Chemical-Shift Perturbations Reflect Bile Acid Binding to Norovirus Coat Protein: Recognition Comes in Different Flavors

Bile acids have been reported as important cofactors promoting human and murine norovirus (NoV) infections in cell culture. The underlying mechanisms are not resolved. Through the use of chemical shift perturbation (CSP) NMR experiments, we identified a low-affinity bile acid binding site of a human GII.4 NoV strain. Long-timescale MD simulations reveal the formation of a ligand-accessible binding pocket of flexible shape, allowing the formation of stable viral coat protein–bile acid complexes in agreement with experimental CSP data. CSP NMR experiments also show that this mode of bile acid binding has a minor influence on the binding of histo-blood group antigens and vice versa. STD NMR experiments probing the binding of bile acids to virus-like particles of seven different strains suggest that low-affinity bile acid binding is a common feature of human NoV and should therefore be important for understanding the role of bile acids as cofactors in NoV infection.     

Structure−Activity Relationships of Cinnamate Ester Analogues as Potent Antiprotozoal Agents

Protozoal infections are still a global health problem, threatening the lives of millions of people around the world, mainly in impoverished tropical and sub-tropical regions. Thus, in view of the lack of efficient therapies and increasing resistances against existing drugs, this study describes the antiprotozoal potential of synthetic cinnamate ester analogues and their structure-activity relationships. In general, Leishmania donovani and Trypanosoma brucei were quite susceptible to the compounds in a structure-dependent manner. Detailed analysis revealed a key role of the substitution pattern on the aromatic ring and a marked effect of the side chain on the activity against these two parasites. The high antileishmanial potency and remarkable selectivity of the nitro-aromatic derivatives suggested them as promising candidates for further studies. On the other hand, the high in vitro potency of catechol-type compounds against T. brucei could not be extrapolated to an in vivo mouse model.     

Screening mixtures for biological activity by NMR

Development of the new drugs often involves the screening of compound libraries for biological activity. Currently, the biologically active component can only be identified if either a pure compound is being tested or if the components of a mixture are spatially separated, for example, on beads. Here, we present an NMR technique based on the transferred nuclear Overhauser effect (transfer NOE) that allows identification and structural characterization of biologically active molecules from a mixture. As an example we demonstrate that from mixtures of oligosaccharides only alpha-L-Fuc-(1-->6)-beta-D-GlcNAc-OMe binds to Aleuria aurantia agglutinin. The sign of transferred NOEs is opposite to NOEs of small molecules that do not bind to the protein and, thus, an unequivocal identification of molecules with binding activity is possible. Normally, the selection of bound ligands is further facilitated in that the absolute intensity of transfer NOEs is much greater than that of NOEs of non-binding molecules. In addition, transfer NOEs provide information on the three-dimensional structure of the ligands in the bound state. Therefore, measuring transfer NOEs of mixtures of small molecules in the presence of large molecules, like proteins, should significantly enhance the options for screening mixtures of compounds for biological activity.     

Electromagnetic scattering by a straight thin wire

The traveling-wave energy, which multiply diffracts on a straight thin wire, is represented as a sum of terms, each with a distinct physical meaning, that can be individually examined in the time domain. Expressions for each scattering mechanism on a straight thin wire are cast in the form of four basic electromagnetic wave concepts: diffraction, attachment, launch, and reflection. Using the basic mechanisms from P.Ya. Ufimtsev (1962), each of the scattering mechanisms is included into the total scattered field for the straight thin wire. Scattering as a function of angle and frequency is then compared to the moment-method solution. These analytic expressions are then extended to a lossy wire with a simple approximate modification using the propagation velocity on the wire as derived from the Sommerfeld wave on a straight lossy wire. Both the perfectly conducting and lossy wire solutions are compared to moment-method results, and excellent agreement is found. As is common with asymptotic solutions, when the electrical length of wire is smaller than 0.2 λ the results lose accuracy. The expressions modified to approximate the scattering for the lossy thin wire yield excellent agreement even for lossy wires where the wire radius is on the order of skin depth     

Finite constants: characterizations of a new decidable set of constants

Constant propagation, the replacement of program terms which represent a unique value at run time by their values, is a classical program optimization method. In spite of being treated for years, constant propagation still has been in the unsatisfactory phase of heuristics. We enhance the known constant propagation techniques to obtain an algorithm which is optimal for programs without loops. Fundamental is the introduction of a new decidable set of constants, the finite constants. This set has two different characterizations: a denotational one, which directly specifies our iterative algorithm and an operational one, which delivers the completeness or optimality of this algorithm for programs without loops. The algorithm is implemented in a commercial compiler project.     

