Innate Immune Response Following AAV Administration.

Recombinant adeno-associated virus (rAAV) is a widely used tool for gene delivery due to its high efficiency to transduce postmitotic cells. However, host immune reactions targeting AAV can limit its therapeutic benefit in clinical applications. While most studies focused on adaptive immunity, initial innate immune responses are the first line of defense against viral vectors and help modulate subsequent adaptive immune responses. The understanding of innate immune responses to AAV can potentially improve safety and therapeutic efficiency of AAV. This article provides an overview of innate immune responses to AAV vectors.

Relative bioavailability and pharmacokinetics: a combination of pentazocine and acetaminophen.

The relative bioavailability and pharmacokinetics of a combination product containing pentazocine and acetaminophen were studied in 20 healthy human males. Each subject, in a single-dose three-way crossover design, received two different preparations containing 50 mg of pentazocine (as base) and 1300 mg of acetaminophen either as capsule-shaped tablets or as a solution. Plasma concentrations of pentazocine and acetaminophen were determined from 0.25 to 12 h following oral administration. The plasma data for both compounds in the tablet formulation were described by an open one-compartment body model with first-order absorption. The average (+/- SD) bioavailability of the tablet relative to that of the solution was 85.0 +/- 31.1 and 88.6 +/- 13.1% for pentazocine and acetaminophen, respectively. The apparent first-order regression-dependent elimination rate constants for pentazocine from the tablet and solution preparations were 0.19 +/- 0.08 and 0.20 +/- 0.06 h-1, respectively, while the rate constants for acetaminophen were 0.26 +/- 0.03 and 0.25 +/- 0.03 h-1 for the tablet and solution preparations, respectively. These rate constants correspond to terminal elimination half-lives of approximately 3.6 h for pentazocine and approximately 2.7 h for acetaminophen.

Performance and Mapping of Leaf Rust Resistance Transferred to Wheat from Triticum timopheevii subsp. armeniacum.

ABSTRACT Host plant resistance is an economical and environmentally sound method of control of leaf rust caused by the fungus Puccinia triticina, which is one of the most serious diseases of wheat (Triticum aestivum) worldwide. Wild relatives of wheat, including the tetraploid T. timopheevii subsp. armeniacum, represent an important source of genes for resistance to leaf rust. The objectives of this study were to (i) evaluate the performance of leaf rust resistance genes previously transferred to wheat from three accessions of T. timopheevii subsp. armeniacum, (ii) determine inheritance and allelic relationship of the new leaf rust resistance genes, and (iii) determine the genetic map location of one of the T. timopheevii subsp. armeniacum-derived genes using microsatellite markers. The leaf rust resistance gene transferred to hexaploid wheat from accession TA 28 of T. timopheevii subsp. armeniacum exhibited slightly different infection types (ITs) to diverse races of leaf rust in inoculated tests of seedlings compared with the gene transferred from TA 870 and TA 874. High ITs were exhibited when seedlings of all the germ plasm lines were inoculated with P. triticina races MBRL and PNMQ. However, low ITs were observed on adult plants of all lines having the T. timopheevii subsp. armeniacum-derived genes for resistance in the field at locations in Kansas and Texas. Analysis of crosses between resistant germ plasm lines showed that accessions TA 870 and TA 874 donated the same gene for resistance to leaf rust and TA 28 donated an independent resistance gene. The gene donated to germ plasm line KS96WGRC36 from TA 870 of T. timopheevii subsp. armeniacum was linked to microsatellite markers Xgwm382 (6.7 cM) and Xgdm87 (9.4 cM) on wheat chromosome arm 2B long. This new leaf rust resistance gene is designated Lr50. It is the first named gene for leaf rust resistance transferred from wild timopheevi wheat and is the only Lr gene located on the long arm of wheat homoeologous group 2 chromosomes.

Cultivar mixtures for the simultaneous management of multiple diseases: tan spot and leaf rust of wheat.

ABSTRACT Because of differences in life histories between Puccinia triticina, a highly specialized, polycyclic, windborne pathogen with a shallow dispersal gradient, and Pyrenophora tritici-repentis, a residue-borne pathogen with a steep dispersal gradient, wheat mixtures are expected to be more effective at controlling leaf rust than tan spot. The objectives of this research were to determine the effect of two-cultivar mixtures with varying proportions and different pathogen resistance profiles on the severity of tan spot and leaf rust, to evaluate yield of the mixtures in the presence or absence of disease, and to directly compare the relative effectiveness of cultivar mixing for tan spot versus leaf rust. In a field experiment at two sites in Kansas over two growing seasons, winter wheat cvs. Jagger and 2145, which have differential resistance reactions to leaf rust and tan spot, each were planted in proportions of 0.25, 0.50, 0.75, and 1.00. Plots were inoculated with each pathogen alone, both pathogens, treated with a fungicide, or exposed to ambient conditions. For both diseases for all siteyears, severity decreased substantially on the susceptible cultivar as the proportion of that cultivar decreased in mixture. Mixtures were significantly more effective at reducing leaf rust than tan spot in three of four site-years. Mixtures generally yielded the same as the weighted mean of components in monoculture although, in two of three site-years, at least one fungicide-treated and one diseased mixture each yielded higher than expected values. Although this particular mixture produced only modest yield benefits, the potential for simultaneous reductions in tan spot and leaf rust was demonstrated.

