrophy. RESULTS: cDNA microarray data showed specifically elevated cyclin A1 levels in FSHD vs. other muscular disorders such as caveolinopathy, dysferlinopathy, four and a half LIM domains protein 1 deficiency and healthy controls. Data could be confirmed with RT-PCR and Western blot analysis showing up-regulated cyclin A1 levels also at protein level. We found also clear signs of hypertrophy within the Vastus lateralis muscle in FSHD-1 patients. CONCLUSIONS: In most somatic human cell lines, cyclin A1 levels are low. Overexpression of cyclin A1 in FSHD indicates cell cycle dysregulation in FSHD and might contribute to clinical symptoms of this disease.

  18. Increased maternal and fetal cholesterol efflux capacity and placental CYP27A1 expression in preeclampsia.

    Science.gov (United States)

    Mistry, Hiten D; Kurlak, Lesia O; Mansour, Yosef T; Zurkinden, Line; Mohaupt, Markus G; Escher, Geneviève

    2017-06-01

    Preeclampsia is a pregnancy-specific condition that leads to increased cardiovascular risk in later life. A decrease in cholesterol efflux capacity is linked to CVD. We hypothesized that in preeclampsia there would be a disruption of maternal/fetal plasma to efflux cholesterol, as well as differences in the concentrations of both placental sterol 27-hydroxylase (CYP27A1) and apoA1 binding protein (AIBP). Total, HDL-, and ABCA1-mediated cholesterol effluxes were performed with maternal and fetal plasma from women with preeclampsia and normotensive controls (both n = 17). apoA1 and apoE were quantified by chemiluminescence, and 27-hydroxycholesterol (27-OHC) by GC-MS. Immunohistochemistry was used to determine placental expression/localization of CYP27A1, AIBP, apoA1, apoE, and SRB1. Maternal and fetal total and HDL-mediated cholesterol efflux capacities were increased in preeclampsia (by 10-20%), but ABCA1-mediated efflux was decreased (by 20-35%; P CYP27A1 and AIBP were localized around fetal vessels and significantly increased in preeclampsia ( P = 0.04). Placental 27-OHC concentrations were also raised in preeclampsia ( P CYP27A1/27-OHC could be a rescue mechanism in preeclampsia, to remove cholesterol from cells to limit lipid peroxidation and increase placental angiogenesis. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  19. Role of CYP27A1 in progesterone metabolism in vitro and in vivo.

    Science.gov (United States)

    Escher, Geneviève; Vögeli, Isabelle; Escher, Robert; Tuckey, Robert C; Erickson, Sandra; Krozowski, Zygmunt; Frey, Felix J

    2009-10-01

    In the kidney, progesterone is inactivated to 20alpha-dihydro-progesterone (20alpha-DH-progesterone) to protect the mineralocorticoid receptor from progesterone excess. In an attempt to clone the enzyme with 20alpha-hydroxysteroid activity using expression cloning in CHOP cells and a human kidney expression library, serendipitously cDNA encoding CYP27A1 was isolated. Overexpression of CYP27A1 in CHOP cells decreased progesterone conversion to 20alpha-DH-progesterone in a dose-dependent manner, an effect enhanced by cotransfection with adrenodoxin and adrenodoxin reductase. Incubation of CHOP cells with 27-hydroxycholesterol, a product of CYP27A1, increased the ratio of progesterone to 20alpha-DH-progesterone in a concentration-dependent manner, indicating that the effect of CYP27A1 overexpression was mediated by 27-hydroxycholesterol. To analyze whether these observations are relevant in vivo, progesterone and 20alpha-DH-progesterone were measured by gas chromatography-mass spectometry in 24-h urine of CYP27A1 gene knockout (ko) mice and their control wild-type and heterozygote littermates. In CYP27A1 ko mice, urinary progesterone concentrations were decreased, 20alpha-DH-progesterone increased, and the progesterone-to-20alpha-DH-progesterone ratio decreased threefold (P CYP27A1 modulates progesterone concentrations. The underlying mechanism is inhibition of 20alpha-hydroxysteroid dehydrogenase by 27-hydroxycholesterol.

