Partial agonism, neutral antagonism, and inverse agonism at the human wild-type and constitutively active cholecystokinin-2 receptors

Cholecystokinin receptor-2 (CCK2R) is a G protein receptor that regulates a number of physiological functions. Activation of CCK2R and/or expression of a constitutively active CCK2R variant may contribute to human diseases, including digestive cancers. Search for antagonists of the CCK2R has been an important challenge during the last few years, leading to discovery of a set of chemically distinct compounds. However, several early-discovered antagonists turned out to be partial agonists. In this context, we carried out pharmacological characterization of six CCK2R antagonists using COS-7 cells expressing the human CCK2R or a CCK2R mutant having a robust constitutive activity on inositol phosphates production, and we investigated the molecular mechanisms which, at a CCK2R binding site, account for these features. Results indicated that three compounds, 3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3- yl)-N'-(3-methylphenyl)urea (L365,260), 4-{[2-[[3-(lH-indol-3-yl)-2- methyl-1-oxo-2-[[[1.7.7-trimethyl-bicyclo[2.2.1]hept-2-yl)-oxy]carbonyl]amino] propyl]amino]-1-phenylethyl]amino-4-oxo-[lS-la.2[S*(S*)]4a]} -butanoate N-methyl-D-glucamine (PD135, 158), and (R)-1-naphthalenepropanoic acid, b-[2-[[2-(8-azaspiro-[4.5]dec-8-ylcarbonyl)-4,6-dimethylphenyl]amino]-2- oxoethyl] (CR2945), were partial agonists; one molecule, 1-[(R)-2,3-dihydro-1- (2,3-dihydro-1-(2-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] -3-(3-methylphenyl)urea (YM022), was a neutral antagonist; and two compounds, N-(+)-[1-(adamant-1-ylmethyl)-2,4-dioxo-5-phenyl2,3,4,5-tetrahydro-1H-1, 5-benzodiazepin-3-yl]-N'-phenylurea (GV150,013X) and ([(N-[methoxy-3 phenyl] N-[N-methyl N-phenyl carbamoylmethyl], carbomoylmethyl)-3 ureido]-3-phenyl)2-propionic acid (RPR101,048), were inverse agonists. Furthermore, target- and pharmacophore-based docking of ligands followed by molecular dynamic simulation experiments resulted in consistent motion of aromatic residues belonging to a network presumably important for activation, thus providing the first structural explanations for the different pharmacological profiles of tested compounds. This study confirms that several referenced so-called antagonists are in fact partial agonists, and because of this undesired activity, we suggest that newly generated molecules should be preferred to efficiently block CCK2R-related physiological effects. Furthermore, data on the structural basis for the different pharmacological features of CCK2R ligands will serve to further clarify CCK2R mechanism of activation. Copyright © 2006 The American Society for Pharmacology and Experimental Therapeutics.

Bit error rate performance enhancement of a retrodirective array over a conventional fixed beam array in a dynamic multipath environment

In this paper, we provide experimental evidence to show that enhanced bit error rate (BER) performance is possible using a retrodirective array operating in a dynamically varying multipath environment. The operation of such a system will be compared to that obtained by a conventional nonretrodirective array. The ability of the array to recover amplitude shift keyed encoded data transmitted from a remote location whose position is not known a priori is described. In addition, its ability to retransmit data inserted at the retrodirective array back to a spatially remote beacon location whose position is also not known beforehand is also demonstrated. Comparison with an equivalent conventional fixed beam antenna array utilizing an identical radiating aperture arrangement to that of the retrodirective array are given. These show that the retrodirective array can effectively exploit the presence of time varying multipath in order to give significant reductions in BER over what can be otherwise achieved. Additionally, the retrodirective system is shown to be able to deliver low BER regardless of whether line of sight is present or absent.

A Wavelet-Prony Method for Modeling of Fixed-Speed Wind Farm Low-Frequency Power Pulsations

The increasing penetration of wind generation on the Island of Ireland has been accompanied by close investigation of low-frequency pulsations contained within active power flow. A primary concern is excitation of low-frequency oscillation modes already present on the system, particularly the 0.75 Hz mode as a consequence of interconnection between the Northern and Southern power system networks. In order to determine whether the prevalence of wind generation has a negative effect (excites modes) or positive impact (damping of modes) on the power system, oscillations must be measured and characterised. Using time – frequency methods, this paper presents work that has been conducted to extract features from low-frequency active power pulsations to determine the composition of oscillatory modes which may impact on dynamic stability. The paper proposes a combined wavelet-Prony method to extract modal components and determine damping factors. The method is exemplified using real data obtained from wind farm measurements.

