The predominant contribution of oligopeptide transporter PepT1 to intestinal absorption of beta-lactam antibiotics in the rat small intestine

Although recent evidence suggests that certain beta-lactam antibiotics are absorbed via a specific transport mechanism, its nature is unclear. To confirm whether peptide transport in the rat can be largely ascribed to the intestinal oligopeptide transporter PepT1, the transporter has been functionally characterized and its significance in the intestinal absorption of beta-lactam antibiotics was evaluated. For evaluation of transport activity complementary RNA (cRNA) of rat PepT1 was synthesized in-vitro and expressed in Xenopus laevis oocytes. cRNA induced uptake of several beta-lactam antibiotics and the dipeptide [14C]glycylsarcosine; this was specifically inhibited by various dipeptides and tripeptides but not by their constituent amino acids or by tetra- or pentapeptides. The transport activity of PepT1 for beta-lactam antibiotics correlated well with their in-vivo intestinal transport and absorption. Furthermore, mutual inhibitory effects on uptake were observed between glyclsarcosine and beta-lactam antibiotics. Hybrid depletion of the functional expression of rat PepT1 in oocytes injected with rat intestinal epithelial total mRNA was studied using an antisense oligonucleotide corresponding to the 5'-coding region of PepT1. In oocytes injected with rat mRNA pre-hybridized with the antisense oligonucleotide against rat PepT1, the uptake of [14C]glycylsarcosine was almost completely abolished, whereas its uptake was not influenced by a sense oligonucleotide for the same region of PepT1. Similarly, the uptake of beta-lactam antibiotics was also reduced by the antisense oligonucleotide against rat PepT1. These results demonstrate that the intestinal proton-coupled oligopeptide transporter PepT1 plays a predominant role in the carrier-mediated intestinal absorption of beta-lactam antibiotics and native oligopeptides in the rat.     

Infrequent mutation of the H-cadherin gene on chromosome 16q24 in human breast cancers

To investigate the molecular basis of altered expression of the H-cadherin gene, we used polymerase chain reaction-single strand conformation polymorphism and DNA sequencing to examine the H-cadherin gene in 48 primary breast cancers in which loss of the long arm of chromosome 16 had been detected. We identified no mutations other than somatic 5-bp deletion within the coding region in a single tumor. The very low frequency of mutation found in these experiments suggests that H-cadherin is usually not a primary target for carcinogenesis in human breast cancers, and that reduction of its expression is likely to be a consequence of some other genetic event(s).     

Polynomial-complexity deadlock avoidance policies for sequentialresource allocation systems

The development of efficient deadlock avoidance policies (DAPs) for sequential resource allocation systems (RASs) is a problem of increasing interest in the scientific community, largely because of its relevance to the design of large-scale flexibly automated manufacturing systems. Much of the work on this problem existing in the literature is focused on the so-called single-unit RAS model, which is the simplest model in the considered class of RASs. Furthermore, due to a well-established result stating that, even for single-unit RASs, the computation of the maximally permissive DAP is intractable (NP-hard), many researchers (including our group) have focused on obtaining good suboptimal policies which are computationally tractable (scalable) and provably correct. In the first part of the paper, it is shown, however, that for a large subset (in fact, a majority) of single-unit RASs, the optimal DAP can be obtained in real-time with a computational cost which is a polynomial function of the system size (i.e., the number of resource types and the distinct route stages of the processes running through the system). The implications of this result for the entire class of single-unit RASs are also explored. With a result on the design of optimal DAPs for single-unit RASs, the second part of the paper concentrates on the development of scalable and provably correct DAPs for the more general case of conjunctive RASs     

Infinite-dimensional convex optimization in optimal and robustcontrol theory

Many engineering problems can be shown to be equivalent to solving semidefinite programs (SPs), i.e., convex optimization problems involving linear matrix inequalities (LMIs). Powerful computation tools are available for such problems in the finite-dimensional case. However, the problems arising in optimal and robust control theory are often infinite dimensional, and so adequate computation tools are not available. The key to tackling such problems with finite computation tools is to have a primal-dual formulation of the problem without duality gap. In this paper we study infinite-dimensional SPs and present a lifting technique to recast SPs as parameterized linear programs (LPs). This enables the wealth of theoretical tools available for infinite-dimensional LPs to be extended to infinite-dimensional SPs. In particular, we develop some new sufficient conditions for the lack of a duality gap for infinite-dimensional SPs and give an exact characterization of the primal and dual problems for these cases. Both primal and dual problems are formed as infinite-dimensional SP problems, with finite truncations to each giving upper and lower bounds, respectively, on the exact solution to the infinite-dimensional problem. Thus, these results can form the basis of practical computation schemes for infinite-dimensional problems, which require only finite-dimensional computation tools. To illustrate the power of these tools we apply the results to two previously unsolved optimization problems, namely minimizing the l₁ norm of a closed-loop system subject to bounds on the frequency response magnitude at a finite number of points and/or bounds on the H₂ norm     

