A Potent Mimetic of the Siglec-8 Ligand 6’-Sulfo-Sialyl Lewisx

Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6’-sulfo-sialyl Lewis^x has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6’-sulfo-sialyl Lewis^x and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved.     

Parameter evaluation in automated digital deep-level transientspectroscopy (DLTS)

A method of directly evaluating the activation energy ΔE, capture cross section σ, and density N_T, of deep-level traps from the pulsed reverse bias capacitance transient is described. The main advantages of this technique are that it requires only a single temperature scan, and it can resolve nonexponential transients due to closely-spaced energy levels. The test samples used for this paper consisted of Schottky diodes fabricated on nonirradiated and 1-MeV electron-irradiated n-type VPE (vapor-phase epitaxy) GaAs wafers. The well known EL2 trap was identified with ΔE of 0.81 eV, and σ _n of 1.0×10^-13 cm² for the nonirradiated sample. These values were found to be in good agreement with published data using established, conventional DLTS techniques. For the irradiated samples a nonexponential capacitance transient was found in the EL2 range of temperatures. The discussed technique was able to resolve two closely spaced deep levels lying at E_c-0.81 eV and E_c-0.84 eV, and with capture cross sections of 1.5×10^-13 cm² and 2.5×10^-12 cm², respectively     

Transient emission from microstrip interconnects: theoreticalformulation and CAD modeling

A hybrid technique suitable for the space-time analysis of the transient spurious emission from microstrip interconnects is presented. The proposed technique requires the preliminary evaluation of the surface current excited on the microstrip interconnecting lines by means of a transmission line model accounting for dispersive effects. The radiated field is then computed in the frequency domain by applying the saddle-point asymptotic technique to the integral expression of the electric field involving the dyadic Green's function. The transient signals excited along the interconnects, and the corresponding radiated field, are finally determined by using the IFFT. Radiation mechanisms are investigated, and the influence of the structure's electrical and geometrical parameters is discussed     

From information to probability: An axiomatic approach—Inference is information processing

We define the very rich language of composed conditionals on a three‐valued logic and use this language as the communication tool between man and machine. Communication takes place for three reasons: knowledge acquisition, query, and response. Learning, thinking, and answering questions are of a pure information theoretical nature. The pivot of this knowledge processing concept is the amount of information (bit) we receive if a conditional becomes true. We follow an axiomatic approach to information theory rather than the classical probabilistic approach of Shannon; information comes first, and then comes probability. In the light of this philosophy, query and response experience new interpretations. Both, acquisition and response are realized by maximizing entropy and minimizing relative entropy, respectively. The iterative solution of these mathematical optimization problems gives new insights into the adaptation of prior knowledge to new information. Our expert system shell SPIRIT supports this kind of knowledge processing, which will be established by suitable examples. © 2003 Wiley Periodicals, Inc.     

Fast, large-scale model predictive control by partial enumeration

Partial enumeration (PE) is presented as a method for treating large, linear model predictive control applications that are out of reach with available MPC methods. PE uses both a table storage method and online optimization to achieve this goal. Versions of PE are shown to be closed-loop stable. PE is applied to an industrial example with more than 250 states, 32 inputs, and a 25-sample control horizon. The performance is less than 0.01% suboptimal, with average speedup factors in the range of 80-220, and worst-case speedups in the range of 4.9-39.2, compared to an existing MPC method. Small tables with only 25-200 entries were used to obtain this performance, while full enumeration is intractable for this example.     

Neuropsychological function in adults with attention-deficit hyperactivity disorder

Pacemaker therapy in patients with atrial fibrillation means the best current pacemaker therapy for patients with bradycardias with the aim to avoid the onset of atrial fibrillation and to establish DDD pacing despite of a history of atrial tachyarrhythmias. The newer application of pacing is the suppression of atrial arrhythmias in patients with medical refractory atrial tachyarrhythmias. Patients with slow ventricular rates and permanent atrial fibrillation should receive a VVI-pacemaker, if the bradycardias causes syncope, dizziness or a decrease of their exercise tolerance. In case of chronotropic incompetence the pacemaker should provide rate responsive pacing. Patients with sick sinus syndrome should receive an atrial (AAI) or dual-chamber (DDD) pacemaker, because patients with these in contrast to VVI-pacemakers develop less often atrial fibrillation and subsequent complications such as atrial thromboembolism. A dual-chamber or VDD-pacemaker--the latter connected to a VDD-single-lead--is indicated in patients with advanced AV-block. Atrial fibrillation occurs in 3 to 6% of the patients with no history of arrythmia and is, if pacemakers have no automatic mode switch, an often reason to program the devices to the VVI-pacing mode. Nowadays, most DDD(R)-pacemakers provide an automatic mode switch: During an atrial tachycardia the pacemaker switches to a VVI/VVIR mode and restores the initial DDD(R)-pacing mode with termination of the arrhythmia. In respect to the newer applications, one approach to prevent atrial tachyarrhythmias is permanent atrial pacing. As lower pacing rates of 80 to 90 ppm are usually needed and many patients hardly tolerate these pacing rates, new algorithms are under clinical investigation. Another approach is the simultaneous depolarization of the right and left atrium. Biatrial pacing is performed with one lead in the high right atrium and another lead in the coronary sinus. Another solution is bifocal atrial pacing with leads placed in the high right atrium and in the coronary sinus ostium. One effect of the new pacing techniques is to shorten interatrial conduction times. Therefore, biatrial pacing has become a therapy to prevent atrial arrhythmias deriving from delayed interatrial conduction times. As atrial reentry circuits seem to be important in atrial fibrillation, multisite atrial pacing is also performed in patients with medical refractory paroxysmal atrial fibrillation. Preliminary results suggest a more effective prevention of atrial fibrillation; nevertheless, these techniques should be still restricted to patients enrolled in clinical studies.     

Semantical investigations into nonmonotonic and probabilistic logics

Different forms of semantics have been proposed for conditionals of the form “Usually, if A then B”, ranging from quantitative probability distributions to qualitative approaches using plausibility orderings, possibility distributions, or conditional objects. Atomic-bound systems, also called big-stepped probabilities, allow qualitative reasoning with probabilities, aiming at bridging the gap between qualitative and quantitative argumentation and providing a model for the nonmonotonic reasoning system P. By using Goguen and Burstall’s notion of institutions for the formalization of logical systems, we elaborate precisely which formal connections exist among big-stepped probabilities, standard probabilities, and qualitative logics. Based on our investigations, we also develop two variants of conditional objects, one of them having a simpler semantics while still providing a model for system P.     

Ionic conductivity of synthetic analcime,sodalite and offretite

The ionic conductivity of pressed pellets of dehydrated synthetic analcime, sodalite and offretite was determined by a.c. measurements within the range 10 Hz to 10 MHz. The ionic conductivity values of those zeolites exchanged with various monovalent cations were determined by the complex impedance plane method. The conduction activation energies range between 63 and 101 kJ mol^–1. Sodium analcime shows the best ionic conductivity, namely 1.8×10^–4–1 cm^–1 at 400° C. A comparison with the conductivity of other ion-conducting solids was made.