  20. The novel role of HtrA1 in gingivitis, chronic and aggressive periodontitis.

    Science.gov (United States)

    Lorenzi, Teresa; Niţulescu, Elena Annabel; Zizzi, Antonio; Lorenzi, Maria; Paolinelli, Francesca; Aspriello, Simone Domenico; Baniţă, Monica; Crăiţoiu, Stefania; Goteri, Gaia; Barbatelli, Giorgio; Lombardi, Tommaso; Di Felice, Roberto; Marzioni, Daniela; Rubini, Corrado; Castellucci, Mario

    2014-01-01

    Proteolytic tissue degradation is a typical phenomenon in inflammatory periodontal diseases. HtrA1 (High temperature requirement A 1) has a serine protease activity and is able to degrade fibronectin whose fragments induce the expression and secretion of several matrix metalloproteinases (MMPs). The aim of this study was to investigate for the first time if HtrA1 has a role in gingivitis and in generalized forms of chronic and aggressive periodontitis. Expression of HtrA1 was investigated in 16 clinically healthy gingiva, 16 gingivitis, 14 generalized chronic periodontitis and 10 generalized aggressive periodontitis by immunohistochemistry and real-time PCR. Statistical comparisons were performed by the Kruskall-Wallis test. Significantly higher levels of HtrA1 mRNA and protein expression were observed in pathological respect to healthy tissues. In particular, we detected an increase of plasma cell HtrA1 immunostaining from gingivitis to chronic and aggressive periodontitis, with the higher intensity in aggressive disease. In addition, we observed the presence of HtrA1 in normal and pathological epithelium, with an increased expression, particularly in its superficial layer, associated with increasingly severe forms of periodontal disease. We can affirm that HtrA1 expression in plasma cells could be correlated with the destruction of pathological periodontal tissue, probably due to its ability to trigger the overproduction of MMPs and to increase the inflammatory mediators TNF-α and IL-1β by inhibition of TGF-β. Moreover, epithelial HtrA1 immunostaining suggests a participation of the molecule in the host inflammatory immune responses necessary for the control of periodontal infection.

  1. The Novel Role of HtrA1 in Gingivitis, Chronic and Aggressive Periodontitis

    Science.gov (United States)

    Zizzi, Antonio; Lorenzi, Maria; Paolinelli, Francesca; Aspriello, Simone Domenico; Baniţă, Monica; Crăiţoiu, Ştefania; Goteri, Gaia; Barbatelli, Giorgio; Lombardi, Tommaso; Di Felice, Roberto; Marzioni, Daniela; Rubini, Corrado; Castellucci, Mario

    2014-01-01

    Proteolytic tissue degradation is a typical phenomenon in inflammatory periodontal diseases. HtrA1 (High temperature requirement A 1) has a serine protease activity and is able to degrade fibronectin whose fragments induce the expression and secretion of several matrix metalloproteinases (MMPs). The aim of this study was to investigate for the first time if HtrA1 has a role in gingivitis and in generalized forms of chronic and aggressive periodontitis. Expression of HtrA1 was investigated in 16 clinically healthy gingiva, 16 gingivitis, 14 generalized chronic periodontitis and 10 generalized aggressive periodontitis by immunohistochemistry and real-time PCR. Statistical comparisons were performed by the Kruskall-Wallis test. Significantly higher levels of HtrA1 mRNA and protein expression were observed in pathological respect to healthy tissues. In particular, we detected an increase of plasma cell HtrA1 immunostaining from gingivitis to chronic and aggressive periodontitis, with the higher intensity in aggressive disease. In addition, we observed the presence of HtrA1 in normal and pathological epithelium, with an increased expression, particularly in its superficial layer, associated with increasingly severe forms of periodontal disease. We can affirm that HtrA1 expression in plasma cells could be correlated with the destruction of pathological periodontal tissue, probably due to its ability to trigger the overproduction of MMPs and to increase the inflammatory mediators TNF-α and IL-1β by inhibition of TGF-β. Moreover, epithelial HtrA1 immunostaining suggests a participation of the molecule in the host inflammatory immune responses necessary for the control of periodontal infection. PMID:24979214

