A pox on thee! Manipulation of the host immune system by myxoma virus and implications for viral-host co-adaptation

The poxviruses have evolved a diverse array of proteins which serve to subvert innate and adaptive host responses that abort or at least limit viral infections. Myxoma virus and its rabbit host are considered to represent an ideal poxvirus-host system in which to study the effects of these immunomodulatory proteins. Studies of laboratory rabbits (Oryctolagus cuniculus) infected with gene knockout variants of myxoma virus have provided compelling evidence that several myxoma virus gene products contribute to the pathogenic condition known as myxomatosis. However, myxomatosis, which is characterized by skin lesions, systemic immunosuppression, and a high mortality rate, does not occur in the virus' natural South American host, Sylvilogus brasiliensis. Moreover, in Australia where myxoma virus was willfully introduced to control populations of O. cuniculus, myxomatosis-resistant rabbits emerged within a year of myxoma virus introduction into the field. In this review I discuss the characterized immunomodulatory proteins of myxoma virus, their biochemical properties, their pathogenic effects in laboratory rabbits, the role of the host immune system in the susceptibility or resistance to myxomatosis, and the evidence that immunomodulatory genes may have been attenuated during the co-adaptation of myxoma virus and O. cuniculus in Australia.     

The human genome browser at UCSC

As vertebrate genome sequences near completion and research refocuses to their analysis, the issue of effective genome annotation display becomes critical. A mature web tool for rapid and reliable display of any requested portion of the genome at any scale, together with several dozen aligned annotation tracks, is provided at http://genome.ucsc.edu. This browser displays assembly contigs and gaps, mRNA and expressed sequence tag alignments, multiple gene predictions, cross-species homologies, single nucleotide polymorphisms, sequence-tagged sites, radiation hybrid data, transposon repeats, and more as a stack of coregistered tracks. Text and sequence-based searches provide quick and precise access to any region of specific interest. Secondary links from individual features lead to sequence details and supplementary off-site databases. One-half of the annotation tracks are computed at the University of California, Santa Cruz from publicly available sequence data; collaborators worldwide provide the rest. Users can stably add their own custom tracks to the browser for educational or research purposes. The conceptual and technical framework of the browser, its underlying MYSQL database, and overall use are described. The web site currently serves over 50,000 pages per day to over 3000 different users.     

Chaperone-mediated protein folding

The folding of most newly synthesized proteins in the cell requires the interaction of a variety of protein cofactors known as molecular chaperones. These molecules recognize and bind to nascent polypeptide chains and partially folded intermediates of proteins, preventing their aggregation and misfolding. There are several families of chaperones; those most involved in protein folding are the 40-kDa heat shock protein (HSP40; DnaJ), 60-kDa heat shock protein (HSP60; GroEL), and 70-kDa heat shock protein (HSP70; DnaK) families. The availability of high-resolution structures has facilitated a more detailed understanding of the complex chaperone machinery and mechanisms, including the ATP-dependent reaction cycles of the GroEL and HSP70 chaperones. For both of these chaperones, the binding of ATP triggers a critical conformational change leading to release of the bound substrate protein. Whereas the main role of the HSP70/HSP40 chaperone system is to minimize aggregation of newly synthesized proteins, the HSP60 chaperones also facilitate the actual folding process by providing a secluded environment for individual folding molecules and may also promote the unfolding and refolding of misfolded intermediates.     

Optical evidence for the unification of active galactic nuclei and quasi-stellar objects

There is a variety of optical evidence for some unification of different types of active galactic nuclei and quasi-stellar objects (QSOs). The case is very strong for the unification of at least some Seyfert galaxies, where polarization data show that the type assigned to the Seyfert galaxy must depend on viewing direction. It has been proposed that Fanaroff-Riley type 2 (FR2) radio galaxies are quasars seen in a direction from which the quasar is obscured, and there is some limited direct evidence for this picture. The broad absorption line QSOs may be normal QSOs seen from a special direction. Some of the sources observed to have high luminosities in the far infrared could be obscured QSOs and active nuclei. Mergers and interactions are likely to play an important role in nuclear activity, and active galaxies and QSOs could change their apparent types through these encounters followed by subsequent evolution.     

