Most of the VP1 Unique Region of B19 Parvovirus Is on the Capsid Surface

AbstractB19 parvovirus is pathogenic in man and a vaccine is desirable. In convalescence after acute infection, the dominant humoral immune response is directed to the minor capsid protein called VP1, which differs from the major capsid protein by an additional NH2-terminal 227 amino acids. We have previously shown that this unique region contains multiple linear neutralizing epitopes. We produced seven recombinant B19 capsids that contained progressively truncated VP1 unique region sequences, each fused to a Flag peptide (AspTyrLysAspAspAspAspLys) at the NH2-terminus. Capsids containing normal VP2 and truncated Flag-VP1 proteins and, in some cases, only truncated Flag-VP1 chimeric proteins, were analyzed by ELISA, affinity chromatography, and electron microscopy using anti-Flag monoclonal antibody. All regions examined showed binding to anti-Flag antibody in multiple assays, indicating that most of the VP1 unique region is external to the capsid and accessible to antibody binding. These results have implications for the design of a B19 parvovirus vaccine and the use of empty capsids for presentation of heterologous protein antigens

Huffman Coding with Letter Costs: A Linear-Time Approximation Scheme

We give a polynomial-time approximation scheme for the generalization of Huffman Coding in which codeword letters have non-uniform costs (as in Morse code, where the dash is twice as long as the dot). The algorithm computes a (1+epsilon)-approximate solution in time O(n + f(epsilon) log^3 n), where n is the input size

Increased Risk for Aplastic Anemia and Myelodysplastic Syndrome in Individuals Lacking Glutathione S-Transferase Genes

BACKGROUND: Aplastic anemia (AA) and myelodysplastic syndrome (MDS) are marrow failure states that may be associated with chromosomal instability. An absence of the glutathione S-transferase (GST) enzyme may genetically predispose individuals to AA or MDS. PROCEDURE AND RESULTS: To test this hypothesis, we determined the GSTM1 and GSTT1 genotypes in a total of 196 patients using multiplex PCR. The GSTT1 null genotype was found to be overrepresented in Caucasian, Asian, and Hispanic patients with either AA or MDS. We confirmed a difference in the expected frequency of the GSTM1 null genotype in Caucasian MDS patients. The double null GSTM1/GSTT1 genotype was also overrepresented in Caucasian AA and MDS patients. In our population, 26% of AA patients and 40% of MDS patients had a chromosomal abnormality identified by karyotype or FISH analyses for chromosomes 7 and 8. Patients with AA and the GSTT1 null genotype had an increased frequency of chromosomal abnormalities (P = 0.003). CONCLUSION: There seems to be an increased risk for AA and MDS in individuals lacking GSTT1 or both GSTM1/GSTT1

A Study of Human Serum Sickness

Twelve patients with bone marrow failure, who were undergoing therapy with daily intravenous infusions of horse antithymocyte globulin, were studied for the development of serum sickness. Eleven of 12 patients developed typical signs and symptoms of serum sickness 8-13 days after the initiation of treatment. These included fever, malaise, cutaneous eruptions, arthralgias, gastrointestinal disturbances, and lymphadenopathy. Eleven of 12 patients developed high levels of circulating immune complexes during serum sickness. All 12 patients also had concomitant decreases of serum C3 and C4 levels. In addition to urticarial and/or morbilliform eruptions, 8 of 11 patients also developed a serpiginous band of erythema along the sides of the fingers, hands, toes, or feet as an early cutaneous sign of serum sickness. Direct immunofluorescence of lesional skin biopsies during serum sickness revealed deposits of immunoglobulin or complement in the walls of small cutaneous blood vessels in 3 of 5 patients. These findings indicate that circulating immune complexes play a central role in the pathophysiology of human serum sickness

