Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation

Rhinoviruses cause serious morbidity and mortality as the major etiological agents of asthma exacerbations and the common cold. A major obstacle to understanding disease pathogenesis and to the development of effective therapies has been the lack of a small-animal model for rhinovirus infection. Of the 100 known rhinovirus serotypes, 90% (the major group) use human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor and do not bind mouse ICAM-1; the remaining 10% (the minor group) use a member of the low-density lipoprotein receptor family and can bind the mouse counterpart. Here we describe three novel mouse models of rhinovirus infection: minor-group rhinovirus infection of BALB/c mice, major-group rhinovirus infection of transgenic BALB/c mice expressing a mouse-human ICAM-1 chimera and rhinovirus-induced exacerbation of allergic airway inflammation. These models have features similar to those observed in rhinovirus infection in humans, including augmentation of allergic airway inflammation, and will be useful in the development of future therapies for colds and asthma exacerbations.     

Strong influences of a dominant,ground‐nesting ant on recruitment,and establishment of ant colonies and communities

Many factors drive the organization of communities including environmental factors, dispersal abilities, and competition. In particular, ant communities have high levels of interspecific competition and dominance that may affect community assembly processes. We used a combination of surveys and nest supplementation experiments to examine effects of a dominant ground‐nesting ant (Pheidole synanthropica) on (1) arboreal twig‐nesting, (2) ground‐foraging, and (3) coffee‐foraging ant communities in coffee agroecosystems. We surveyed these communities in high‐ and low‐density areas of P. synanthropica over 2 years. To test for effects on twig ant recruitment, we placed artificial nesting resources on coffee plants in areas with and without P. synanthropica. The first sampling period revealed differences in ant species composition on the ground, in coffee plants, and artificial nests between high‐ and low‐density sites of P. synanthropica. High‐density sites also had significantly lower recruitment of twig ants and had species‐specific effects on twig ant species. Prior to the second survey period, abundance of P. synanthropica declined in the high‐density sites, such that P. synanthropica densities no longer differed. Subsequent sampling revealed no difference in total recruitment of twig ants to artificial nests between treatments. Likewise, surveys of ground and coffee ants no longer showed significant differences in community composition. The results from the first experimental period, followed by survey results after the decline in P. synanthropica densities suggest that dominant ants can drive community assembly via both recruitment and establishment of colonies within the community.     

Can the invasive European rabbit (Oryctolagus cuniculus) assume the soil engineering role of locally-extinct natives?

Habitat modifying species can play crucial roles in ecosystem function. Invasive engineers may assume these roles where native engineers have been lost from the system. We compared the dynamics of the foraging pits of an invasive engineer, the European rabbit (Oryctolagus cuniculus) with two native mammals, the greater bilby (Macrotis lagotis) and the burrowing bettong (Bettongia lesueur). Foraging pits are small surface depressions created by animals when they forage for seeds, bulbs, roots, invertebrates and fungi. We measured foraging pit density and turnover, and density and richness of plant seedlings in pits and adjacent surfaces across three landforms representing a gradient in resource availability inside (bilbies and bettongs), and outside (rabbits only) a reserve in an arid Australian shrubland over 2 years. Pits of the native engineers contained 80% more seedlings (11.2 plants m⁻²) than rabbit pits (6.22 plants m⁻²). Further, rabbit pits supported 3.6-times fewer seedlings than equivalent non-pit surfaces outside the exclosure. Only one plant species was restricted entirely to pits. The reserve had more foraging pits and greater turnover than outside, but contrary to prediction, pit effects on seedling density were no greater in the more resource-limited dunes. There were some strong temporal and landscape effects on pit density and species composition, but generally trends were similar inside and outside the reserve. Overall, despite their functional similarities, invasive rabbits created fewer pits that were less favourable patches for seedlings than those of native engineers. Our work suggests that a suite of ecosystem processes associated with fertile patch creation has potentially been lost with the extirpation of bilbies and bettongs.     