Hsp60-Induced Tolerance in the Rotifer Brachionus plicatilis Exposed to Multiple Environmental Contaminants

Hsp60 induction was selected as a sublethal endpoint of toxicity for Brachionus plicatilis exposed to a water accommodated fraction (WAF) of Prudhoe Bay crude oil (PBCO), a PBCO/dispersant (Corexit 9527(R)) fraction and Corexit 9527(R) alone. To examine the effect of multiple stressors, exposures modeled San Francisco Bay, where copper levels are approximately 5 microgram/L, salinity is 22 per thousand, significant oil transport and refining occurs, and petroleum releases have occurred historically. Rotifers were exposed to copper at 5 microgram/L for 24 h, followed by one of the oil/dispersant preparations for 24 h. Batch-cultured rotifers were used in this study to model wild populations instead of cysts. SDS-PAGE with Western Blotting using hsp60-specific antibodies and chemiluminescent detection were used to isolate, identify, and measure induced hsp60 as a percentage of control values. Both PBCO/dispersant and dispersant alone preparations induced significant levels of hsp60. However, hsp60 expression was reduced to that of controls at high WAF concentrations, suggesting interference with protein synthesis. Rotifers that had been preexposed to copper maintained elevated levels of hsp60 upon treatment with WAF at all concentrations. Results suggest that induction of hsp60 by chronic low-level exposure may serve as a protective mechanism against subsequent or multiple stressors and that hsp60 levels are not additive for the toxicants tested in this study, giving no dose-response relationship. The methods employed in this study could be useful for quantifying hsp60 levels in wild rotifer populations.     

The effects of CaNa(2)EDTA on brain lead mobilization in rodents determined using a stable lead isotope tracer.

Studies have demonstrated the efficacy of CaNa(2)EDTA for reducing lead (Pb) levels in blood and soft tissues, including brain. However, a concern remains that a single dose of CaNa(2)EDTA may cause a significant increase in brain Pb levels due to a redistribution of endogenous Pb. Here we utilized a rodent model of Pb exposure in combination with a sensitive stable Pb isotope tracer methodology to assess the effects of CaNa(2)EDTA chelation treatment on the redistribution of Pb in brain, blood, kidney, and bone tissues. Thirty-two adult female albino rats (n = 6-7 animals/group) were exposed to 100 microg Pb/mL in drinking water for 4 weeks. Stable (204)Pb tracer was administered via i.p. injection over 2 days prior to chelation. CaNa(2)EDTA was administered i.p. at a dose of 150 mg/kg/day for 1 to 5 days. Statistical differences were evaluated with univariate ANOVA. Under the Pb exposure and chelation treatment regimens utilized here, there was no evidence of a measurable redistribution of endogenous Pb (as total Pb or labile (204)Pb tracer) into the brain after a single CaNa(2)EDTA dose. Further, CaNa(2)EDTA was not efficacious in measurably reducing brain or bone Pb levels, although brain levels of labile (204)Pb tracer were significantly reduced after 5 days of chelation. CaNa(2)EDTA treatment was effective in significantly reducing both blood and kidney Pb levels. Overall, these data substantiate the efficacy of CaNa(2)EDTA for reducing soft tissue Pb levels, but not total brain Pb, and they do not support concern for a transient increase in brain Pb levels with treatment.     

