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Patients infected with influenza are at high risk of secondary bacterial infection, which is a major proximate cause of morbidity and mortality. We have shown that in mice, prior infection with influenza results in increased inflammation and mortality upon Staphylococcus aureus infection, recapitulating the human disease. Lipidomic profiling of the lungs of superinfected mice revealed an increase in CYP450 metabolites during lethal superinfection. These lipids are endogenous ligands for the nuclear receptor PPARα, and we demonstrate that Ppara-/- mice are less susceptible to superinfection than wild-type mice. PPARα is an inhibitor of NFκB activation, and transcriptional profiling of cells isolated by bronchoalveolar lavage confirmed that influenza infection inhibits NFκB, thereby dampening proinflammatory and prosurvival signals. Furthermore, network analysis indicated an increase in necrotic cell death in the lungs of superinfected mice compared to mice infected with S. aureus alone. Consistent with this, we observed reduced NFκB-mediated inflammation and cell survival signaling in cells isolated from the lungs of superinfected mice. The kinase RIPK3 is required to induce necrotic cell death and is strongly induced in cells isolated from the lungs of superinfected mice compared to mice infected with S. aureus alone. Genetic and pharmacological perturbations demonstrated that PPARα mediates RIPK3-dependent necroptosis and that this pathway plays a central role in mortality following superinfection. Thus, we have identified a molecular circuit in which infection with influenza induces CYP450 metabolites that activate PPARα, leading to increased necrotic cell death in the lung which correlates with the excess mortality observed in superinfection.

Mutations in ADAR, which encodes the ADAR1 RNA-editing enzyme, cause Aicardi-Goutières syndrome (AGS), a severe autoimmune disease associated with an aberrant type I interferon response. How ADAR1 prevents autoimmunity remains incompletely defined. Here, we demonstrate that ADAR1 is a specific and essential negative regulator of the MDA5-MAVS RNA sensing pathway. Moreover, we uncovered a MDA5-MAVS-independent function for ADAR1 in the development of multiple organs. We showed that the p150 isoform of ADAR1 uniquely regulated the MDA5 pathway, whereas both the p150 and p110 isoforms contributed to development. Abrupt deletion of ADAR1 in adult mice revealed that both of these functions were required throughout life. Our findings delineate genetically separable roles for both ADAR1 isoforms in vivo, with implications for the human diseases caused by ADAR mutations.

To study the evolutionary dynamics of regulatory DNA, we mapped >1.3 million deoxyribonuclease I-hypersensitive sites (DHSs) in 45 mouse cell and tissue types, and systematically compared these with human DHS maps from orthologous compartments. We found that the mouse and human genomes have undergone extensive cis-regulatory rewiring that combines branch-specific evolutionary innovation and loss with widespread repurposing of conserved DHSs to alternative cell fates, and that this process is mediated by turnover of transcription factor (TF) recognition elements. Despite pervasive evolutionary remodeling of the location and content of individual cis-regulatory regions, within orthologous mouse and human cell types the global fraction of regulatory DNA bases encoding recognition sites for each TF has been strictly conserved. Our findings provide new insights into the evolutionary forces shaping mammalian regulatory DNA landscapes.

Bioactive lipid mediators play a crucial role in the induction and resolution of inflammation. To elucidate their involvement during influenza infection, liquid chromatography/mass spectrometry lipidomic profiling of 141 lipid species was performed on a mouse influenza model using two viruses of significantly different pathogenicity. Infection by the low-pathogenicity strain X31/H3N2 induced a proinflammatory response followed by a distinct anti-inflammatory response; infection by the high-pathogenicity strain PR8/H1N1 resulted in overlapping pro- and anti-inflammatory states. Integration of the large-scale lipid measurements with targeted gene expression data demonstrated that 5-lipoxygenase metabolites correlated with the pathogenic phase of the infection, whereas 12/15-lipoxygenase metabolites were associated with the resolution phase. Hydroxylated linoleic acid, specifically the ratio of 13- to 9-hydroxyoctadecadienoic acid, was identified as a potential biomarker for immune status during an active infection. Importantly, some of the findings from the animal model were recapitulated in studies of human nasopharyngeal lavages obtained during the 2009-2011 influenza seasons.

Investigated construct validity of Behavior Intervention Rating Scale (BIRS) to develop instrument to measure teachers' perceptions of treatment acceptability and perceived effectiveness of classroom interventions. Oblique factor analysis revealed three factors (Acceptability, Effectiveness, Time of Effect). Correlational analysis demonstrated moderate to strong relations among factors. Concluded BIRS was valid measure of treatment evaluation constructs of acceptability and effectiveness. (Author/NB)

Over a 3-y period, 12 adult New Zealand white (NZW) rabbits were presented for postmortem examination following variably long periods of inappetence and soft-to-liquid stool production. Postmortem findings included serosanguineous fluid in abdominal and thoracic cavities, dark-red-to-white renal foci, reddened intestinal serosa, and pulmonary edema. Microscopically, mesangial changes and thrombi were observed in renal glomeruli, and mild-to-severe enteritis was observed. These findings resemble hemolytic uremic syndrome, which typically follows enterocolitis associated with Shiga toxin (Stx)-producing Escherichia coli infection. In our case series, various gram-negative bacteria, most commonly E. coli, were isolated from the intestinal tracts; however, Stx production was not demonstrated. Evidence of Encephalitozoon cuniculi infection, a common cause of renal disease in rabbits, was also not found. Our cases suggest that gram-negative enteric bacteria should be included in the differential diagnosis of renal disease in NZW rabbits, especially in cases with an accompanying clinical history of gastrointestinal disorder. [ABSTRACT FROM AUTHOR]

