Detecting disease outbreaks using local spatiotemporal methods

A real-time surveillance method is developed with emphasis on rapid and accurate detection of emerging outbreaks. We develop a model with relatively weak assumptions regarding the latent processes generating the observed data, ensuring a robust prediction of the spatiotemporal incidence surface. Estimation occurs via a local linear fitting combined with day-of-week effects, where spatial smoothing is handled by a novel distance metric that adjusts for population density. Detection of emerging outbreaks is carried out via residual analysis. Both daily residuals and AR model-based detrended residuals are used for detecting abnormalities in the data given that either a large daily residual or an increasing temporal trend in the residuals signals a potential outbreak, with the threshold for statistical significance determined using a resampling approach.     

Bayesian variable selection for latent class models

In this article, we develop a latent class model with class probabilities that depend on subject-specific covariates. One of our major goals is to identify important predictors of latent classes. We consider methodology that allows estimation of latent classes while allowing for variable selection uncertainty. We propose a Bayesian variable selection approach and implement a stochastic search Gibbs sampler for posterior computation to obtain model-averaged estimates of quantities of interest such as marginal inclusion probabilities of predictors. Our methods are illustrated through simulation studies and application to data on weight gain during pregnancy, where it is of interest to identify important predictors of latent weight gain classes.     

Catabolism of 4-hydroxy-2-trans-nonenal by THP1 monocytes/macrophages and inactivation of carboxylesterases by this lipid electrophile

Oxidative stress in cells and tissues leads to the formation of an assortment of lipid electrophiles, such as the quantitatively important 4-hydroxy-2-trans-nonenal (HNE). Although this cytotoxic aldehyde is atherogenic the mechanisms involved are unclear. We hypothesize that elevated HNE levels can directly inactivate esterase and lipase activities in macrophages via protein adduction, thus generating a biochemical lesion that accelerates foam cell formation and subsequent atherosclerosis. In the present study we examined the effects of HNE treatment on esterase and lipase activities in human THP1 monocytes/macrophages at various physiological scales (i.e., pure recombinant enzymes, cell lysate, and intact living cells). The hydrolytic activities of bacterial and human carboxylesterase enzymes (pnbCE and CES1, respectively) were inactivated by HNE in vitro in a time- and concentration-dependent manner. In addition, so were the hydrolytic activities of THP1 cell lysates and intact THP1 monocytes and macrophages. A single lysine residue (Lys105) in recombinant CES1 was modified by HNE via a Michael addition reaction, whereas the lone reduced cysteine residue (Cys389) was found unmodified. The lipolytic activity of cell lysates and intact cells was more sensitive to the inhibitory effects of HNE than the esterolytic activity. Moreover, immunoblotting analysis using HNE antibodies confirmed that several cellular proteins were adducted by HNE following treatment of intact THP1 monocytes, albeit at relatively high HNE concentrations (>50 μM). Unexpectedly, in contrast to CES1, the treatment of a recombinant human CES2 with HNE enhanced its enzymatic activity ∼3-fold compared to untreated enzyme. In addition, THP1 monocytes/macrophages can efficiently metabolize HNE, and glutathione conjugation of HNE is responsible for ∼43% of its catabolism. The functional importance of HNE-mediated inactivation of cellular hydrolytic enzymes with respect to atherogenesis remains obscure, although this study has taken a first step toward addressing this important issue by examining the potential of HNE to inhibit this biochemical activity in a human monocyte/macrophage cell line.     

SWI/SNF complexes containing Brahma or Brahma-related gene 1 play distinct roles in smooth muscle development

