(-)-CGP12177 increases contractile force through beta1l-adrenoceptors but not through beta3-adrenoceptors in human right atrial myocardium

(-)-CGP12177 is a non-conventional partial agonist that causes modest and transient increases of contractile force in human atrial trabeculae (Kaumann and Molenaar, 2008). These effects are markedly increased and maintained by inhibition of phosphodiesterase PDE3. As verified with recombinant receptors, the cardiostimulant effect of (-)-CGP12177 is mediated through a site at the beta1-adrenoceptor with lower affinity (beta1LAR) compared to the site through which (-)-CGP12177 antagonizes the effects of catecholamines (beta1HAR). However, in a recent report it was proposed that the positive inotropic effects of CGP12177 are mediated through beta3-adrenoceptors (Skeberdis et al 2008). We therefore investigated whether the effects of (-)-CGP12177 on human atrial trabeculae are antagonized by the beta3-adrenoceptor-selective antagonist L-748,337 (1 microM). (-)-CGP12177 (200 nM) caused a stable increase in force which was significantly reduced by the addition of (-)-bupranolol (1 microM), P = 0.002, (basal 4.45 ± 0.78 mN, IBMX (PDE inhibitor) 5.47 ± 1.01 mN, (-)-CGP12177 9.34 ± 1.33 mN, (-)-bupranolol 5.79 ± 1.08 mN, n = 6) but not affected by the addition of L-748,337 (1 microM), P = 0.12, (basal 4.48 ± 1.32 mN, IBMX 7.15 ± 2.28 mN, (-)-CGP12177 12.51 ± 3.71 mN, L-748,337 10.90 ± 3.49 mN, n = 6). Cumulative concentration-effect curves for (-)-CGP12177 were not shifted to the right by L-748,337 (1 microM). The –logEC50M values of (-)-CGP12177 in the absence and presence of L-748,337 were 7.21±0.09 and 7.41±0.13, respectively (data from 25 trabeculae from 8 patients, P=0.2) The positive inotropic effects of (-)-CGP12177 (IBMX present) were not antagonized by L-748,337 but were blunted by (-)-bupranolol (1 microM). The results rule out an involvement of beta3-adrenoceptors in the positive inotropic effects (-)-CGP12177 in human right atrial myocardium and are consistent with mediation through beta1LAR. Kaumann A and Molenaar P (2008) Pharmacol Ther 118, 303-336 Skeberdis VA et al (2008) J Clin Invest, 118, 3219-3227

Contribution of transmembrane domain V amino acids to β1l-adrenoceptor activity and affinity

There are two binding sites on the β1-adrenoceptor (AR), β1H and β1L corresponding to high and low affinity binding sites respectively, which can be activated to cause cardiostimulation (reviewed Kaumann and Molenaar, 2008). Some β-blockers that block β1AR and β2ARs can activate β1LARs at higher concentrations than those required to cause blockade. The β2AR does not form a corresponding low affinity binding site (Baker et al 2002) and therefore we postulated that heterologous amino acids are responsible for the formation of β1LAR. Our aim was to investigate whether heterologous amino acids of transmembrane domain V (TMDV) of β1AR and β2ARs contribute to β1LAR. β1ARs, β2ARs and mutant β1ARs containing all (β1(β2TMDV)AR) or single amino acids of TMDV of the β2AR were prepared and stably expressed in Chinese Hamster Ovary cells. Concentration-effect curves for cyclicAMP accumulation were carried out for (-)-CGP12177 or (-)-isoprenaline in the absence or presence of (-)-bupranolol. _______________________________________________________________________ (-)-CGP 12177 (-)-Bupranolol affinity (pKB) pEC50 vs (-)-CGP 12177 vs (-)-isoprenaline _______________________________________________________________________ β1AR 8.00 ± 0.11 (11) 7.23 ± 0.23 (5) 9.52 ± 0.28 (5) β2AR (high density) 9.24 ± 0.14 (5) 9.82 ± 0.52 (8) xPaulxxxxxxx β2AR (low density) no effect β1(β2TMV)AR 8.86 ± 0.10 (15) 8.06 ± 0.17 (8) 9.08 ± 0.22 (6) β1(V230I)AR 9.07 ± 0.07 (10) 7.64 ± 0.12 (8) 9.36 ± 0.28 (9) β1(R222Q)AR 8.09 ± 0.29 (6) 7.33 ± 0.23 (5) 9.36 ± 0.08 (6) β1(V230A)AR 7.59 ± 0.09 (6) 7.32 ± 0.24 (4) 8.62 ± 0.18 (5) _______________________________________________________________________ The potency of (-)-CGP12177 was higher at β2AR than at β1AR consistent with activation through a low affinity site at the β1AR (β1LAR) but not β2AR. The presence of V230 in β1AR accounted for the lower potency of (-)-CGP 12177. The affinity of (-)-bupranolol at β1AR and mutants was higher when determined with (-)-isoprenaline than with (-)-CGP 12177. The affinity of (-)-bupranolol determined against (-)-CGP 12177 was lower at β1AR compared to β2AR. The presence of V230 in β1AR accounted in part for the lower affinity. In conclusion V230 of the β1AR contributes in part to the low affinity binding site of β1AR. Baker JG, Hall IP, Hill SJ (2002). Pharmacological characterization of CGP12177 at the human β2-adrenoceptor. Br J Pharmacol 137, 400−408 Kaumann AJ, Molenaar P (2008) The low-affinity site of the β1-adrenoceptor and its relevance to cardiovascular pharmacology. Pharmacol Ther 118, 303-336

