Carvedilol blocks beta(2)- more than beta(1)-adrenoceptors in human heart

Objective: To understand the basis of the effectiveness of carvedilol in heart failure by determining its specific properties at human heart and beta(2)-adrenoceptors. Methods: The positive inotropic effects of noradrenaline (in the presence of the beta(2)-selective antagonist ICI118551) and adrenaline (in the presence of the beta(1)-selective antagonist CGP20712), mediated through beta(1)- and beta(2)-adrenoceptors, respectively, were investigated in atrial and ventricular trabeculae. The patch-clamp technique was used to investigate effects of noradrenaline and adrenaline on L-type Ca2+ current in human atrial myocytes. Results: Carvedilol was a 13-fold more potent competitive antagonist of the effects of adrenaline at 1 2-adrenoceptors (-logK(B) = 10.13 +/- 0.08) than of noradrenaline at beta(1)-adrenoceptors (-logK(B) = 9.02 +/- 0.07) in human right atrium. Chronic carvedilol treatment of patients with non-terminal heart failure reduced the inotropic sensitivity of atrial trabeculae to noradrenaline and adrenaline 5.6-fold and 91.2-fold, respectively, compared to beta(1)-blocker-treated patients, consistent with persistent preferential blockade of beta(2)-adrenoceptors. In terminal heart failure carvedilol treatment reduced 1.8-fold and 25.1-fold the sensitivity of right ventricular trabeculae to noradrenaline and adrenaline, respectively, but metoprolol treatment did not reduce the sensitivity to the catecholamines. Increases of current (I-Ca,I-L) produced by noradrenaline and adrenaline were not different in atrial myocytes obtained from non-terminal heart failure patients treated with metoprolol or carvedilol, consistent with dissociation of both beta-blockers from the receptors. Conclusions: Carvedilol blocks human cardiac beta(2)-adrenoceptors more than beta(1)-adrenoceptors, thereby conceivably contributing to the beneficial effects in heart failure. The persistent blockade of beta-adrenoceptors is attributed to accumulation of carvedilol in cardiac tissue. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Inhibition of transforming growth factor-beta 1 signaling attenuates ataxia telanglectasia mutated activity in response to genotoxic stress

Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor beta (TGF beta)-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGF beta inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf beta 1 nail murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGF beta type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced gamma H2AX radiation-induced foci; and increased radiosensitivity compared with TGF beta competent cells. We determined that loss of TGF beta signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGF beta restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM, which directs epithelial cell stress responses, cell fate, and tissue integrity. Thus, Tgf beta 1, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGF beta may be used to advantage in cancer therapy.

Synthesis and evaluation of N1-substituted-3-propyl-1,4-benzodiazepine-2-ones as cholecystokinin (CCK2) receptor ligands

A novel synthetic approach towards N1-alkylated 3-propyl-1,4-benzodiazepines was developed in five synthetic steps from 2-amino-4-chlorobenzophenone, in which the N-oxide 4 served as a key intermediate. The structure-activity relationship optimization of this 3-prophyl-1,4-benzodiazepine template was carried out on the N1-position by selective alkylation reactions and resulted in a ligand with an improved affinity on the cholecystokinin (CCK2) receptor. The N-allyl-3-propyl-benzodiazepine 6d displayed an affinity towards the CCK2 (CCK-B) receptor of 170 nM in a radiolabelled receptor-binding assay. The anxiolytic activity of this allyl-3-propyl-1,4-benzodiazepine 6d was subsequently determined in in-vivo psychotropic assays. This novel ligand had ED50 values of 4.7 and 5.2 mg kg-1 in the black and white box test and the x-maze, respectively, and no significant sedation/muscle relaxation was observed.