Advanced backcross QTL analysis of a hard winter wheat x synthetic wheat population.

Advanced backcross quantitative trait locus (AB-QTL) analysis was used to identify QTLs for yield and yield components in a backcross population developed from a cross between hard red winter wheat (Triticum aestivum L.) variety Karl 92 and the synthetic wheat line TA 4152-4. Phenotypic data were collected for agronomic traits including heading date, plant height, kernels per spike, kernel weight, tiller number, biomass, harvest index, test weight, grain yield, protein content, and kernel hardness on 190 BC2F(2:4) lines grown in three replications in two Kansas environments. Severity of wheat soil-borne mosaic virus (WSBMV) reaction was evaluated at one location. The population was genotyped using 151 microsatellite markers. Of the ten putative QTLs identified, seven were located on homologous group 2 and group 3 chromosomes. The favorable allele was contributed by cultivated parent Karl 92 at seven QTLs including a major one for WSBMV resistance, and by the synthetic parent at three QTLs: for grain hardness, kernels per spike, and tiller number.

H9, H10, and H11 compose a cluster of Hessian fly-resistance genes in the distal gene-rich region of wheat chromosome 1AS.

H9, H10, and H11 are major dominant resistance genes in wheat, expressing antibiosis against Hessian fly [(Hf) Mayetiola destructor (Say)] larvae. Previously, H9 and H10 were assigned to chromosome 5A and H11 to 1A. The objectives of this study were to identify simple-sequence-repeat (SSR) markers for fine mapping of these genes and for marker-assisted selection in wheat breeding. Contrary to previous results, H9 and H10 did not show linkage with SSR markers on chromosome 5A. Instead, H9, H10, and H11 are linked with SSR markers on the short arm of chromosome 1A. Both H9 and H10 are tightly linked to flanking markers Xbarc263 and Xcfa2153 within a genetic distance of 0.3-0.5 cM. H11 is tightly linked to flanking markers Xcfa2153 and Xbarc263 at genetic distances of 0.3 cM and 1.7 cM. Deletion bin mapping assigned these markers and genes to the distal 14% of chromosome arm 1AS, where another Hf-resistance gene, Hdic (derived from emmer wheat), was also mapped previously. Marker polymorphism results indicated that a small terminal segment of chromosome 1AS containing H9 or H10 was transferred from the donor parent to the wheat lines Iris or Joy, and a small intercalary fragment carrying H11 was transferred from the resistant donor to the wheat line Karen. Our results suggest that H9, H10, H11, Hdic, and the previously identified H9- or H11-linked genes (H3, H5, H6, H12, H14, H15, H16, H17, H19, H28, and H29) may compose a cluster (or family) of Hf-resistance genes in the distal gene-rich region of wheat chromosome 1AS; and H10 most likely is the same gene as H9.

Identification and molecular tagging of a gene from PI 289824 conferring resistance to leaf rust (Puccinia triticina) in wheat.

Host-plant resistance is the most economically viable and environmentally responsible method of control for Puccinia triticina, the causal agent of leaf rust in wheat (Triticum aestivum L.). The identification and utilization of new resistance sources is critical to the continued development of improved cultivars as shifts in pathogen races cause the effectiveness of widely deployed genes to be short lived. The objectives of this research were to identify and tag new leaf rust resistance genes. Forty landraces from Afghanistan and Iran were obtained from the National Plant Germplasm System and evaluated under field conditions at two locations in Texas. PI 289824, a landrace from Iran, was highly resistant under field infection. Further evaluation revealed that PI 289824 is highly resistant to a broad spectrum of leaf rust races, including the currently prevalent races of leaf rust in the Great Plains area of the USA. Eight F1 plants, 176 F2 individuals and 139 F2:3 families of a cross between PI 289824 and T112 (susceptible) were evaluated for resistance to leaf rust at the seedling stage. Genetic analysis indicated resistance in PI 289824 is controlled by a single dominant gene. The AFLP analyses resulted in the identification of a marker (P39 M48-367) linked to resistance. The diagnostic AFLP band was sequenced and that sequence information was used to develop an STS marker (TXW200) linked to the gene at a distance of 2.3 cM. The addition of microsatellite markers allowed the gene to be mapped to the short arm of Chromosome 5B. The only resistance gene to be assigned to Chr 5BS is Lr52. The Lr52 gene was reported to be 16.5 cM distal to Xgwm443 while the gene in PI 289824 mapped 16.7 cM proximal to Xgwm443. Allelism tests are needed to determine the relationship between the gene in PI 289824 and Lr52. If the reported map positions are correct, the gene in PI 289824 is unique.

Metabolism of arildone, an antiviral agent, in laboratory animals.

After arildone administration, four compounds were identified in the excreta of laboratory animals: unchanged drug, arildone; the O-desmethyl metabolite, 4-[6-(2-chloro-4-hydroxy)phenoxy]hexyl-3,5-heptanedione; the sulfate ester of 2-chloro-4-methoxyphenol; and a labile conjugate of chlorohydroquinone, tentatively characterized as the sulfate ester. The concentrations of each of these were determined in the urine and/or plasma of rats, dogs, and mice after administration of 14C-arildone.