The Function of Peroxisome Proliferator-Activated Receptor-Gamma in the Urothelium

The urothelium is a stratified epithelium that serves as a barrier between the urinary tract and blood. It consists of terminally differentiated umbrella cells, which are specialized for synthesizing and assembling uroplakins into a tough apical plaque and responsible for the barrier function; intermediate cells which are few in number but serve as umbrella cell progenitors; and unipotent basal cells, which populate the majority of the urothelium. The urothelium is one of the most quiescent epithelia in the body but can rapidly regenerate in response to damage. The urothelium is also a source of cells that give rise to bladder cancer. Patients with chronic inflammation caused by indwelling catheters or repeated urinary tract infections have a higher risk of developing bladder cancer. Bladder cancers with squamous histological features are considered to be more aggressive with poor prognosis and the majority are categorized as basal subtype. The expression of Peroxisome Proliferator-Activated Receptor-gamma (PPARG) is strongly down regulated in the basal subtype of bladder cancer, suggesting that its removal might be essential in tumorigenesis. PPARG is a nuclear hormone receptor that was originally described as a master regulator of adipogenesis but could also promote cellular differentiation in a number of epithelium. PPARG also serves as an important regulator in anti-inflammatory activity after a variety of injuries, acting in part by antagonizing the NF-B pathway. In urothelial cells, it has been shown that PPARG promotes urothelial differentiation in vitro, but its function in vivo remains unexplored. To determine the role of PPARG in vivo, we used Cre-Lox recombination to conditionally delete the Pparg gene in the mouse urothelium using the ShhCre driver, which drives recombination in basal and intermediate cells, and their respective daughters. Interestingly, ShhCre;Ppargfl/fl mutants lack umbrella and intermediate cells which normally populate the luminal and sub-luminal layers, and are instead populated with an abnormal cell population negative for classical urothelial markers. The basal compartment, which in wild type mice is largely populated by P63+ KRT5+ basal cells with a small sub-population expressing KRT14; has an increased number of KRT14-expressing cells in the mutants and exhibits squamous features that are not present in the normal urothelium. In wild type animals, urinary tract infection (UTI) with uropathogenic E.coli results in a transient innate immune response, followed by proliferation and repair, which is largely complete within 2 weeks. When ShhCre;Ppargfl/fl mutants were challenged with urinary tract infection, the innate immune response was not resolved even after several weeks, as characterized by persistent NF-B activity, excessive influx of neutrophils and macrophages, and massive granulation tissue in the stroma. In addition, the Pparg-knockout urothelium exhibited squamous metaplasia. The Krt14+ basal cell population, which is considered to be the cells of origin of bladder cancer, greatly expanded in the Pparg-deleted urothelium after infection, and some lesions progressed to acquire invasive features. Together these findings suggest that PPARG is essential for the normal differentiation of the urothelium and is a potent regulator of the inflammatory response after UTI. Understanding the link between the loss of PPARG, chronic inflammation and tumorigenesis in the urothelium could shed light on the urothelial differentiation network and pave the way for the development of therapeutic approaches to various urinary diseases

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 243)

This bibliography lists 282 reports, articles and other documents introduced into the NASA scientific and technical information system in February 1983

Integrated Water Resources Research

Anthropogenic and natural disturbances to freshwater quantity and quality are a greater issue for society than ever before. To successfully restore water resources requires understanding the interactions between hydrology, climate, land use, water quality, ecology, and social and economic pressures. This Special Issue of Water includes cutting edge research broadly addressing investigative areas related to experimental study designs and modeling, freshwater pollutants of concern, and human dimensions of water use and management. Results demonstrate the immense, globally transferable value of the experimental watershed approach, the relevance and critical importance of current integrated studies of pollutants of concern, and the imperative to include human sociological and economic processes in water resources investigations. In spite of the latest progress, as demonstrated in this Special Issue, managers remain insufficiently informed to make the best water resource decisions amidst combined influences of land use change, rapid ongoing human population growth, and changing environmental conditions. There is, thus, a persistent need for further advancements in integrated and interdisciplinary research to improve the scientific understanding, management, and future sustainability of water resources

Hardware and software integration and testing for the automation of bright-field microscopy for tuberculosis detection

Automated microscopy for the detection of tuberculosis (TB) in sputum smears would reduce the load on technicians, especially in countries with a high TB burden. This dissertation reports on the development and testing of an automated system built around a conventional microscope for the detection of TB in Ziehl-Neelsen (ZN) stained sputum smears. Microscope auto-focusing, image analysis and stage movement were integrated. Images were captured at 40x magnification