Minors held by majors: the H13 minor histocompatibility locus defined as a peptide/MHC class I complex

The products of minor histocompatibility (H) loci are serious barriers to tissue transplantation even among major histocompatibility complex (MHC) identical individuals, frequently causing chronic graft rejection and graft versus host disease. Over 50 minor H loci map to mouse autosomal chromosomes but none are known at the molecular level. By expression cloning, we identified the H13 locus, a classical minor H locus first detected 30 years ago by the trait of graft rejection. The H13a allele is located on chromosome 2 and encodes a novel protein that yields the rare naturally processed nonapeptide SSVVGVWYL (SVL9) for presentation by the Db MHC class I molecule. The SVL9 peptide binds Db MHC despite the absence of the consensus binding motif, and a conservative methyl group substitution (Valine 4 <--> Isoleucine) explains why reciprocal T cell responses are elicited in H13a and H13b congenic strains.     

Synthesis and cytotoxicity of potential tumor-inhibitory analogues of trimelamol (2,4,6-tris[(hydroxymethyl)methylamino]-1,3,5-triazine) having electron-withdrawing groups in place of methyl

In exploring the structural features which determine the antitumor activity of 2,4,6-tris-[(hydroxymethyl)methylamino]-1,3,5-triazine (trimelamol, 1), we have synthesized analogues in which the methyl groups have been replaced by the electron-withdrawing substituents 2,2,2-trifluoroethyl (5), propargyl (13), and cyanomethyl (15) via the respective tris(alkylamino)triazines 3, 12, and 14. Three mono[(hydroxymethyl)amino]triazines (4, 7, and 10) were also prepared. All the new tris(hydroxymethyl) derivatives showed cytotoxicities toward a variety of experimental rodent and human ovarian tumor cell lines similar to those shown by 1, the cyanomethyl analogue (15) having the most favorable profile. Mono(hydroxymethyl) derivatives (4 and 7) were ca. one-third as toxic. The new tris(hydroxymethyl) analogues were more stable to aqueous hydrolysis than was 1. Half-life (pH 7.5) values were, for 1, 120 min, for 5, 690 min, for 13, 450 min, and for 15, 275 min, but at pH 2.0, 15 (t1/2 350 min) was the most stable. This cyanomethyl analogue was also the most water-soluble, being comparable to 1 whereas 5 and 13 were poorly soluble.     

A stochastic maximum principle for systems with jumps, with applications to finance

We consider a stochastic control problem with linear dynamics with jumps, convex cost criterion, and convex state constraint, in which the control enters the drift, the diffusion, and the jump coefficients. We allow these coefficients to be random, and do not impose any L^p-bounds on the control.

We obtain a stochastic maximum principle for this model that provides both necessary and sufficient conditions of optimality. This is the first version of the stochastic maximum principle that covers the consumption–investment problem in which there are jumps in the price system.     

Multidrug resistance-reversing agents increase vinblastine distribution in normal tissues expressing the P-glycoprotein but do not enhance drug penetration in brain and testis

The aim of this study was to assess whether P-glycoprotein (Pgp) inhibitors altered the blood-brain barrier and enhanced vinblastine (VBL) distribution in brain, testis and other Pgp-expressing tissues. Trifluoperazine, cyclosporin A, amiodarone, quinidine, the nifedipine analog Bay K8644 and verapamil were selected among Pgp inhibitors and were administered intraperitoneally 1 hr before an intravenous dose of 10 mg/kg VBL. Trifluoperazine and cyclosporin A were also administered intraperitoneally for 7 days before VBL. VBL and its metabolite O4-deacetylvinblastine were measured in tissues by high-performance liquid chromatography assay. None of the reversing agents (RA) appreciably raised VBL concentrations in brain and testis, whereas all except quinidine significantly enhanced VBL distribution in liver and kidney; the most effective were trifluoroperazine and cyclosporin A. In mice treated with RA and VBL combined, O4-deacetylvinblastine levels in liver and kidney reached either the same or higher levels than in mice treated with VBL alone, indicating that the increase in VBL levels is not due to inhibition of its metabolism. The main conclusions are that (1) inhibitors of Pgp, even at high doses, do not increase the permeability of the blood-brain barrier in mice, suggesting caution in the clinical use of RA combined with antitumor agents for brain tumors; and (2) several RA achieve high enough concentrations to enhance the distribution of VBL in other normal tissues expressing Pgp, thus potentially increasing VBL toxicity.     

Testing of the multi-application small light water reactor (MASLWR) passive safety systems

Experimental thermal hydraulic research has been conducted at Oregon State University for the purpose of assessing the performance of a new reactor design concept, the multi-application small light water reactor (MASLWR). The MASLWR is a pressurized light water reactor design with a net output of 35 MWe that uses natural circulation in both normal and transient operation. Due to its small size, portability and modularity, the MASLWR design is well suited to help fill the potential need for grid appropriate reactor designs for smaller electricity grids as may be found in developing or remote regions. The purpose of the OSU MASLWR test facility is to assess the operation of the MASLWR under normal full operating pressure and full temperature conditions and to assess the passive safety systems under transient conditions. The data generated by the testing program will be used to assess computer code calculations and to provide a better understanding of the thermal-hydraulic phenomena in the design of the MASLWR NSSS. During this testing program, four tests were conducted at the OSU MASLWR test facility. These tests included one design basis accident and one beyond design basis accident. During the performance of these tests, plant operations to include start up, normal operation and shut down evolutions were demonstrated successfully.     

Does Physiological Blood Glucose Control Require an Adaptive Control Strategy?

To test the hypothesis that only an adaptive algorithm would guarantee optimal feedback control of glycemia in insulin-dependent diabetes, fasting chronically diabetic dogs at rest were subjected to short-term artificial beta cell treatment. Insulin was applied intravenously and an oral glucose load was given during the experiment. Employing the same dosing algorithm, three different control strategies were employed in a random order on different days: adaptive control (minimum variance controller, Test A), fixed command control using on-line parameter estimates (Test B), and fixed command control using off-line individually optimized dosage constants (Test C). Comparison was made to nondiabetic control animals. The glycemic profiles were entirely normal in Test A and C, but were distinctly elevated in Test B. The peripheral hyperinsulinaemia could, however, not be avoided by adaptive control. It is concluded that the restoration of physiological blood glucose control in insulin-dependent diabetes requires dosage parameters which are either continually adapted to the actual situation (adaptive control) or are optimized to meet the individual's needs. In the latter case, fixed command control may be employed. Peripheral hyperinsulinaemia cannot be avoided as long as insulin is administered by a posthepatic route.     

Stress concentration and fatigue of profiled reinforcing steels

Stress concentrations arise from profiles of ribbed reinforcing steel bars and in this study the results of calculated stress concentration factors (SCF), by using finite element method, are related to the fatigue test results. It is apparent that the degree of confinement of a ribbed bar embedded in concrete not only affects the magnitude of the ultimate bond stress but also the bond stress-slip relation. Thus the rib geometry or profile pattern is designed for optimum bond characteristics and not for fatigue considerations. However the rib geometry influences the fatigue performance through the SCFs arising from the root radius, width and flank angles of the profiles. It is shown that these latter factors have a significant influence on the fatigue behaviour of reinforcing steel bars.