Convergence of partial-wave expansions for energies, scattering amplitudes and positron annihilation rates

We use many-body theory to find the asymptotic behaviour of second-order correlation corrections to the energies and positron annihilation rates in many- electron systems with respect to the angular momenta l of the single-particle orbitals included. The energy corrections decrease as 1/(l+1/2)4, in agreement with the result of Schwartz, whereas the positron annihilation rate has a slower 1/(l+1/2)2 convergence rate. We illustrate these results by numerical calculations of the energies of Ne and Kr and by examining results from extensive con?guration-interaction calculations of PsH binding and annihilation.

Partial Cooperative Equilibria: Existence and Characterization

We study the solution concepts of partial cooperative Cournot-Nash equilibria and partial cooperative Stackelberg equilibria. The partial cooperative Cournot-Nash equilibrium is axiomatically characterized by using notions of rationality, consistency and converse consistency with regard to reduced games. We also establish sufficient conditions for which partial cooperative Cournot-Nash equilibria and partial cooperative Stackelberg equilibria exist in supermodular games. Finally, we provide an application to strategic network formation where such solution concepts may be useful.

Robust face recognition with partial occlusion, illumination variation and limited training data by optimal feature selection

This study investigates face recognition with partial occlusion, illumination variation and their combination, assuming no prior information about the mismatch, and limited training data for each person. The authors extend their previous posterior union model (PUM) to give a new method capable of dealing with all these problems. PUM is an approach for selecting the optimal local image features for recognition to improve robustness to partial occlusion. The extension is in two stages. First, authors extend PUM from a probability-based formulation to a similarity-based formulation, so that it operates with as little as one single training sample to offer robustness to partial occlusion. Second, they extend this new formulation to make it robust to illumination variation, and to combined illumination variation and partial occlusion, by a novel combination of multicondition relighting and optimal feature selection. To evaluate the new methods, a number of databases with various simulated and realistic occlusion/illumination mismatches have been used. The results have demonstrated the improved robustness of the new methods.

PANEL DATA UNIT ROOT TEST WITH FIXED TIME DIMENSION

The consideration of the limit theory in which T is fixed and N is allowed to go to infinity improves the finite-sample properties of the tests and avoids the imposition of the relative rates at which T and N go to infinity.

Fixed-dose combination therapy for type 2 diabetes: sitagliptin plus pioglitazone

Importance of the field: Type 2 diabetes is typically associated with insulin resistance and dysfunction of insulin-secreting pancreatic beta-cells. Addressing these defects often requires therapy with a combination of differently acting antidiabetic agents. A potential novel combination in development brings together the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin with the thiazolidinedione pioglitazone into a fixed-dose single-tablet combination. The former component acts mainly to increase prandial insulin secretion; the latter improves insulin sensitivity.

Purchasing power parity versus fixed exchange rate rules: A stability and welfare analysis

This paper evaluates the desirability of PPP rules vis-á-vis fixed exchange rates both in terms of welfare and stability properties. The analysis is conducted within a small open-economy New Keynesian framework extended to include a cost channel. In terms of stability, we find that while the equilibrium is always unique under fixed exchange rates its uniqueness critically depends upon the presence/absence of the cost channel under a PPP rule. Overall, then, in terms of welfare a fixed exchange rate always outperforms a PPP rule.

Long-term occlusal and soft-tissue profile outcomes after treatment of Class II Division 1 malocclusion with fixed appliances

Introduction: Our objective was to determine which factors were predictive of good long-term outcomes after fixed appliance treatment of Class II Division 1 malocclusion. Methods: Two hundred seven patients with Class II Division 1 malocclusion were examined in early adulthood at a mean of 4.6 years after treatment with fixed appliances. The peer assessment rating index was used to evaluate dental alignment and occlusal relationships. The soft-tissue profile was assessed with the Holdaway angle. Results: Logistic regression identified 3 pretreatment variables that were predictive of a good facial profile (Holdaway angle) at recall: the lower lip to E-plane distance (P

Real-valued fixed-complexity sphere decoder for high dimensional QAM-MIMO systems

The development of high performance, low computational complexity detection algorithms is a key challenge for real-time Multiple-Input Multiple-Output (MIMO) communication system design. The Fixed-Complexity Sphere Decoder (FSD) algorithm is one of the most promising approaches, enabling quasi-ML decoding accuracy and high performance implementation due to its deterministic, highly parallel structure. However, it suffers from exponential growth in computational complexity as the number of MIMO transmit antennas increases, critically limiting its scalability to larger MIMO system topologies. In this paper, we present a solution to this problem by applying a novel cutting protocol to the decoding tree of a real-valued FSD algorithm. The new Real-valued Fixed-Complexity Sphere Decoder (RFSD) algorithm derived achieves similar quasi-ML decoding performance as FSD, but with an average 70% reduction in computational complexity, as we demonstrate from both theoretical and implementation perspectives for Quadrature Amplitude Modulation (QAM)-MIMO systems.