  2. Maternal diabetes and neonatal macrosomia. I. Postpartum maternal hemoglobin A1c levels and neonatal hypoglycemia.

    Science.gov (United States)

    Brans, Y W; Huff, R W; Shannon, D L; Hunter, M A

    1982-10-01

    Hemoglobin A1c (HgbA1c) levels were determined within 24 hours after delivery in 88 nondiabetic and 73 diabetic women belonging to White's classes A to D. Diet-controlled gestational diabetic women had mean (+/- SE) Hgb A1c levels similar to those of nondiabetics (5.8 +/- 0.18% vs 5.7 +/- 0.08%). Mean Hgb A1c levels were higher in insulin-requiring gestational (6.4 +/- 0.20%, P less than .05) and permanent (6.5 +/- 0.27%, P less than .05) diabetics than in nondiabetics. The proportions of subjects with levels above the normal range were also larger in the insulin-requiring groups. Mean Hgb A1c levels and the proportions of abnormally high levels were similar for mothers of macrosomic and of normally grown neonates in the nondiabetic as well as in the various diabetes groups. There was no correlation between maternal Hgb A1c level and neonatal birth weight, either real or relative. There were also no statistically significant differences in mean Hgb A1c levels between mothers of neonates with or without hypoglycemia within four hours of birth. Hgb A1c measurement did not permit differentiation between those mothers of macrosomic neonates who were diabetic and those who were not. In conclusion, although Hgb A1c level has been shown to reflect diabetic control, our data suggest that it may not be reliable as an indicator of fine tuning during the third trimester of pregnancy or as a predictor of the effects of diabetes on the fetus.

  3. Gambaran Populasi Golongan Darah Subgroup A (A1, A2) di PMI Kulon Progo

    OpenAIRE

    Hieronymus Rayi Prasetya; Bambang Heru Budianto; Hernayanti Hernayanti

    2017-01-01

    Subgroup A1 and A2 are the most important in the blood group A. Subgroup A1 has the A antigen more than A2 subgroup, the A2 subgroup can cause misidentification of blood group due to poor A antigen and genetic variation possessed. Misidentification of the blood group will increase the risk of transfusion reactions. This research aims to describe the A1 and A2 subgroup population in Kulon Progo district. This study was conducted with a cross sectional sampling technique. The sample in this stu...

  4. Assessment of the Distal Extent of the A1 Pulley Release: A New Technique

    OpenAIRE

    Hazani, Ron; Engineer, Nitin J.; Zeineh, Linda L.; Wilhelmi, Bradon J.

    2008-01-01

    Objective: Sharp division of the A1 pulley is a time-honored technique for the treatment of flexor tendon entrapment; however, this procedure is not without complications. The anatomy of the A1 pulley system has been carefully investigated. Knowledge of superficial anatomic landmarks can assist with demarcating the distal edge of the A1 pulley and prevent damage to the critical A2 pulley. Methods: Nine fresh cadaveric hands were dissected with the aid of loupe magnification. On the basis of k...

  5. Sleep deprivation increases A1 adenosine receptor density in the rat brain

    OpenAIRE

    Elmenhorst, David; Basheer, Radhika; McCarley, Robert W.; Bauer, Andreas

    2008-01-01

    Adenosine, increasing after sleep deprivation and acting via the A1 adenosine receptor (A1AR), is likely a key factor in the homeostatic control of sleep. This study examines the impact of sleep deprivation on A1AR density in different parts of the rat brain with [3H]CPFPX autoradiography. Binding of [3H]CPFPX was significantly increased in parietal cortex (PAR) (7%), thalamus (11%) and caudate-putamen (9%) after 24 h of sleep deprivation compared to a control group with an undisturbed circad...