SWI/SNF ATP-dependent chromatin-remodeling complexes containing either Brahma-related gene 1 (Brg1) or Brahma (Brm) play important roles in mammalian development. In this study we examined the roles of Brg1 and Brm in smooth muscle development, in vivo, through generation and analysis of mice harboring a smooth muscle-specific knockout of Brg1 on wild-type and Brm null backgrounds. Knockout of Brg1 from smooth muscle in Brg1(flox/flox) mice expressing Cre recombinase under the control of the smooth muscle myosin heavy-chain promoter resulted in cardiopulmonary defects, including patent ductus arteriosus, in 30 to 40% of the mice. Surviving knockout mice exhibited decreased expression of smooth muscle-specific contractile proteins in the gastrointestinal tract, impaired contractility, shortened intestines, disorganized smooth muscle cells, and an increase in apoptosis of intestinal smooth muscle cells. Although Brm knockout mice had normal intestinal structure and function, knockout of Brg1 on a Brm null background exacerbated the effects of knockout of Brg1 alone, resulting in an increase in neonatal lethality. These data show that Brg1 and Brm play critical roles in regulating development of smooth muscle and that Brg1 has specific functions within vascular and gastrointestinal smooth muscle that cannot be performed by Brm.     

Genome-wide association and genomic prediction for host response to porcine reproductive and respiratory syndrome virus infection

Background

Host genetics has been shown to play a role in porcine reproductive and respiratory syndrome (PRRS), which is the most economically important disease in the swine industry. A region on Sus scrofa chromosome (SSC) 4 has been previously reported to have a strong association with serum viremia and weight gain in pigs experimentally infected with the PRRS virus (PRRSV). The objective here was to identify haplotypes associated with the favorable phenotype, investigate additional genomic regions associated with host response to PRRSV, and to determine the predictive ability of genomic estimated breeding values (GEBV) based on the SSC4 region and based on the rest of the genome. Phenotypic data and 60 K SNP genotypes from eight trials of ~200 pigs from different commercial crosses were used to address these objectives.

Results

Across the eight trials, heritability estimates were 0.44 and 0.29 for viral load (VL, area under the curve of log-transformed serum viremia from 0 to 21 days post infection) and weight gain to 42 days post infection (WG), respectively. Genomic regions associated with VL were identified on chromosomes 4, X, and 1. Genomic regions associated with WG were identified on chromosomes 4, 5, and 7. Apart from the SSC4 region, the regions associated with these two traits each explained less than 3% of the genetic variance. Due to the strong linkage disequilibrium in the SSC4 region, only 19 unique haplotypes were identified across all populations, of which four were associated with the favorable phenotype. Through cross-validation, accuracies of EBV based on the SSC4 region were high (0.55), while the rest of the genome had little predictive ability across populations (0.09).

Conclusions

Traits associated with response to PRRSV infection in growing pigs are largely controlled by genomic regions with relatively small effects, with the exception of SSC4. Accuracies of EBV based on the SSC4 region were high compared to the rest of the genome. These results show that selection for the SSC4 region could potentially reduce the effects of PRRS in growing pigs, ultimately reducing the economic impact of this disease.     

Movement of the epiglottis in mammals

In contrast to adult humans, the epiglottis of other mammals and infant humans is situated close to the soft palate. It has been argued that this posture is maintained during swallowing, with food passing laterally around an intact airway. To test this supposition, the movement of the epiglottis in two contrasting mammalian species, pigs and ferrets, was studied by placing radiopaque markers on the epiglottis and soft palate. Swallowing was observed with videofluoroscopy while the animals were feeding on hard and soft foods, liquids, and food mixed with barium sulfate. Analysis of the images showed that bolus formation and downward movement of the epiglottis away from the soft palate were unvarying phenomena in both animals for all tested foods. The duration of the epiglottic movement was approximately 0.3 s for liquids and slightly longer for solids. Because swallowing never occurred past an upright epiglottis, the results of this study do not support the hypothesis that adult animals maintain a patent airway during swallowing. Instead, the epiglottis in nonhuman mammals downfolds similarly to that of adult humans during swallowing. © 1996 Wiley-Liss, Inc.     