Efficacy of succimer chelation for reducing brain lead in a primate model of human lead exposure

The extent to which succimer (meso-2,3-dimercaptosuccinic acid [DMSA], Chemet) reduces brain lead (Pb) levels may be a primary consideration in evaluating its efficacy for reducing neurotoxicity. Clinical research in this area has been hampered by the need to use blood Pb levels as the index of treatment efficacy, despite the fact that brain Pb level is the exposure parameter of greater relevance to cognitive outcomes. Here, a nonhuman primate model of human Pb exposure was used to determine: (1) The efficacy of oral succimer for reducing brain Pb derived from chronic or recent exposures, and (2) The extent to which blood Pb levels reflect brain Pb prior to and following chelation. Adult rhesus monkeys were chronically exposed to Pb orally for 5 weeks to reach and maintain a target blood Pb level of 35-40 microg/dL. Chelation of Pb from recent exposures was assessed using a stable (204)Pb isotope tracer administered over 4 days prior to treatment. Immediately prior to chelation, a prefrontal cortex (PFC) biopsy was collected to determine pretreatment brain Pb levels. Subsequently, monkeys were assigned to vehicle (n = 5) or succimer (n = 6, 30 mg/kg/day x 5 days followed by 20 mg/kg/day x 14 days) groups. Blood and brain PFC, frontal lobe (FL), hippocampus (H), and striatum (S) were analyzed for total Pb and (204)Pb tracer concentrations by magnetic sector inductively coupled plasma-mass spectrometry. There were no measurable differences in brain Pb concentrations between the succimer and vehicle groups, indicating that succimer treatment was not efficacious in reducing brain Pb levels. In contrast, the cessation of Pb exposure significantly reduced brain (PFC) Pb ( approximately 34%) when compared to pretreatment levels (succimer and vehicle groups). Pb concentrations also varied among brain regions (PFC > FL approximately H > S). Finally, pretreatment PFC Pb concentrations were significantly correlated with the integrated blood Pb level (AUC) over the Pb exposure period, but not with the single pretreatment blood Pb collected concurrently with the PFC biopsy. Following treatment, blood Pb levels correlated only with Pb in the PFC, and not the other brain regions measured (FL, H, S). These data indicate that, under the conditions of this study, succimer treatment did not reduce brain Pb levels beyond the cessation of Pb exposure alone. Moreover, a single blood Pb measurement may be a poor predictor of brain Pb levels, reflecting limitations in the use of blood Pb level as an indicator of treatment efficacy.     

Use of endogenous, stable lead isotopes to determine release of lead from the skeleton.

The stable lead isotope methodology can be used to study the release of lead from bone into the circulation because of its potential to distinguish circulatory lead from "older" and isotopically different skeletal lead that may have been accumulated years or decades earlier. Here we report the initial results from a larger ongoing study that evaluates the skeleton as a source of lead to the circulation in environmentally exposed human subjects. Lead concentrations and stable lead isotopic compositions were measured in blood and trabecular bone samples obtained from five patients who underwent total hip or knee joint replacement. All subjects contained low blood (1-6 micrograms/dl) and bone (0.6-7 micrograms/g dry weight) lead concentrations typical of environmentally exposed individuals. There were relatively large differences in the lead isotopic compositions between the paired blood and bone samples from each subject. These isotopic differences are attributed to differences in the lead isotopic compositions of past versus current lead exposures and to the long elimination half-life of lead in the skeleton compared to lead in the circulation. Based on these data, we determined that the skeleton contributed 40-70% of the lead in the blood of these subjects. This initial study demonstrates the utility of the stable lead isotope methodology for investigating the release of lead from the skeleton. It also shows that the skeleton can be an important endogenous source of lead exposure in environmentally exposed humans.     

What Ancestry Can Tell Us About the Genetic Origins of Inter-Ethnic Differences in Asthma Expression

Differences in asthma prevalence have been described across different populations, suggesting that genetic ancestry can play an important role in this disease. In fact, several studies have demonstrated an association between African ancestry with increased asthma susceptibility and severity, higher immunoglobulin E levels, and lower lung function. In contrast, Native American ancestry has been shown to have a protective role for this disease. Genome-wide association studies have allowed the identification of population-specific genetic variants with varying allele frequency among populations. Additionally, the correlation of genetic ancestry at the chromosomal level with asthma and related traits by means of admixture mapping has revealed regions of the genome where ancestry is correlated with the disease. In this review, we discuss the evidence supporting the association of genetic ancestry with asthma susceptibility and asthma-related traits, and highlight the regions of the genome harboring ancestry-specific genetic risk factors.