Rapid access to unexplored chemical space by ligand scanning around a ruthenium center: discovery of potent and selective protein kinase inhibitors

An important objective for the discovery of compounds with unique biological activities is the development of methods for the synthesis of molecular scaffolds with defined three-dimensional shapes. We are currently investigating the scope of using metal complexes to accomplish this goal. In these compounds, the metal center has the role of organizing the orientation of the organic ligands, thus defining the overall shape of the molecule. A strategy is presented that allows a rapid scanning of ligands around a ruthenium center in the search for ligand spheres that are complementary in shape and functional group presentation to ATP binding sites of protein kinases. Following this approach, we have identified octahedral ruthenium complexes as potent inhibitors for the protein kinases Pim1, MSK1, and GSK3alpha.     

Bottleneck analysis in multiclass closed queueing networks and its application

Asymptotic behavior of queues is studied for large closed multi-class queueing networks consisting of one infinite server station with K classes and M processor sharing (PS) stations. A simple numerical procedure is derived that allows us to identify all bottleneck PS stations. The bottleneck station is defined asymptotically as the station where the number of customers grows proportionally to the total number of customers in the network, as the latter increases simultaneously with service rates at PS stations. For the case when K=M=2, the set of network parameters is identified that corresponds to each of the three possible types of behavior in heavy traffic: both PS stations are bottlenecks, only one PS station is a bottleneck, and a group of two PS stations is a bottleneck while neither PS station forms a bottleneck by itself. In the last case both PS stations are equally loaded by each customer class and their individual queue lengths, normalized by the large parameter, converge to uniformly distributed random variables. These results are directly generalized for arbitrary K=M. Generalizations for K≠M are also indicated. The case of two bottlenecks is illustrated by its application to the problem of dimensioning bandwidth for different data sources in packet-switched communication networks. An engineering rule is provided for determining the link rates such that a service objective on a per-class throughput is satisfied. This revised version was published online in June 2006 with corrections to the Cover Date.     

On the beam propagation through active media

An analytical iterative procedure has been established to determine the amplitude of a laser beam propagating through an active medium. The treatment is valid for both homogeneous and inhomogeneous broadening, and for arbitrary inhomogeneities of the parameters characterizing the active medium, namely, the refractive index, the small-signal gain and the saturation intensity. After a supplementary approximation, a thin-sheet gain approach is derived from the first iteration. The formalism enables us to provide analytical criteria for evaluating both the accuracy of each iteration and the propagation distances for which the thin-sheet solution can be used. This revised version was published online in November 2006 with corrections to the Cover Date.     

The Effect of the Timing of Disbursements on Order Quantities

This paper looks at the effect that the timing of disbursements may have on order quantities. Traditional analyses for determining order quantities assume that all disbursements are made at the same point in time. In this paper it is shown that large timing differences may significantly affect order quantities. Firms operating in these environments may want to adjust their order quantities accordingly.     

Ruthenium half-sandwich complexes as protein kinase inhibitors: derivatization of the pyridocarbazole pharmacophore ligand

A general route to ruthenium pyridocarbazole half-sandwich complexes is presented and applied to the synthesis of sixteen new compounds, many of which have modulated protein kinase inhibition properties. For example, the incorporation of a fluorine into the pyridine moiety increases the binding affinity for glycogen synthase kinase 3 by almost one order of magnitude. These data are supplemented with cyclic voltammetry experiments and a protein co-crystallographic study.     

Greatly attenuated experimental autoimmune encephalomyelitis in aquaporin-4 knockout mice

Background  

The involvement of astrocyte water channel aquaporin-4 (AQP4) in autoimmune diseases of the central nervous system has been suggested following the identification of AQP4 autoantibodies in neuromyelitis optica, an inflammatory demyelinating disease.     

Spatial characterization of the transversal structure of rotationally symmetric pulsed beams

A simple analytical model is proposed to describe the transversal spatial structure of a tridimensional rotationally symmetric pulsed beam. The spatial behaviour of the pulse amplitude is shown to be linked to its (measurable) second- and higher-order intensity moments, namely, beam width, quality parameter and kurtosis. As an illustrative experimental example, this model has been applied to high-quality TEA CO2 laser pulses. This revised version was published online in November 2006 with corrections to the Cover Date.     

A heuristic procedure for solving the dynamic probabilistic project expediting problem

Because of activity duration uncertainties, large-scale projects can often be modeled most realistically as probabilistic activity networks. The complex interactions among activities with uncertain durations virtually assures a low probability that these projects will be completed before predetermined due dates. As a result, it is often necessary to expedite individual activities in these projects to improve due date performance. This research introduces a dynamically applied matrix simulation approach for selecting expediting options in order to control the probability of successful project completion before predefined due dates. Experiments are conducted to demonstrate the ability of this new approach to generate quality alternatives and efficiently evaluate large-scale projects.     

Rhythmic masking release: contribution of cues for perceptual organization to the cross-spectral fusion of concurrent narrow-band noises

The contribution of temporal asynchrony, spatial separation, and frequency separation to the cross-spectral fusion of temporally contiguous brief narrow-band noise bursts was studied using the Rhythmic Masking Release paradigm (RMR). RMR involves the discrimination of one of two possible rhythms, despite perceptual masking of the rhythm by an irregular sequence of sounds identical to the rhythmic bursts, interleaved among them. The release of the rhythm from masking can be induced by causing the fusion of the irregular interfering sounds with concurrent "flanking" sounds situated in different frequency regions. The accuracy and the rated clarity of the identified rhythm in a 2-AFC procedure were employed to estimate the degree of fusion of the interferring sounds with flanking sounds. The results suggest that while synchrony fully fuses short-duration noise bursts across frequency and across space (i.e., across ears and loudspeakers), an asynchrony of 20-40 ms produces no fusion. Intermediate asynchronies of 10-20 ms produce partial fusion, where the presence of other cues is critical for unambiguous grouping. Though frequency and spatial separation reduced fusion, neither of these manipulations was sufficient to abolish it. For the parameters varied in this study, stimulus onset asynchrony was the dominant cue determining fusion, but there were additive effects of the other cues. Temporal synchrony appears to be critical in determining whether brief sounds with abrupt onsets and offsets are heard as one event or more than one.