Effects of GH and/or sex steroids on circulating IGF-I and IGFBPs in healthy, aged women and men

Circulating GH, IGF-I, IGFBP-3, and sex steroid concentrations decrease with age. GH or sex steroid treatment increases IGFBP-3, but little is known regarding the effects of these hormones on other IGFBPs. We assessed the effects of 26 wk of administration of GH, sex steroids, or GH + sex steroids on AM levels of IGF-I, IGFBPs 1-5, insulin, glucose, and osteocalcin and 2-h urinary excretion of deoxypyridinolline (DPD) cross-links in 53 women and 71 men aged 65-88 yr. Before treatment, in women and men, IGF-I was directly related to IGFBP-3 (P < 0.001 and P < 0.0001) and IGFBP-1 to IGFBP-2 (P = 0.0001). In women, IGFBP-1 was inversely related to insulin (P < 0.0005) and glucose (P < 0.005) and IGFBP-4 to osteocalcin (P < 0.01). IGFBP-4 and IGFBP-5 were not significantly related to DPD cross-links. GH and/or sex steroid increased IGF-I levels in both sexes, with higher concentrations in men (P < 0.001). In women, the IGF-I increment after GH was attenuated by hormone replacement therapy (HRT) coadministration (P < 0.05). Hormone administration also increased IGFBP-3. IGFBP-1 was unaffected by GH + sex steroids, whereas GH decreased IGFBP-2 by 15% in men (P < 0.05). Hormone administration did not change IGFBP-4, whereas in men IGFBP-5 increased by 20% after GH (P < 0.05) and 56% after GH + testosterone (P = 0.0003). These data demonstrate sexually dimorphic IGFBP responses to GH. Additionally, HRT attenuated or prevented GH-mediated increases in IGF-I and IGFBP-3. Whether GH and/or sex steroid administration alters local tissue production of IGFBPs and whether the latter influence autocrine or paracrine actions of IGF-I remain to be determined.     

Adenovirus Entry From the Apical Surface of Polarized Epithelia Is Facilitated by the Host Innate Immune Response

Prevention of viral-induced respiratory disease begins with an understanding of the factors that increase or decrease susceptibility to viral infection. The primary receptor for most adenoviruses is the coxsackievirus and adenovirus receptor (CAR), a cell-cell adhesion protein normally localized at the basolateral surface of polarized epithelia and involved in neutrophil transepithelial migration. Recently, an alternate isoform of CAR, CAR^Ex8, has been identified at the apical surface of polarized airway epithelia and is implicated in viral infection from the apical surface. We hypothesized that the endogenous role of CAR^Ex8 may be to facilitate host innate immunity. We show that IL-8, a proinflammatory cytokine and a neutrophil chemoattractant, stimulates the protein expression and apical localization of CAR^Ex8 via activation of AKT/S6K and inhibition of GSK3β. Apical CAR^Ex8 tethers infiltrating neutrophils at the apical surface of a polarized epithelium. Moreover, neutrophils present on the apical-epithelial surface enhance adenovirus entry into the epithelium. These findings suggest that adenovirus evolved to co-opt an innate immune response pathway that stimulates the expression of its primary receptor, apical CAR^Ex8, to allow the initial infection the intact epithelium. In addition, CAR^Ex8 is a new target for the development of novel therapeutics for both respiratory inflammatory disease and adenoviral infection.     

Exploring how patients understand and assess their diabetes control

Background

Poor understanding of diabetes management targets is associated with worse disease outcomes. Patients may use different information than providers to assess their diabetes control. In this study, we identify the information patients use to gauge their current level of diabetes control and explore patient-perceived barriers to understanding the hemoglobin A1c value (HbA1c).

Methods

Adults who self-reported a diagnosis of diabetes were recruited from outpatient, academically-affiliated, Internal Medicine clinics. Semi-structured interviews were conducted with participants and collected data were analyzed using thematic analysis.

Results

The mean age of the 25 participants was 56.8 years. HbA1c was one of several types of information participants used to assess diabetes control. Other information included perceived self-efficacy and adherence to self-care, the type and amount of medications taken, the presence or absence of symptoms attributed to diabetes, and feedback from self-monitoring of blood glucose. Most participants reported familiarity with the HbA1c (22 of 25), though understanding of the value’s meaning varied significantly. Inadequate diabetes education and challenges with patient-provider communication were cited as common barriers to understanding the HbA1c.

