The Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell clones that express NKB1, a putative HLA receptor.

Although inhibition of natural killer (NK) cell-mediated lysis by the class I HLA molecules of target cells is an established phenomenon, knowledge of the features of class I molecules which induce this effect remains rudimentary. Using class I alleles HLA-B*1502 and B*1513 which differ only at residues 77-83 which define the Bw4 and Bw6 serological epitopes, we tested the hypothesis that the presence of the Bw4 epitope on class I molecules determines recognition by NKB1+ NK cells. HLA-B*1513 possesses the Bw4 epitope, whereas B*1502 has the Bw6 epitope. Lysis by NKB1+ NK cell clones of transfected target cells expressing B*1513 as the only HLA-A, -B, or -C molecule was inhibited, whereas killing of transfectants expressing B*1502 was not. Addition of an an anti-NKB1 monoclonal antibody reconstituted lysis of the targets expressing B*1513, but did not affect killing of targets bearing B*1502. The inhibitory effect of B*1513 could be similarly prevented by the addition of an anti-class I monoclonal antibody. These results show that the presence of the Bw4 epitope influences recognition of HLA-B molecules by NK cells that express NKB1, and suggest that the NKB1 molecule may act as a receptor for Bw4+ HLA-B alleles. Sequences outside of the Bw4 region must also affect recognition by NKB1+ NK cells, because lysis of transfectants expressing HLA-A*2403 or A*2501, which possess the Bw4 epitope but are in other ways substantially different from HLA-B molecules, was not increased by addition of the anti-NKB1 antibody. Asparagine 86, the single site of N-linked glycosylation on class I molecules, is in close proximity to the Bw4/Bw6 region. The glycosylation site of the Bw4-positive molecule B*5801 was mutated, and the mutant molecules tested for inhibition of NKB1+ NK cells. Inhibition that could be reversed by addition of the anti-NKB1 monoclonal antibody was observed, showing the presence of the carbohydrate moiety is not essential for class I recognition by NKB1+ NK cell clones

Severity of cardiovascular disease and health-related quality of life in men with prostate cancer: a longitudinal analysis from CaPSURE.

ObjectiveTo evaluate the influence of comorbid cardiovascular disease severity on health-related quality of life (HRQL) in men treated with radical prostatectomy (RP) or radiotherapy (RT) for early stage prostate cancer.MethodsSubjects (n=830) with non-metastatic disease who had been diagnosed in 2000-2002 were drawn from Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE). We evaluated the influence of cardiovascular disease (CVD) severity on generic and disease-specific HRQL before and 6, 12, 18, and 24 months after treatment with RP or RT. HRQL was measured with the SF-36 and the UCLA Prostate Cancer Index.ResultsMen with moderate (n=193) or severe (n=51) cardiovascular disease had worse pre-treatment HRQL than did men without CVD (n=293) (P<0.01); HRQL scores were worse in men referred for RT. During 24 months of follow-up, men with moderate or severe CVD had worse SF-36 physical and mental component summaries and worse bowel function at all time points (P<0.05). Men with severe CVD also experienced a slower recovery in physical function (P=0.03) and sexual functioning (P=0.02) than did men without CVD.ConclusionsProstate cancer patients with moderate to severe CVD have worse HRQL during follow-up. Those with severe CVD recover their physical and sexual functioning more slowly after treatment

Dysregulated Choline, Methionine, and Aromatic Amino Acid Metabolism in Patients with Wilson Disease: Exploratory Metabolomic Profiling and Implications for Hepatic and Neurologic Phenotypes.

Wilson disease (WD) is a genetic copper overload condition characterized by hepatic and neuropsychiatric symptoms with a not well-understood pathogenesis. Dysregulated methionine cycle is reported in animal models of WD, though not verified in humans. Choline is essential for lipid and methionine metabolism. Defects in neurotransmitters as acetylcholine, and biogenic amines are reported in WD; however, less is known about their circulating precursors. We aimed to study choline, methionine, aromatic amino acids, and phospholipids in serum of WD subjects. Hydrophilic interaction chromatography-quadrupole time-of-flight mass spectrometry was employed to profile serum of WD subjects categorized as hepatic, neurologic, and pre-clinical. Hepatic transcript levels of genes related to choline and methionine metabolism were verified in the Jackson Laboratory toxic milk mouse model of WD (tx-j). Compared to healthy subjects, choline, methionine, ornithine, proline, phenylalanine, tyrosine, and histidine were significantly elevated in WD, with marked alterations in phosphatidylcholines and reductions in sphingosine-1-phosphate, sphingomyelins, and acylcarnitines. In tx-j mice, choline, methionine, and phosphatidylcholine were similarly dysregulated. Elevated choline is a hallmark dysregulation in WD interconnected with alterations in methionine and phospholipid metabolism, which are relevant to hepatic steatosis. The elevated phenylalanine, tyrosine, and histidine carry implications for neurologic manifestations and are worth further investigation