Nonequilibrium work on spin glasses in longitudinal and transverse fields

We derive a number of exact relations between equilibrium and nonequilibrium quantities for spin glasses in external fields using the Jarzynski equality and gauge symmetry. For randomly-distributed longitudinal fields, a lower bound is established for the work done on the system in nonequilibrium processes, and identities are proven to relate equilibrium and nonequilibrium quantities. In the case of uniform transverse fields, identities are proven between physical quantities and exponentiated work done to the system at different parts of the phase diagram with the context of quantum annealing in mind. Additional relations are given, which relate the exponentiated work in quantum and simulated (classical) annealing. It is also suggested that the Jarzynski equality may serve as a guide to develop a method to perform quantum annealing under non-adiabatic conditions.Comment: 17 pages, 5 figures, submitted to JPS

On a Linear Program for Minimum-Weight Triangulation

Minimum-weight triangulation (MWT) is NP-hard. It has a polynomial-time constant-factor approximation algorithm, and a variety of effective polynomial- time heuristics that, for many instances, can find the exact MWT. Linear programs (LPs) for MWT are well-studied, but previously no connection was known between any LP and any approximation algorithm or heuristic for MWT. Here we show the first such connections: for an LP formulation due to Dantzig et al. (1985): (i) the integrality gap is bounded by a constant; (ii) given any instance, if the aforementioned heuristics find the MWT, then so does the LP.Comment: To appear in SICOMP. Extended abstract appeared in SODA 201

Incremental Medians via Online Bidding

In the k-median problem we are given sets of facilities and customers, and distances between them. For a given set F of facilities, the cost of serving a customer u is the minimum distance between u and a facility in F. The goal is to find a set F of k facilities that minimizes the sum, over all customers, of their service costs. Following Mettu and Plaxton, we study the incremental medians problem, where k is not known in advance, and the algorithm produces a nested sequence of facility sets where the kth set has size k. The algorithm is c-cost-competitive if the cost of each set is at most c times the cost of the optimum set of size k. We give improved incremental algorithms for the metric version: an 8-cost-competitive deterministic algorithm, a 2e ~ 5.44-cost-competitive randomized algorithm, a (24+epsilon)-cost-competitive, poly-time deterministic algorithm, and a (6e+epsilon ~ .31)-cost-competitive, poly-time randomized algorithm. The algorithm is s-size-competitive if the cost of the kth set is at most the minimum cost of any set of size k, and has size at most s k. The optimal size-competitive ratios for this problem are 4 (deterministic) and e (randomized). We present the first poly-time O(log m)-size-approximation algorithm for the offline problem and first poly-time O(log m)-size-competitive algorithm for the incremental problem. Our proofs reduce incremental medians to the following online bidding problem: faced with an unknown threshold T, an algorithm submits "bids" until it submits a bid that is at least the threshold. It pays the sum of all its bids. We prove that folklore algorithms for online bidding are optimally competitive.Comment: conference version appeared in LATIN 2006 as "Oblivious Medians via Online Bidding

A Nearly Linear-Time PTAS for Explicit Fractional Packing and Covering Linear Programs

We give an approximation algorithm for packing and covering linear programs (linear programs with non-negative coefficients). Given a constraint matrix with n non-zeros, r rows, and c columns, the algorithm computes feasible primal and dual solutions whose costs are within a factor of 1+eps of the optimal cost in time O((r+c)log(n)/eps^2 + n).Comment: corrected version of FOCS 2007 paper: 10.1109/FOCS.2007.62. Accepted to Algorithmica, 201

Functional characterization of telomerase RNA variants found in patients with hematologic disorders

Human telomerase uses a specific cellular RNA, called hTERC, as the template to synthesize telomere repeats at chromosome ends. Approximately 10% to 15% of patients with aplastic anemia or other bone marrow failure syndromes are carriers of hTERC sequence variants whose functional significance, in most cases, is unknown. We screened 10 reported and 2 newly discovered hTERC variants from such patients and found that 10 of these negatively affected telomerase enzymatic function when they were used to reconstitute telomerase enzymatic function in human cells. Most functional deficits were due to perturbations of hTERC secondary structure and correlated well with the degrees of telomere shortening and reduced telomerase activity observed in peripheral blood lymphocytes of the representative patients. We also found no evidence of dominant-negative activity in any of the mutants. Therefore, loss of telomerase activity and of telomere maintenance resulting from inherited hTERC mutations may limit marrow stem cell renewal and predispose some patients to bone marrow failure. (Blood. 2005;105: 2332-2339