Personal Injuries Proceedings Act 2002, s 32 - Duty to Disclose - consequences of non-disclosure - discretion to excuse non-compliance

In Newson v Aust Scan Pty Ltd t/a Ikea Springwood [2010] QSC 223 the Supreme Court examined the discretion under s 32(2) of the Personal Injuries Proceedings Act 2002 (Qld), to permit a document which has not been disclosed as required by the pre-court procedures under the PIPA to be used in a subsequent court proceeding. This appears to be the first time that the nature and parameters of the discretion have been judicially considered.

Cerebral cortex activation mapping upon electrical muscle stimulation by 32-channel time-domain functional near-infrared spectroscopy

The application of different EMS current thresholds on muscle activates not only the muscle but also peripheral sensory axons that send proprioceptive and pain signals to the cerebral cortex. A 32-channel time-domain fNIRS instrument was employed to map regional cortical activities under varied EMS current intensities applied on the right wrist extensor muscle. Eight healthy volunteers underwent four EMS at different current thresholds based on their individual maximal tolerated intensity (MTI), i.e., 10 % < 50 % < 100 % < over 100 % MTI. Time courses of the absolute oxygenated and deoxygenated hemoglobin concentrations primarily over the bilateral sensorimotor cortical (SMC) regions were extrapolated, and cortical activation maps were determined by general linear model using the NIRS-SPM software. The stimulation-induced wrist extension paradigm significantly increased activation of the contralateral SMC region according to the EMS intensities, while the ipsilateral SMC region showed no significant changes. This could be due in part to a nociceptive response to the higher EMS current intensities and result also from increased sensorimotor integration in these cortical regions.

Vibrational spectroscopic study of the sulphate mineral glaucocerinite (Zn,Cu)10Al6(SO4)3(OH)32⋅18H2O – a natural layered double hydroxide

We have studied the molecular structure of the mineral glaucocerinite (Zn,Cu)5Al3(SO4)1.5(OH)16�9(H2O) using a combination of Raman and infrared spectroscopy. The mineral is one of the hydrotalcite supergroup of natural layered double hydroxides. The Raman spectrum is characterised by an intense Raman band at 982 cm�1 with a low intensity band at 1083 cm�1. These bands are attributed to the sulphate symmetric and antisymmetric stretching mode. The infrared spectrum is quite broad with a peak at 1020 cm�1. A series of Raman bands at 546, 584, 602, 625 and 651 cm�1 are assigned to the m4 (SO4)2� bending modes. The observation of multiple bands provides evidence for the reduction in symmetry of the sulphate anion from Td to C2v or even lower symmetry. The Raman band at 762 cm�1 is attributed to a hydroxyl deformation mode associated with AlOH units. Vibrational spectroscopy enables aspects of the molecular structure of glaucocerinite to be determined.