The held out wings (how) Drosophila gene encodes a putative RNA-binding protein involved in the control of muscular and cardiac activity

In an attempt to identify genes that are involved in Drosophila embryonic cardiac development, we have cloned and characterized a gene whose function is required late in embryogenesis to control heart rate and muscular activity. This gene has been named held out wings (how) because hypomorphic mutant alleles produce adult animals that have lost their ability to fly and that keep their wings horizontal at a 90 degree angle from the body axis. In contrast to the late phenotype observed in null mutants, the How protein is expressed early in the invaginating mesoderm and this expression is apparently under the control of twist. When the different mesodermal lineages segregate, the expression of How becomes restricted to the myogenic lineage, including the cardioblasts and probably all the myoblasts. Antibodies directed against the protein demonstrate that How is localized to the nucleus. how encodes a protein containing one KH-domain which has been implicated in binding RNA. how is highly related to the mouse quaking gene which plays a role at least in myelination and that could serve to link a signal transduction pathway to the control of mRNA metabolism. The properties of the how gene described herein suggest that this gene participates in the control of expression of as yet unidentified target mRNAs coding for proteins essential to cardiac and muscular activity.     

Viscoelastic response of solid rocket motor components for service life assessment

A methodology for determining the response of rocket motor materials and bondlines to thermal loadings by measuring their dynamic mechanical properties is reported. The critical temperatures at which debonding and/or propellant cracking occur and the number of thermal cycles required to induce failure were evaluated. These results were compared with those from instrumented rocket motors subjected to similar thermal loadings. A model, developed for fibre reinforced composites, was applied to the propellant-inhibitor bimaterial obtained from a rocket motor. The internal energy dissipation due to a lack of perfect adhesion at the propellant–inhibitor interface, tan δ_adh, was used to give an indication of the failure mode of the bondline (i.e., adhesive failure at the interface or cohesive failure in the propellant) and the bond adhesion parameter, C, was related to the bond strength measured by rectangular bond-in-tension tests. This revised version was published online in November 2006 with corrections to the Cover Date.     

A process model for active brazing of ceramics: Part II Optimization of brazing conditions and joint properties

In the present investigation, the process model developed in Part I has been applied to evaluate the microstructure and strength evolution during active brazing of ceramics. As a starting point, reaction-layer growth is assumed to occur isothermally with no restrictions in the supply of reactive element. Different kinds of diagrams are then constructed to show how specific process variables (e.g. the heating and cooling period, the limiting layer thickness, and the diffusion mechanism) affect the growth kinetics. It is concluded that the key to improved joint properties lies in control of the reaction-layer thickness through optimization of the brazing conditions, and an illustration of this is given. This revised version was published online in November 2006 with corrections to the Cover Date.     

Chebyshev multilevel absorber design concept

Pyramidal- and wedge-absorber materials are used extensively in anechoic measurement chambers to attenuate stray signals. Typical absorber layouts result in large absorber walls in which the absorber tips and bases are roughly aligned in the same plane. Such a quasi-periodic configuration produces a strong coherent specular reflection which dominates the absorber scattered field. Based on the multisection impedance transformer concept, one can divide absorber elements into different levels (layers) so that this coherence can be destroyed to reduce the specular absorber scattering level. The synthesis of this desired behavior can be implemented by the Chebyshev transformer technique, which provides the largest bandwidth given a passband ripple threshold. The resulting reflected field is then the product of the original absorber response times the Chebyshev reduction factor, which is independent of polarization and absorber properties. Various measured results are used to show that more than a 10-dB improvement can be achieved at the critical low end of the frequency band using this approach. This improvement cannot be achieved using conventional design concepts unless the absorber size is doubled     

Genetic algorithms in engineering electromagnetics

This paper presents a tutorial and overview of genetic algorithms for electromagnetic optimization. Genetic-algorithm (GA) optimizers are robust, stochastic search methods modeled on the concepts of natural selection and evolution. The relationship between traditional optimization techniques and the GA is discussed. Step-by-step implementation aspects of the GA are detailed, through an example with the objective of providing useful guidelines for the potential user. Extensive use is made of sidebars and graphical presentation to facilitate understanding. The tutorial is followed by a discussion of several electromagnetic applications in which the GA has proven useful. The applications discussed include the design of lightweight, broadband microwave absorbers, the reduction of array sidelobes in thinned arrays, the design of shaped-beam antenna arrays, the extraction of natural resonance modes of radar targets from backscattered response data, and the design of broadband patch antennas. Genetic-algorithm optimization is shown to be suitable for optimizing a broad class of problems of interest to the electromagnetic community. A comprehensive list of key references, organized by application category, is also provided