  6. Celecoxib influences steroid sulfonation catalyzed by human recombinant sulfotransferase 2A1

    OpenAIRE

    Ambadapadi, Sriram; Wang, Peter L.; Palii, Sergiu P.; James, Margaret O.

    2015-01-01

    Celecoxib has been reported to switch the human SULT2A1-catalyzed sulfonation of 17βestradiol (17β-E2) from the 3- to the 17-position. The effects of celecoxib on the sulfonation of selected steroids catalyzed by human SULT2A1 were assessed through in vitro and in silico studies. Celecoxib inhibited SULT2A1-catalyzed sulfonation of dehydroepiandrosterone (DHEA), androst-5-ene-3β, 17β-diol (AD), testosterone (T) and epitestosterone (Epi-T) in a concentration-dependent manner. Low μM concentrat...

  7. Hormonal Regulation of the Human CYP27A1 and CYP7B1 Genes

    OpenAIRE

    Tang, Wanjin

    2007-01-01

    CYP27A1 and CYP7B1 are widely expressed in various human tissues and are two key enzymes involved in the pathways for conversion of cholesterol to bile acids. Also, CYP27A1 is involved in bioactivation of vitamin D3 and CYP7B1 plays a role in 7alpha-hydroxylation of dehydroepiandrosterone and other steroids. Both enzymes have been reported to be relevant to prostate cell proliferation. The current study examines the hormonal regulation of CYP27A1 and CYP7B1. CYP7B1 was shown to be regulated b...

  8. Intestinal bacterium-derived cyp27a1 prevents colon cancer cell apoptosis

    OpenAIRE

    Ji, Yan-Chao; Liu, Chang; Zhang, Xia; Zhang, Cheng-Sen; Wang, Dong; Zhang, Yan

    2016-01-01

    The pathogenesis of metastasis of colon cancer (Cca) is to be further investigated. The dysfunction of apoptotic mechanism plays a role in the cancer cell over growth. This study tests a hypothesis by which intestinal bacterium-derived cyp27a1 prevents apoptosis in colon cancer cells. In this study, the levels of cyp27a1 in human stool samples were assessed by enzyme-linked immunosorbent assay. The apoptosis of Cca cells was observed by flow cytometry. The expression of cyp27a1 was assessed b...

  9. The Role of Adenosine Receptors in Psychostimulant Addiction

    Directory of Open Access Journals (Sweden)

    Inmaculada Ballesteros-Yáñez

    2018-01-01

    Full Text Available Adenosine receptors (AR are a family of G-protein coupled receptors, comprised of four members, named A1, A2A, A2B, and A3 receptors, found widely distributed in almost all human body tissues and organs. To date, they are known to participate in a large variety of physiopathological responses, which include vasodilation, pain, and inflammation. In particular, in the central nervous system (CNS, adenosine acts as a neuromodulator, exerting different functions depending on the type of AR and consequent cellular signaling involved. In terms of molecular pathways and second messengers involved, A1 and A3 receptors inhibit adenylyl cyclase (AC, through Gi/o proteins, while A2A and A2B receptors stimulate it through Gs proteins. In the CNS, A1 receptors are widely distributed in the cortex, hippocampus, and cerebellum, A2A receptors are localized mainly in the striatum and olfactory bulb, while A2B and A3 receptors are found at low levels of expression. In addition, AR are able to form heteromers, both among themselves (e.g., A1/A2A, as well as with other subtypes (e.g., A2A/D2, opening a whole range of possibilities in the field of the pharmacology of AR. Nowadays, we know that adenosine, by acting on adenosine A1 and A2A receptors, is known to antagonistically modulate dopaminergic neurotransmission and therefore reward systems, being A1 receptors colocalized in heteromeric complexes with D1 receptors, and A2A receptors with D2 receptors. This review documents the present state of knowledge of the contribution of AR, particularly A1 and A2A, to psychostimulants-mediated effects, including locomotor activity, discrimination, seeking and reward, and discuss their therapeutic relevance to psychostimulant addiction. Studies presented in this review reinforce the potential of A1 agonists as an effective strategy to counteract psychostimulant-induced effects. Furthermore, different experimental data support the hypothesis that A2A/D2 heterodimers are