Modellqualität als Indikator für Softwarequalität: eine Taxonomie

Zusammenfassung  Komplexit?t, Anforderungsmanagement und Variantenvielfalt sind zentrale Herausforderungen bei der Entwicklung und Evolution heutiger softwaregesteuerter Systeme. Diesen wird zunehmend durch den Einsatz modellbasierter Entwicklungsmethoden begegnet. Dadurch wird das Modell zum zentralen Artefakt und die Erstellung und Nutzung von Modellen zu einer zentralen T?tigkeit in der Softwareentwicklung. Mit der Bedeutung der Modelle steigen auch die Ansprüche an ihre Qualit?t. Dieser Beitrag untersucht die Implikationen, die daraus entstehen, insbesondere werden sinnvolle Qualit?tsmerkmale für softwarebeschreibende Modelle identifiziert und diskutiert.     

Choice With Initial and Terminal Link Reinforcement: An Alternative Self-Control Paradigm.

Self-control is demonstrated when a less desirable immediate outcome is chosen to ensure a substantially better future. In a novel animal analogue of this situation, primary reinforcement was delivered in both the initial and terminal links of a concurrent chain schedule. Rats made initial link choices between equal amounts of ethanol-free or ethanol-containing milk. Choosing the ethanol-free reinforcer resulted in delivery of the larger terminal link reinforcer and was thus analogous to self-control. Self-control decreased as the delay between initial and terminal links increased. The results have implications for human choice situations where decisions are made between two immediately available reinforcement alternatives each associated with a different delayed outcome. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

What do we learn from binding features? Evidence for multilevel feature integration.

Four experiments were conducted to investigate the relationship between the binding of visual features (as measured by their aftereffects on subsequent binding) and the learning of feature-conjunction probabilities. Both binding and learning effects were obtained, but they did not interact. Interestingly, (shape-color) binding effects disappeared with increasing practice, presumably because of the fact that only 1 of the features involved was relevant to the task. However, this instability was only observed for arbitrary, not highly overlearned combinations of simple geometric features and not for real objects (colored pictures of a banana and strawberry), where binding effects were strong and resistant to practice. These findings suggest that learning has no direct impact on the strength or resistance of bindings or on speed with which features are bound; however, learning does affect the amount of attention particular feature dimensions attract, which again can influence which features are considered in binding. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Value of transcranial Doppler indices in predicting raised ICP in infantile hydrocephalus. A study with review of the literature

Cerebral hemodynamic changes in infants with progressive hydrocephalus have been studied with the transcranial Doppler (TCD) technique. Several authors have referred to the correlation between the hemodynamic changes and increased intracranial pressure (ICP). Despite conflicting conclusions on the value of pulsatility index (PI) and resistance index (RI) measurements for monitoring infantile hydrocephalus, these pulsatility indices are the most commonly used for this purpose. Although clinical signs of raised ICP are highly variable and unreliable in infants, assumptions have been made in most of the studies about the presence of elevated ICP on the basis of the patient's clinical state. Few studies have reported on actual ICP values, however, and a direct relationship between ICP and TCD changes has never been adequately demonstrated. In the present study, this relationship was investigated in long-term simultaneous TCD/ICP measurements, in an attempt to develop a noninvasive method of monitoring the effect of ICP on intracranial hemodynamics. Two groups of data sets were established. Group I consisted of pre- and postoperative (shunt implantation) TCD/ICP measurements. Group II were long-term simultaneous TCD/ICP recordings showing significant ICP variations. In most of the postoperative measurements there was a decrease in the average PI and RI values. The correlation between PI or RI and ICP in the long-term simultaneous recordings, however, was generally poor. The risk of obtaining false positive or false negative PI or RI values in short-term measurements was also demonstrated. It can be concluded from our results, besides the wide range of reference values for the Doppler indices and extracranial influences upon them, that the present Doppler indices are inadequate for monitoring the complex intracranial dynamic responses in patients with raised ICP.