Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice

The function of the central cannabinoid receptor (CB1) was investigated by invalidating its gene. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive role of the CB1 receptor in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced. These observations suggest that the CB1 receptor is involved in the motivational properties of opiates and in the development of physical dependence and extend the concept of an interconnected role of CB1 and opiate receptors in the brain areas mediating addictive behavior.     

A Framework for the Verification of Certifying Computations

Formal verification of complex algorithms is challenging. Verifying their implementations goes beyond the state of the art of current automatic verification tools and usually involves intricate mathematical theorems. Certifying algorithms compute in addition to each output a witness certifying that the output is correct. A checker for such a witness is usually much simpler than the original algorithm—yet it is all the user has to trust. The verification of checkers is feasible with current tools and leads to computations that can be completely trusted. We describe a framework to seamlessly verify certifying computations. We use the automatic verifier VCC for establishing the correctness of the checker and the interactive theorem prover Isabelle/HOL for high-level mathematical properties of algorithms. We demonstrate the effectiveness of our approach by presenting the verification of typical examples of the industrial-level and widespread algorithmic library LEDA.     

Beitrag zur quantitativen Bestimmung der Stearins?ure in Fetten

Ohne Zusammenfassung     

Synthesis and characterization of a novel unsaturated polyester based on poly(trimethylene terephthalate)

Unsaturated aromatic polyesters were obtained by glycolysis of poly(trimethylene terephthalate) with cis-2-buten-1,4-diol followed by a solid-state polymerization. The glycolysis was performed in a batch mode as well as through a continuous process in a twin screw extruder. The degradation and subsequent rebuilding of the polymer chain during the course of reaction was followed by means of inherent and melt viscosity measurements, and ¹H NMR terminal group analysis of the intermediates and the final products. Structural investigations revealed that this new approach resulted in melt processible unsaturated polyesters with cross-linkable sites having similar characteristics to that of the virgin saturated polyester. Although the processing temperature for the different reaction steps was sufficiently high (180−260 °C), no thermally induced cross-linking of the incorporated unsaturated bonds could be evidenced indicating that the obtained products remained stable during the production stage. For comparison purposes, a commercial unsaturated polyester (Vestodur^©) was included in the investigations. UV irradiation of thin polyester films did not result in cross-linked products but in cis-trans isomerization of the incorporated bisoxybutenyl unit.     

PDZ-domain-mediated interaction of the Eph-related receptor tyrosine kinase EphB3 and the ras-binding protein AF6 depends on the kinase activity of the receptor

Eph-related receptor tyrosine kinases (RTKs) have been implicated in intercellular communication during embryonic development. To elucidate their signal transduction pathways, we applied the yeast two-hybrid system. We could demonstrate that the carboxyl termini of the Eph-related RTKs EphA7, EphB2, EphB3, EphB5, and EphB6 interact with the PDZ domain of the ras-binding protein AF6. A mutational analysis revealed that six C-terminal residues of the receptors are involved in binding to the PDZ domain of AF6 in a sequence-specific fashion. Moreover, this PDZ domain also interacts with C-terminal sequences derived from other transmembrane receptors such as neurexins and the Notch ligand Jagged. In contrast to the association of EphB3 to the PDZ domain of AF6, the interaction with full-length AF6 clearly depends on the kinase activity of EphB3, suggesting a regulated mechanism for the PDZ-domain-mediated interaction. These data gave rise to the idea that the binding of AF6 to EphB3 occurs in a cooperative fashion because of synergistic effects involving different epitopes of both proteins. Moreover, in NIH 3T3 and NG108 cells endogenous AF6 is phosphorylated specifically by EphB3 and EphB2 in a ligand-dependent fashion. Our observations add the PDZ domain to the group of conserved protein modules such as Src-homology-2 (SH2) and phosphotyrosine-binding (PTB) domains that regulate signal transduction through their ability to mediate the interaction with RTKs.     

Estimates of the Wigner Distribution in Gaussian Noise Environment

The influence of Gaussian noise to the Wigner distribution is considered.Due to the quadratic nature of the Wigner distribution, the resulting noise exhibits impulse nature even in the case of Gaussian input noise. Estimators of the Wigner distribution which take into account this fact are considered.They can outperform the standard and the robust Wignerdistribution.     

Dietary L-arginine reduces the progression of atherosclerosis in cholesterol-fed rabbits: comparison with lovastatin

BACKGROUND: We investigated whether L-arginine induces regression of preexisting atheromatous lesions and reversal of endothelial dysfunction in hypercholesterolemic rabbits, whether similar effects can be obtained by cholesterol-lowering therapy with lovastatin, and which mechanism leads to these effects. METHODS AND RESULTS: Rabbits were fed 1% cholesterol for 4 weeks and 0.5% cholesterol for an additional 12 weeks. Two groups of cholesterol-fed rabbits were treated with L-arginine (2.0% in drinking water) or lovastatin (10 mg/d) during weeks 5 through 16. Systemic nitric oxide (NO) formation was assessed as the urinary excretion rates of nitrate and cGMP in weekly intervals. Cholesterol feeding progressively reduced urinary nitrate excretion to approximately 40% of baseline (P<.05) and increased plasma concentrations of asymmetrical dimethylarginine (ADMA), an endogenous NO synthesis inhibitor. Dietary L-arginine reversed the reduction in plasma L-arginine/ADMA ratio and partly restored urinary excretion of nitrate and cGMP (each P<.05 vs cholesterol) but did not change plasma cholesterol levels. L-Arginine completely blocked the progression of carotid intimal plaques, reduced aortic intimal thickening, and preserved endothelium-dependent vasodilator function. Lovastatin treatment reduced plasma cholesterol by 32% but did not improve urinary nitrate or cGMP excretion or endothelium-dependent vasodilation. Lovastatin had a weaker inhibitory effect on carotid plaque formation and aortic intimal thickening than L-arginine. L-Arginine inhibited but lovastatin potentiated superoxide radical generation in the atherosclerotic vascular wall. CONCLUSIONS: Dietary L-arginine improves NO-dependent vasodilator function in cholesterol-fed rabbits and completely blocks the progression of plaques via restoration of NO synthase substrate availability and reduction of vascular oxidative stress. Lovastatin treatment has a weaker inhibitory effect on the progression of atherosclerosis and no effect on vascular NO elaboration, which may be due to its stimulatory effect on vascular superoxide radical generation.