  10. A history of HbA1c through Clinical Chemistry and Laboratory Medicine.

    Science.gov (United States)

    Gillery, Philippe

    2013-01-01

    HbA(1c) was discovered in the late 1960s and its use as marker of glycemic control has gradually increased over the course of the last four decades. Recognized as the gold standard of diabetic survey, this parameter was successfully implemented in clinical practice in the 1970s and 1980s and internationally standardized in the 1990s and 2000s. The use of standardized and well-controlled methods, with well-defined performance criteria, has recently opened new directions for HbA(1c) use in patient care, e.g., for diabetes diagnosis. Many reports devoted to HbA1c have been published in Clinical Chemistry and Laboratory Medicine (CCLM) journal. This review reminds the major steps of HbA(1c) history, with a special emphasis on the contribution of CCLM in this field.

  11. Association of fibrinogen with HbA1C in diabetic foot ulcer

    Science.gov (United States)

    Pase, M. A.; Gatot, D.; Lindarto, D.

    2018-03-01

    Fibrinogen is one of the inflammatory markers of vascular changes and endothelial dysfunction in diabetic patients. The aim of this study to associate serum fibrinogen levels with HbA1C in diabetic foot ulcer (DFU). This study was cross-sectional and retrospective in DFU patients from January to July 2017 in Haji Adam Malik Central General Hospital. The patients enrolled in the study were T2DM with DFU as a complication. The grading of DFU was evaluated according to the Wagner’s Classification. Serum fibrinogen level, HbA1C and ankle-brachial index (ABI) were carried out directly in the patients. Fibrinogen serum levels were found significantly with HbA1C (P=0.001, r=0.387) and ABI (P=0.008, r=-0.454). Fibrinogen serum levels in DFU patients were positively correlated with HbA1C and significantly higher in patients with poor glycemic control.

  12. Annexin A1 influences in breast cancer: Controversies on contributions to tumour, host and immunoediting processes.

    Science.gov (United States)

    Tu, Yan; Johnstone, Cameron N; Stewart, Alastair G

    2017-05-01

    Annexin A1 is a multifunctional protein characterised by its actions in modulating the innate and adaptive immune response. Accumulating evidence of altered annexin A1 expression in many human tumours raises interest in its functional role in cancer biology. In breast cancer, altered annexin A1 expression levels suggest a potential influence on tumorigenic and metastatic processes. However, reports of conflicting results reveal a relationship that is much more complex than first conceptualised. In this review, we explore the diverse actions of annexin A1 on breast tumour cells and various host cell types, including stromal immune and structural cells, particularly in the context of cancer immunoediting. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Experimental verification of the new RISOe-A1 airfoil family for wind turbines

    Energy Technology Data Exchange (ETDEWEB)

    Dahl, K.S.; Fuglsang, P.; Antoniou, I. [Risoe National Lab., Roskilde (Denmark)

    1999-03-01

    This paper concerns the experimental verification of a new airfoil family for wind turbines. The family consist of airfoils in the relative thickness range from 15% to 30%. Three airfoils, Risoe-A1-18, Risoe-A1-21, and Risoe-A1-24 were tested in a wind tunnel. The verification consisted of both static and dynamic measurements. Here, the static results are presented for a Reynolds number of 1.6x10{sup 6} for the following airfoil configurations: smooth surface (all three airfoils) and Risoe-A1-24 mounted with leading edge roughness, vortex generators, and Gurney-flaps, respectively. All three airfoils have constant lift curve slope and almost constant drag coefficient until the maximum lift coefficient of about 1.4 is reached. The experimental results are compared with corresponding computational from the general purpose flow solver, EllipSys2D, showing good agreement. (au)