Isotropic Conductivity of Two-Dimensional Three-Component Symmetric Composites

The effective dc-conductivity problem of isotropic, two-dimensional (2D), three-component, symmetric, regular composites is considered. A simple cubic equation with one free parameter for $\sigma_{e}(\sigma_1,\sigma_2,\sigma_3)$ is suggested whose solutions automatically have all the exactly known properties of that function. Numerical calculations on four different symmetric, isotropic, 2D, three-component, regular structures show a non-universal behavior of $\sigma_{e}(\sigma_1,\sigma_2,\sigma_3)$ with an essential dependence on micro-structural details, in contrast with the analogous two-component problem. The applicability of the cubic equation to these structures is discussed. An extension of that equation to the description of other types of 2D three-component structures is suggested, including the case of random structures. Pacs: 72.15.Eb, 72.80.Tm, 61.50.AhComment: 8 pages (two columns), 8 figures. J. Phys. A - submitte

Radiative acceleration and transient, radiation-induced electric fields

The radiative acceleration of particles and the electrostatic potential fields that arise in low density plasmas hit by radiation produced by a transient, compact source are investigated. We calculate the dynamical evolution and asymptotic energy of the charged particles accelerated by the photons and the radiation-induced electric double layer in the full relativistic, Klein-Nishina regime. For fluxes in excess of $10^{27}$ ${\rm erg} {\rm cm}^{-2} {\rm s}^{-1}$, the radiative force on a diluted plasma (n\la 10^{11} cm$^{-3}$) is so strong that electrons are accelerated rapidly to relativistic speeds while ions lag behind owing to their larger inertia. The ions are later effectively accelerated by the strong radiation-induced double layer electric field up to Lorentz factors $\approx 100$, attainable in the case of negligible Compton drag. The asymptotic energies achieved by both ions and electrons are larger by a factor 2--4 with respect to what one could naively expect assuming that the electron-ion assembly is a rigidly coupled system. The regime we investigate may be relevant within the framework of giant flares from soft gamma-repeaters.Comment: 14 pages, 7 figures, ApJ, in press (tentatively scheduled for the v. 592, 2003 issue

Force-Free Models of Magnetically Linked Star-Disk Systems

Disk accretion onto a magnetized star occurs in a variety of astrophysical contexts, from young stars to X-ray pulsars. The magnetohydrodynamic interaction between the stellar field and the accreting matter can have a strong effect on the disk structure, the transfer of mass and angular momentum between the disk and the star, and the production of bipolar outflows, e.g., plasma jets. We study a key element of this interaction - the time evolution of the magnetic field configuration brought about by the relative rotation between the disk and the star - using simplified, largely semianalytic, models. We first discuss the rapid inflation and opening up of the magnetic field lines in the corona above the accretion disk, which is caused by the differential rotation twisting. Then we consider additional physical effects that tend to limit this expansion, such as the effect of plasma inertia and the possibility of reconnection in the disk's corona, the latter possibly leading to repeated cycles in the evolution. We also derive the condition for the existence of a steady state for a resistive disk and conclude that a steady state configuration is not realistically possible. Finally, we generalize our analysis of the opening of magnetic field lines by using a non-self-similar numerical model that applies to an arbitrarily rotating (e.g. keplerian) disk.Comment: 75 pages, 22 figures, 2 tables. Submitted to Astrophysical Journa

Phenotypic microarrays suggest Escherichia coli ST131 is not a metabolically distinct lineage of extra-intestinal pathogenic E. coli

Extraintestinal pathogenic E. coli (ExPEC) are the major aetiological agent of urinary tract infections (UTIs) in humans. The emergence of the CTX-M producing clone E. coli ST131 represents a major challenge to public health worldwide. A recent study on the metabolic potential of E. coli isolates demonstrated an association between the E. coli ST131 clone and enhanced utilisation of a panel of metabolic substrates. The studies presented here investigated the metabolic potential of ST131 and other major ExPEC ST isolates using 120 API test reagents and found that ST131 isolates demonstrated a lower metabolic activity for 5 of 120 biochemical tests in comparison to non-ST131 ExPEC isolates. Furthermore, comparative phenotypic microarray analysis showed a lack of specific metabolic profile for ST131 isolates countering the suggestion that these bacteria are metabolically fitter and therefore more successful human pathogens

Complexity without chaos: Plasticity within random recurrent networks generates robust timing and motor control

It is widely accepted that the complex dynamics characteristic of recurrent neural circuits contributes in a fundamental manner to brain function. Progress has been slow in understanding and exploiting the computational power of recurrent dynamics for two main reasons: nonlinear recurrent networks often exhibit chaotic behavior and most known learning rules do not work in robust fashion in recurrent networks. Here we address both these problems by demonstrating how random recurrent networks (RRN) that initially exhibit chaotic dynamics can be tuned through a supervised learning rule to generate locally stable neural patterns of activity that are both complex and robust to noise. The outcome is a novel neural network regime that exhibits both transiently stable and chaotic trajectories. We further show that the recurrent learning rule dramatically increases the ability of RRNs to generate complex spatiotemporal motor patterns, and accounts for recent experimental data showing a decrease in neural variability in response to stimulus onset