Improved linear cryptanalysis of reduced-round SIMON-32 and SIMON-48

In this paper we analyse two variants of SIMON family of light-weight block ciphers against variants of linear cryptanalysis and present the best linear cryptanalytic results on these variants of reduced-round SIMON to date. We propose a time-memory trade-off method that finds differential/linear trails for any permutation allowing low Hamming weight differential/linear trails. Our method combines low Hamming weight trails found by the correlation matrix representing the target permutation with heavy Hamming weight trails found using a Mixed Integer Programming model representing the target differential/linear trail. Our method enables us to find a 17-round linear approximation for SIMON-48 which is the best current linear approximation for SIMON-48. Using only the correlation matrix method, we are able to find a 14-round linear approximation for SIMON-32 which is also the current best linear approximation for SIMON-32. The presented linear approximations allow us to mount a 23-round key recovery attack on SIMON-32 and a 24-round Key recovery attack on SIMON-48/96 which are the current best results on SIMON-32 and SIMON-48. In addition we have an attack on 24 rounds of SIMON-32 with marginal complexity.

Heb. U. (Hebrew University) - Grad. (Graduation) '32 - High Commissioner

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Plan zemelʻnogo otvoda kolfonda "Novai︠a︡ Zhiznʻ" Krivorogskogo okruga Mikhaĭlovskogo raĭona ploshchadi︠u︡ 303 desi︠a︡tin

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Plan zemelʻnogo otvoda kolfonda "Novai︠a︡ Zhiznʻ" Krivorogskogo okruga, Mikhaĭlovskogo raĭona ploshchadiʻ︠u︡ 303 desi︠a︡tin

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Plan zemelʻnogo uchastka N 32

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Biotechnological potential of plant-associated endophytic fungi:hope versus hype

The potential of endophytes, particularly endophytic fungi, capable of demonstrating desirable functional traits worth exploitation using red biotechnology is well established. However, these discoveries have not yet translated into industrial bioprocesses for commercial production of biopharmaceuticals using fungal endophytes. Here, we define the current challenges in transforming curiosity driven discoveries into industrial scale endophyte biotechnology. The possible practical, feasible, and sustainable strategies that can lead to harnessing fungal endophyte-mediated pharmaceutical products are discussed.

Efecto de concentraciones de aceite de algodón sobre la viabilidad, patogenicidad, estabilidad de la cepa CB-32 de Beauveria bassiana (Bals y vuils)

En Nicaragua, Plutella xylostella es la plaga que causa mayores daños al cultivo de repollo (Brassica oleracea) lo que implica una gran inversión en el control de la misma. Para contribuir a la búsqueda de alternativas para el Manejo integrado de esta plaga se realizó este estudio en las instalaciones del Centro Nacional de Protección Vegetal (CENAPROVE) y en la Universidad Nacional Agraria durante el periodo comprendido entre Febrero 1991 y Febrero 1992. Se evaluó la Cepa CB-32 del hongo entomopatógeno Beauveria bassiana (Bals & Vuils) en 6 formulaciones conteniendo 0%, 2%, 4%, 6%. 8% y 10% de aceite de algodón en agua sobre larvas del segundo instar de P. xylostella. La concentración de conidias en las formulaciones fué de 3.35x108 En un rango de tiempo de 14-30 horas después de la inoculación en PDA se distinguieron con un mayor porcentaje de germinación de conidias las formulaciones con O y 2% de aceite de algodón. Las mismas demostraron mayor sedimentación reportando 0.2 y 0.5 ml seis horas después de ser sometidas a reposo. Para la evaluación del efecto de la radiación solar sobre las conidias de B. bassiana se realizó un análisis de varianza y pruebas de Tukey con un 95% de confianza, las respaldan que las formulaciones pueden separarse en cuatro categorías estadísticas diferentes de las cuales en primer lugar tenemos las formulaciones con O y 2% de aceite que presentan el mayor porcentaje de germinación de conidias expuestas a 24 horas de radiación solar (86.61% y 80.36%) respectivamente. A la variable patogenicidad de las conidias de B. bassiana en huésped de Plutella xylostella se efectúo un análisis de varianza y prueba de Tuckey y resulto que las formulaciones pueden clasificarse en 3 categorías estadísticas, sobresaliendo la patogenicidad de las conidias de las formulaciones con O y 2% de aceite reportando 95 y 80% respectivamente. El tiempo letal para las formulaciones no varió provocando la mortalidad dos días después de la inoculación de las larvas por el método de inmersión.