X-ray crystallographic and theoretical studies of an anticonvulsant enaminone:methyl 4-(4'-bromophenyl)amino-6-methyl-2-oxocyclohex-3-en-1-oate

Objective: The aims of this study were to establish the structure of the potent anticonvulsant enaminone methyl 4-(4′-bromophenyl)amino-6-methyl-2- oxocyclohex-3-en-1-oate (E139), and to determine the energetically preferred conformation of the molecule, which is responsible for the biological activity. Materials and Methods: The structure of the molecule was determined by X-ray crystallography. Theoretical ab initio calculations with different basis sets were used to compare the energies of the different enantiomers and to other structurally related compounds. Results: The X-ray crystal structure revealed two independent molecules of E139, both with absolute configuration C11(S), C12(R), and their inverse. Ab initio calculations with the 6-31G, 3-21G and STO-3G basis sets confirmed that the C11(S), C12(R) enantiomer with both substituents equatorial had the lowest energy. Compared to relevant crystal structures, the geometry of the theoretical structures shows a longer C-N and shorter C=O distance with more cyclohexene ring puckering in the isolated molecule. Conclusion: Based on a pharmacophoric model it is suggested that the enaminone system HN-C=C-C=O and the 4-bromophenyl group in E139 are necessary to confer anticonvulsant property that could lead to the design of new and improved anticonvulsant agents. Copyright © 2003 S. Karger AG, Basel.

MIUS News: Maps and Imagery User Services @ FIU Green Library: Vol. 3, Issue 1 Fall 2009

Florida International University's Fall 2009 Map and User Imagery Services Newsletter.

(Table 2) Metazoan meiofauna abundance in sediments obtained during POLARSTERN cruise ANT-XIX/3 (ANDEEP-1)

Meiofauna standing stocks and community structure are reported for the first time for abyssal soft-sediment samples in Antarctic waters. At seven stations within a depth range of 2274-5194 m a total of 128 sediment cores were retrieved with a multiple corer (MUC) on board of the R.V. Polarstern during the ANDEEP-1 cruise (ANT XIX/3). The metazoan meiofauna (defined by a lower size limit of 40 µm) was identified and counted, and one core per station was preserved for CPE, C/N, TOM and grain size analyses. Meiofauna densities are in the range of 2731 Ind./10 cm² at 2290 m depth and 75 Ind./10 cm² at 3597 m depth, with nematodes being the dominant group at all stations. Nematodes account for 84-94% followed by copepods with 2-8% of the total meiofauna. Other frequent taxa found at each station are kinorhynchs, loriciferans, tantulocarids, ostracods and tardigrades. There is a general tendency of decreasing abundances of metazoan meiofauna with increasing depth, but not all higher level taxa displayed this pattern. In addition, a tendency of decreasing higher taxon density with increasing depth was observed. Standing stocks are higher than the average found at similar depths in other oceans.

Rôle du facteur de croissance transforming growth factor beta-1 (TGF[beta]1) dans la synthèse d'oestradiol par les follicules ovariens bovins

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Rôle du facteur de croissance transforming growth factor beta-1 (TGF[beta]1) dans la synthèse d'oestradiol par les follicules ovariens bovins

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Geological reference standards (JLK-1,JSD-1, JSD-2, JSD-3,JMS-1, JMS-2) measured by Itrax-XRF core scanner in different exposure times

X-ray fluorescence (XRF) core-scanning is a fast and nondestructive technique to assess elemental variations of unprocessed sediments. However, although the exposure time of XRF-scanning directly affects the scanning counts and total measurement time, only a few studies have considered the influence of exposure time during the scan. How to select an optimal exposure time to achieve reliable results and reduce the total measurement time is an important issue. To address this question, six geological reference materials from the Geological Survey of Japan (JLK-1, JMS-1, JMS-2, JSD-1, JSD-2, and JSD-3) were scanned by the Itrax-XRF core scanner using the Mo- and the Cr-tube with different exposure times to allow a comparison of scanning counts with absolute concentrations. The regression lines and correlation coefficients of elements that are generally used in paleoenvironmental studies were examined for the different exposure times and X-ray tubes. The results show that for those elements with relatively high concentrations or high detectability, the correlation coefficients are higher than 0.90 for all exposure times. In contrast, for the low detectability or low concentration elements, the correlation coefficients are relatively low, and improve little with increased exposure time. Therefore, we suggest that the influence of different exposure times is insignificant for the accuracy of the measurements. Thus, caution must be taken when interpreting the results of elements with low detectability, even when the exposure times are long and scanning counts are reasonably high.

IDPH Preparedness, EMS, and Trauma Update, January 28, 2016, Vol. 3, no. 1

Emergency preparedness, trauma and EMS update from The Iowa Department of Public Health.