Differential physiological responses to prey availability by the great egret and white Ibis

In long-lived species, the balance between the benefits of reproduction and the costs from reduced survival or productivity is particularly challenging in dynamic environments like wetlands, where food levels vary greatly year to year. Some wetland species exhibit changes in reproductive strategies in response to food availability but whether physiological responses function in a similar manner is unclear. We compared the pre-breeding physiological responses (fecal corticosterone [FCORT], heat shock protein 60 [HSP60], and mass) of 2 species of wading birds with contrasting foraging strategies (great egret [Ardea alba], an exploiter, and white ibis [Eudocimus albus], a searcher) during years with contrasting levels of prey availability. Both species were in good physiological condition, with low levels of HSP60 and FCORT, during a year with high prey availability (2006). In a contrasting year with lesser prey availability (2007), HSP60 and FCORT concentrations indicated that ibis physiological condition was reduced, whereas egrets showed little change. Egrets and male ibis increased body mass, whereas female ibis decreased mass, in the year with low prey availability. Although poorly understood, we hypothesize that the differential response between female ibis and the others is associated with differential investment strategies based on long-term costs of reproduction. Model results identified prey availability and the 2-week water recession rate as the primary habitat variables that were associated with the physiological condition of white ibises, whereas great egret physiological condition was influenced mostly by 2-week water recession rate. Our results support the hypothesis that prey availability and hydrological factors play crucial roles in regulating populations of wading birds in the Florida Everglades. The results of this study show a more complete pathway by which hydrologic patterns affect wading birds, and it suggests that ibis are more sensitive to habitat conditions than are egrets. This information can be used to refine species models designed to evaluate water management scenarios and will improve our ability to manage and restore wetland ecosystems © 2012 The Wildlife Society.     

Restoration of Northwest Florida Sandhills Through Harvest of Invasive Pinus clausa

Across much of the southeastern U.S.A., sandhills have become dominated by hardwoods or invasive pine species following logging of Pinus palustris (longleaf pine) and fire suppression. At Eglin Air Force Base where this study was conducted, Pinus clausa (sand pine) has densely colonized most southeastern sandhill sites, suppressing groundcover vegetation. The objectives of this study were: to determine if suppressed groundcover vegetation recovers following the removal of P. clausa; to compare species composition and abundance in removal plots with that in reference, high quality sandhills; to test the assumption that recolonization by P. clausa seedlings decreases with proximity to the centers of removal plots; and to measure the survival of containerized P. palustris seedlings that were planted on P. clausa removal plots. One year post‐removal (1995), the number of plant species decreased by 50%, but then increased by 100% from 1995 to 1997, followed by a small reduction in 1998. The number of plant species was greater in reference plots than in removal plots prior to 1997. Eighty‐five percent of the original species were recorded 4 years post‐harvest in removal plots. Shrubs and large trees remained at low density after harvest. Densities of graminoids, legumes, other forbs, woody vines, and small trees increased after harvest. Plant densities of all life forms, except woody vines, were greater in reference plots than in removal plots. The density of recolonizing P. clausa seedlings 2–4 years post‐harvest significantly decreased with increasing proximity to the centers of removal plots. On average, 80% of planted P. palustris seedlings survived their first 2 years. Harvest of P. clausa followed by fire and the planting of P. palustris is a reasonably effective restoration approach in invaded sandhills. However, supplementary plantings of some herbaceous species may be necessary for full restoration.     

Domain characterization of rabbit skeletal muscle myosin light chain kinase.

Myosin light chain kinase can be divided into three distinct structural domains, an amino-terminal "tail," of unknown function, a central catalytic core and a carboxy-terminal calmodulin-binding regulatory region. We have used a combination of deletion mutagenesis and monoclonal antibody epitope mapping to define these domains more closely. A 2.95-kilobase cDNA has been isolated that includes the entire coding sequence of rabbit skeletal muscle myosin light chain kinase (607 amino acids). This cDNA, expressed in COS cells encoded a Ca2+/calmodulin-dependent myosin light chain kinase with a specific activity similar to that of the enzyme purified from rabbit skeletal muscle. Serial carboxy-terminal deletions of the regulatory and catalytic domains were constructed and expressed in COS cells. The truncated kinases had no detectable myosin light chain kinase activity. Monoclonal antibodies which inhibit the activity of the enzyme competitively with respect to myosin light chain were found to bind between residues 235-319 and 165-173, amino-terminal of the previously defined catalytic core. Thus, residues that are either involved in substrate binding or in close proximity to a light chain binding site may be located more amino-terminal than the previously defined catalytic core.