  14. Mice deleted for heart-type cytochrome c oxidase subunit 7a1 develop dilated cardiomyopathy.

    Science.gov (United States)

    Hüttemann, Maik; Klewer, Scott; Lee, Icksoo; Pecinova, Alena; Pecina, Petr; Liu, Jenney; Lee, Michael; Doan, Jeffrey W; Larson, Douglas; Slack, Elise; Maghsoodi, Bita; Erickson, Robert P; Grossman, Lawrence I

    2012-03-01

    Subunit 7a of mouse cytochrome c oxidase (Cox) displays a contractile muscle-specific isoform, Cox7a1, that is the major cardiac form. To gain insight into the role of this isoform, we have produced a new knockout mouse line that lacks Cox7a1. We show that homozygous and heterozygous Cox7a1 knockout mice, although viable, have reduced Cox activity and develop a dilated cardiomyopathy at 6 weeks of age. Surprisingly, the cardiomyopathy improves and stabilizes by 6 months of age. Cox7a1 knockout mice incorporate more of the "liver-type" isoform Cox7a2 into the cardiac Cox holoenzyme and, also surprisingly, have higher tissue ATP levels. Copyright © 2011 Elsevier B.V. and Mitochondria Research Society. All rights reserved. All rights reserved.

  15. The role of SCL2A1 in Early Onset and Childhood Absence Epilepsies

    DEFF Research Database (Denmark)

    Brusgaard, Klaus

    cases. The role of SLC2A1 mutations in absence epilepsies with a later onset has not been assessed so far. Therefore, we aimed to compare the role of SLC2A1 mutations in EOAE and Childhood and Juvenile Absence Epilepsy (CAE, JAE). Method: 26 cases with EOAE and 40 probands with CAE or JAE were screened...... brother and the paternal grandmother. Conclusion: Our study confirmed the role of SLC2A1 mutation carriers in EOAE and demonstrated that SLC2A1 do not seem to play a major role in CAE and JAE. Since ketogenic diet is a well known treatment option in GLUT-1-deficiency, pediatricians as well as neurologists...

  16. Tsukamurella pulmonis Bloodstream Infection Identified by secA1 Gene Sequencing

    OpenAIRE

    Pérez del Molino Bernal, Inmaculada C.; Cano, María E.; García de la Fuente, Celia; Martínez-Martínez, Luis; López, Mónica; Fernández-Mazarrasa, Carlos; Agüero, Jesús

    2014-01-01

    Recurrent bloodstream infections caused by a Gram-positive bacterium affected an immunocompromised child. Tsukamurella pulmonis was the microorganism identified by secA1 gene sequencing. Antibiotic treatment in combination with removal of the subcutaneous port healed the patient.

  17. Translating HbA1cmeasurements into estimated average glucose values in pregnant women with diabetes.

    Science.gov (United States)

    Law, Graham R; Gilthorpe, Mark S; Secher, Anna L; Temple, Rosemary; Bilous, Rudolf; Mathiesen, Elisabeth R; Murphy, Helen R; Scott, Eleanor M

