Environmental release, fate and ecotoxicological effects of manufactured ceria nanomaterials

Recent interest in the environmental fate and effects of manufactured CeO2 nanomaterials (nanoceria) has stemmed from its expanded use for a variety of applications including fuel additives, catalytic converters, chemical and mechanical planarization media and other uses. This has led to a wave of publications on the toxicological effects of nanoceria in ecological receptor species, but only limited information is available on possible environmental releases, concentrations in environmental media, or environmental transformations. In this paper, we make initial estimates of likely environmental releases and exposure concentrations in soils and water and compare them to published toxicity values. Insufficient information was available to estimate aquatic exposures, but we estimated inputs to a hypothetical wastewater treatment plant that could result in effluent concentrations that would result in acute toxicity to the most sensitive aquatic organisms tested so far, cyanobacteria. The purpose of this exercise is to identify which areas are lacking in data to perform either regional or site specific ecological risk assessments. While estimates can be made for releases from use as a diesel fuel additive, and predicted toxicity is low in most terrestrial species tested to date, estimates for releases from other uses are difficult at this stage. We recommend that future studies focus on environmentally realistic exposures that take into account potential environmental transformations of the nanoceria surface as well as chronic toxicity studies in benthic aquatic organisms, soil invertebrates and microorgansims

De Novo Formation of Insulin-Producing “Neo-β Cell Islets” from Intestinal Crypts

SUMMARY The ability to interconvert terminally differentiated cells could serve as a powerful tool for cell-based treatment of degenerative diseases, including diabetes mellitus. To determine which, if any, adult tissues are competent to activate an islet β cell program, we performed an in vivo screen by expressing three β cell “reprogramming factors” in a wide spectrum of tissues. We report that transient intestinal expression of these factors—Pdx1, MafA, and Ngn3 (PMN)—promotes rapid conversion of intestinal crypt cells into endocrine cells, which coalesce into “neoislets” below the crypt base. Neoislet cells express insulin and show ultrastructural features of β cells. Importantly, intestinal neoislets are glucose-responsive and able to ameliorate hyperglycemia in diabetic mice. Moreover, PMN expression in human intestinal “organoids” stimulates the conversion of intestinal epithelial cells into β-like cells. Our results thus demonstrate that the intestine is an accessible and abundant source of functional insulin-producing cells

APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death

p53 is a transcriptional activator which has been implicated as a key regulator of neuronal cell death after acute injury. We have shown previously that p53-mediated neuronal cell death involves a Bax-dependent activation of caspase 3; however, the transcriptional targets involved in the regulation of this process have not been identified. In the present study, we demonstrate that p53 directly upregulates Apaf1 transcription as a critical step in the induction of neuronal cell death. Using DNA microarray analysis of total RNA isolated from neurons undergoing p53-induced apoptosis a 5–6-fold upregulation of Apaf1 mRNA was detected. Induction of neuronal cell death by camptothecin, a DNA-damaging agent that functions through a p53-dependent mechanism, resulted in increased Apaf1 mRNA in p53-positive, but not p53-deficient neurons. In both in vitro and in vivo neuronal cell death processes of p53-induced cell death, Apaf1 protein levels were increased. We addressed whether p53 directly regulates Apaf1 transcription via the two p53 consensus binding sites in the Apaf1 promoter. Electrophoretic mobility shift assays demonstrated p53–DNA binding activity at both p53 consensus binding sequences in extracts obtained from neurons undergoing p53-induced cell death, but not in healthy control cultures or when p53 or the p53 binding sites were inactivated by mutation. In transient transfections in a neuronal cell line with p53 and Apaf1 promoter–luciferase constructs, p53 directly activated the Apaf1 promoter via both p53 sites. The importance of Apaf1 as a p53 target gene in neuronal cell death was evaluated by examining p53-induced apoptotic pathways in primary cultures of Apaf1-deficient neurons. Neurons treated with camptothecin were significantly protected in the absence of Apaf1 relative to those derived from wild-type littermates. Together, these results demonstrate that Apaf1 is a key transcriptional target for p53 that plays a pivotal role in the regulation of apoptosis after neuronal injury

Fundamentals of reservoir surface energy as related to surface properties, wettability, capillary action, and oil recovery from fractured reservoirs by spontaneous imbibition

The objective of this project is to increase oil recovery from fractured reservoirs through improved fundamental understanding of the process of spontaneous imbibition by which oil is displaced from the rock matrix into the fractures. Spontaneous imbibition is fundamentally dependent on the reservoir surface free energy but this has never been investigated for rocks. In this project, the surface free energy of rocks will be determined by using liquids that can be solidified within the rock pore space at selected saturations. Thin sections of the rock then provide a two-dimensional view of the rock minerals and the occupant phases. Saturations and oil/rock, water/rock, and oil/water surface areas will be determined by advanced petrographic analysis and the surface free energy which drives spontaneous imbibition will be determined as a function of increase in wetting phase saturation. The inherent loss in surface free energy resulting from capillary instabilities at the microscopic (pore level) scale will be distinguished from the decrease in surface free energy that drives spontaneous imbibition. A mathematical network/numerical model will be developed and tested against experimental results of recovery versus time over broad variation of key factors such as rock properties, fluid phase viscosities, sample size, shape and boundary conditions. Two fundamentally important, but not previously considered, parameters of spontaneous imbibition, the capillary pressure acting to oppose production of oil at the outflow face and the pressure in the non-wetting phase at the no-flow boundary versus time, will also be measured and modeled. Simulation and network models will also be tested against special case solutions provided by analytic models. In the second stage of the project, application of the fundamental concepts developed in the first stage of the project will be demonstrated. The fundamental ideas, measurements, and analytic/numerical modeling will be applied to mixed-wet rocks. Imbibition measurements will include novel sensitive pressure measurements designed to elucidate the basic mechanisms that determine induction time and drive the very slow rate of spontaneous imbibition commonly observed for mixed-wet rocks. In further demonstration of concepts, three approaches to improved oil recovery from fractured reservoirs will be tested; use of surfactants to promote imbibition in oil wet rocks by wettability alteration: manipulation of injection brine composition: reduction of the capillary back pressure which opposes production of oil at the fracture face

The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts

Objective: To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART). Design: Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women's Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively. Methods: Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era. Results: Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2-2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3-1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8-2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02-8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3-1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5-2.4; p<0.001). Conclusion: HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality. © 2013 Gingo et al