Conclusions

In addition to the HbA1c, several categories of information influenced participants’ assessments of their diabetes control. Increased provider awareness of the factors that influence patients’ perceptions of diabetes control can inform effective, patient-centered approaches for communicating vital diabetes-related information, facilitating behavior change towards improved patient outcomes.

     

Global DNA methylation (LINE-1) associated with exposure to arsenic-contaminated environment and with type of arsenical skin lesions in Thailand

The effects of chronic arsenic exposure mode on DNA methylation and skin lesion type are unclear. These relationships were investigated in an arsenic-contaminated area of southern Thailand. Cases with arsenical skin lesions (n = 131) and lesion-free controls (n = 163) were selected from an arsenic-contaminated sub-district, as well as 105 controls from a non-contaminated area. Type and severity of skin lesions and salivary global DNA methylation (LINE-1) were determined. Arsenic exposure was characterized as occupational, domestic and current (toe-nail arsenic). Associations were explored using logistic regression. Cases and controls had lower LINE-1 methylation and higher toenail arsenic than external controls (74.65% and 74.61% vs 76.05%, p < 0.001 for each). Cases were more likely to have been exposed domestically (OR_total 1.76, 95% ci 1.00, 3.11; and 2.22, 95% ci 1.22, 4.03; P_trend = 0.005 for exposure <36 and ≥36 years). More severe spotty hyperpigmentation was related to higher LINE-1 methylation (P_trend=0.006). LINE-1 methylation was positively associated with toenail arsenic only among non-symptomatic exposed subjects (OR 1.31, 95% ci 1.06, 1.64; p = 0.014). Exposure to an arsenic-contaminated environment results in global DNA hypomethylation. However, among symptomatic subjects, increased global DNA methylation was associated with increased severity of spotty hyperpigmentation.     

Examining the evidence for chytridiomycosis in threatened amphibian species

Extinction risks are increasing for amphibians due to rising threats and minimal conservation efforts. Nearly one quarter of all threatened/extinct amphibians in the IUCN Red List is purportedly at risk from the disease chytridiomycosis. However, a closer look at the data reveals that Batrachochytrium dendrobatidis (the causal agent) has been identified and confirmed to cause clinical disease in only 14% of these species. Primary literature surveys confirm these findings; ruling out major discrepancies between Red List assessments and real-time science. Despite widespread interest in chytridiomycosis, little progress has been made between assessment years to acquire evidence for the role of chytridiomycosis in species-specific amphibian declines. Instead, assessment teams invoke the precautionary principle when listing chytridiomycosis as a threat. Precaution is valuable when dealing with the world's most threatened taxa, however scientific research is needed to distinguish between real and predicted threats in order to better prioritize conservation efforts. Fast paced, cost effective, in situ research to confirm or rule out chytridiomycosis in species currently hypothesized to be threatened by the disease would be a step in the right direction. Ultimately, determining the manner in which amphibian conservation resources are utilized is a conversation for the greater conservation community that we hope to stimulate here.     

CD200 expression on tumor cells suppresses antitumor immunity: new approaches to cancer immunotherapy

Although the immune system is capable of mounting a response against many cancers, that response is insufficient for tumor eradication in most patients due to factors in the tumor microenvironment that defeat tumor immunity. We previously identified the immune-suppressive molecule CD200 as up-regulated on primary B cell chronic lymphocytic leukemia (B-CLL) cells and demonstrated negative immune regulation by B-CLL and other tumor cells overexpressing CD200 in vitro. In this study we developed a novel animal model that incorporates human immune cells and human tumor cells to address the effects of CD200 overexpression on tumor cells in vivo and to assess the effect of targeting Abs in the presence of human immune cells. Although human mononuclear cells prevented tumor growth when tumor cells did not express CD200, tumor-expressed CD200 inhibited the ability of lymphocytes to eradicate tumor cells. Anti-CD200 Ab administration to mice bearing CD200-expressing tumors resulted in nearly complete tumor growth inhibition even in the context of established receptor-ligand interactions. Evaluation of an anti-CD200 Ab with abrogated effector function provided evidence that blocking of the receptor-ligand interaction was sufficient for control of CD200-mediated immune modulation and tumor growth inhibition in this model. Our data indicate that CD200 expression by tumor cells suppresses antitumor responses and suggest that anti-CD200 treatment might be therapeutically beneficial for treating CD200-expressing cancers.