    2017-04-01

    This study aimed to examine the relationship between average glucose levels, assessed by continuous glucose monitoring (CGM), and HbA 1c levels in pregnant women with diabetes to determine whether calculations of standard estimated average glucose (eAG) levels from HbA 1c measurements are applicable to pregnant women with diabetes. CGM data from 117 pregnant women (89 women with type 1 diabetes; 28 women with type 2 diabetes) were analysed. Average glucose levels were calculated from 5-7 day CGM profiles (mean 1275 glucose values per profile) and paired with a corresponding (±1 week) HbA 1c measure. In total, 688 average glucose-HbA 1c pairs were obtained across pregnancy (mean six pairs per participant). Average glucose level was used as the dependent variable in a regression model. Covariates were gestational week, study centre and HbA 1c . There was a strong association between HbA 1c and average glucose values in pregnancy (coefficient 0.67 [95% CI 0.57, 0.78]), i.e. a 1% (11 mmol/mol) difference in HbA 1c corresponded to a 0.67 mmol/l difference in average glucose. The random effects model that included gestational week as a curvilinear (quadratic) covariate fitted best, allowing calculation of a pregnancy-specific eAG (PeAG). This showed that an HbA 1c of 8.0% (64 mmol/mol) gave a PeAG of 7.4-7.7 mmol/l (depending on gestational week), compared with a standard eAG of 10.2 mmol/l. The PeAG associated with maintaining an HbA 1c level of 6.0% (42 mmol/mol) during pregnancy was between 6.4 and 6.7 mmol/l, depending on gestational week. The HbA 1c -average glucose relationship is altered by pregnancy. Routinely generated standard eAG values do not account for this difference between pregnant and non-pregnant individuals and, thus, should not be used during pregnancy. Instead, the PeAG values deduced in the current study are recommended for antenatal clinical care.

  18. Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals.

    Science.gov (United States)

    Domenice, Sorahia; Machado, Aline Zamboni; Ferreira, Frederico Moraes; Ferraz-de-Souza, Bruno; Lerario, Antonio Marcondes; Lin, Lin; Nishi, Mirian Yumie; Gomes, Nathalia Lisboa; da Silva, Thatiana Evelin; Silva, Rosana Barbosa; Correa, Rafaela Vieira; Montenegro, Luciana Ribeiro; Narciso, Amanda; Costa, Elaine Maria Frade; Achermann, John C; Mendonca, Berenice Bilharinho

    2016-12-01

    Steroidogenic factor 1 (NR5A1, SF-1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1-related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype-phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian-determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1-related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever-expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction

  19. Annexin A1 and A2: roles in retrograde trafficking of Shiga toxin.

    Directory of Open Access Journals (Sweden)

    Lionel Tcatchoff

    Full Text Available Annexins constitute a family of calcium and membrane binding proteins. As annexin A1 and A2 have previously been linked to various membrane trafficking events, we initiated this study to investigate the role of these annexins in the uptake and intracellular transport of the bacterial Shiga toxin (Stx and the plant toxin ricin. Once endocytosed, both toxins are retrogradely transported from endosomes to the Golgi apparatus and the endoplasmic reticulum before being targeted to the cytosol where they inhibit protein synthesis. This study was performed to obtain new information both about toxin transport and the function of annexin A1 and annexin A2. Our data show that depletion of annexin A1 or A2 alters the retrograde transport of Stx but not ricin, without affecting toxin binding or internalization. Knockdown of annexin A1 increases Golgi transport of Stx, whereas knockdown of annexin A2 slightly decreases the same transport step. Interestingly, annexin A1 was found in proximity to cytoplasmic phospholipase A2 (cPLA(2, and the basal as well as the increased Golgi transport of Stx upon annexin A1 knockdown is dependent on cPLA(2 activity. In conclusion, annexin A1 and A2 have different roles in Stx transport to the trans-Golgi network. The most prominent role is played by annexin A1 which normally works as a negative regulator of retrograde transport from the endosomes to the Golgi network, most likely by complex formation and inhibition of cPLA(2.

  20. Comparison of Hemoglobin A1c assay performance on two different commercial systems

    Directory of Open Access Journals (Sweden)

    Jozo Ćorić

    2015-04-01

    Full Text Available Introduction: Glycated hemoglobin (HbA1c is formed by non-enzymatic binding of glucose to the free amino group of the N-terminal end of the ß-chain of hemoglobin A. HbA1c is representative of