To achieve a contemporary understanding of the common and rare lesions that affect wild, urban Norway rats (Rattus norvegicus), we conducted a detailed pathology analysis of 672 rats from Vancouver, British Columbia, Canada. Grossly evident lesions, such as wounds, abscesses, and neoplasms, were present in 71 of 672 rats (11%) and tended to be severe. The most common and significant lesions were infectious and inflammatory, most often affecting the respiratory tract and associated with bite wounds. We assessed a subset of rats (up to n = 406 per tissue) for the presence of microscopic lesions in a variety of organ systems. The most frequent lesions that could impact individual rat health included cardiomyopathy (128 of 406; 32%), chronic respiratory tract infections as indicated by pulmonary inducible bronchus-associated lymphoid tissue (270 of 403; 67%), tracheitis (192 of 372; 52%), and thyroid follicular hyperplasia (142 of 279; 51%). We isolated 21 bacterial species from purulent lesions in rats with bacterial infections, the most frequent of which were Escherichia coli, Enterococcus sp., and Staphylococcus aureus. Parasitic diseases in rats resulted from infection with several invasive nematodes: Capillaria hepatica in the liver (242 of 672; 36%), Eucoleus sp. in the upper gastrointestinal tract (164 of 399; 41%), and Trichosomoides crassicauda in the urinary bladder (59 of 194; 30%). Neoplastic, congenital, and degenerative lesions were rare, which likely reflects their adverse effect on survival in the urban environment. Our results establish a baseline of expected lesions in wild urban rats, which may have implications for urban rat and zoonotic pathogen ecology, as well as rat control in cities worldwide. [ABSTRACT FROM AUTHOR]

Summary Background Retinoic acid (RA) is known to play a role in weight regulation. Because mice without ALDH1A1, a major RA synthesizing enzyme, are resistant to diet-induced obesity, we tested a hypothesis that pharmacological inhibition of RA synthesis can suppress weight gain in a murine model of diet-induced obesity. Methods C57BL/6J male mice were fed a high fat diet (HFD) for 8 weeks to induce obesity and then randomized to a HFD with or without WIN 18,446, an RA synthesis inhibitor, for an additional 9 weeks. Body weight, body composition, energy expenditure, activity, and food intake were measured. Levels of retinoids, lipids, and genes involved in the metabolism of retinoid and lipids were also determined. Result s Mice treated with WIN 18,446 gained significantly less weight and had decreased adipose tissue weight, adipocyte size, and macrophage infiltration in adipose tissue. In addition, we observed higher UCP1 expression in adipose tissues and decreased expression of RA responsive genes and genes involved in fatty acid synthesis in the livers and lungs of mice treated with WIN 18,446. Conclusions Pharmacological suppression of RA synthesis via inhibition of ALDH1A1 may be a potential target for treatment of obesity. [ABSTRACT FROM AUTHOR]

In research studies using rats or mice, the cause of death is often not evaluated or reported. An analysis of the causes of death is particularly valuable for aging and carcinogenesis studies. Comparing causes of death among the study groups is often an important adjunct to the biochemical, molecular, clinical, and histopathologic findings. The methods for evaluating causes of death, contributing causes of death, and comorbidities have been suggested in several publications. Surprisingly, in important mouse aging studies, causes of death are often not reported. Cause-of-death assignment in preclinical rodent model aging research suffers from a lack of a standardized approach and an understanding of the value that it can add to longevity and interventional studies. While assigning single cause of death may facilitate data analysis, defining and publishing data on contributing causes (comorbidities) provides more information on associated underlying chronic conditions and health span in mouse models. This article reviews factors that affect determination of cause of death and the methods for evaluating causes of death and comorbidities. The proposed systematic pathology analysis includes assigning cause of death and comorbidities to define total disease burden. The combination of pathology with in vivo data will fully characterize the effect of tested interventions on multiple chronic diseases and health span of aging mice with improved translation to human aging and age-associated lesions. [ABSTRACT FROM AUTHOR]

The naked mole-rat (NMR; Heterocephalus glaber) is growing in popularity as a model for aging research due to its extreme longevity (up to 30 years), highly adapted physiology, and resistance to cancer, particularly when compared with traditional aging models such as laboratory mice and rats. Despite the NMR’s seemingly lengthy health span, several age-related lesions have been documented. During a 15-year retrospective evaluation of a zoo-housed population, histologic changes in the kidneys were reported in 127 of 138 (92%) adult NMRs. Of these, renal tubular mineralization was very common (115 of 127; 90.6%) and found in NMRs without concurrent renal lesions (36 of 127; 28.3%). Many of the other described lesions were considered progressive stages of a single process, generally referred to as chronic nephritis or nephropathy, and diagnosed in 73 of 127 (57.5%), while end-stage renal disease was reported in only 12 (9.4%) NMRs. Renal lesions of these NMRs were comparable to disease entities reported in laboratory rats and certain strains of inbred and noninbred mice. Although many lesions of NMR kidneys were similar to those found in aged laboratory rodents, some common urinary diseases were not represented in the examined colonies. The goal of this study was to describe renal lesions in NMRs from a zoologic setting to familiarize investigators and pathologists with an apparently common and presumably age-related disease in this nontraditional model. [ABSTRACT FROM AUTHOR]