Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses.

Although it has recently been shown that A/J mice are highly susceptible to Staphylococcus aureus sepsis as compared to C57BL/6J, the specific genes responsible for this differential phenotype are unknown. Using chromosome substitution strains (CSS), we found that loci on chromosomes 8, 11, and 18 influence susceptibility to S. aureus sepsis in A/J mice. We then used two candidate gene selection strategies to identify genes on these three chromosomes associated with S. aureus susceptibility, and targeted genes identified by both gene selection strategies. First, we used whole genome transcription profiling to identify 191 (56 on chr. 8, 100 on chr. 11, and 35 on chr. 18) genes on our three chromosomes of interest that are differentially expressed between S. aureus-infected A/J and C57BL/6J. Second, we identified two significant quantitative trait loci (QTL) for survival post-infection on chr. 18 using N(2) backcross mice (F(1) [C18A]xC57BL/6J). Ten genes on chr. 18 (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTL regions and were also identified by the expression array selection strategy. Using real-time PCR, 6 of these 10 genes (Chmp1b, Dtwd2, Isoc1, Lman1, Tnfaip8, and Seh1l) showed significantly different expression levels between S. aureus-infected A/J and C57BL/6J. For two (Tnfaip8 and Seh1l) of these 6 genes, siRNA-mediated knockdown of gene expression in S. aureus-challenged RAW264.7 macrophages induced significant changes in the cytokine response (IL-1 beta and GM-CSF) compared to negative controls. These cytokine response changes were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18 mice (which contain A/J chromosome 18 but are otherwise C57BL/6J), but not C57BL/6J mice. These findings suggest that two genes, Tnfaip8 and Seh1l, may contribute to susceptibility to S. aureus in A/J mice, and represent promising candidates for human genetic susceptibility studies.

Environmental impacts of the coal ash spill in Kingston, Tennessee: an 18-month survey.

An 18 month investigation of the environmental impacts of the Tennessee Valley Authority (TVA) coal ash spill in Kingston, Tennessee combined with leaching experiments on the spilled TVA coal ash have revealed that leachable coal ash contaminants (LCACs), particularly arsenic, selenium, boron, strontium, and barium, have different effects on the quality of impacted environments. While LCACs levels in the downstream river water are relatively low and below the EPA drinking water and ecological thresholds, elevated levels were found in surface water with restricted water exchange and in pore water extracted from the river sediments downstream from the spill. The high concentration of arsenic (up to 2000 μg/L) is associated with some degree of anoxic conditions and predominance of the reduced arsenic species (arsenite) in the pore waters. Laboratory leaching simulations show that the pH and ash/water ratio control the LCACs' abundance and geochemical composition of the impacted water. These results have important implications for the prediction of the fate and migration of LCACs in the environment, particularly for the storage of coal combustion residues (CCRs) in holding ponds and landfills, and any potential CCRs effluents leakage into lakes, rivers, and other aquatic systems.

Exhausted CD8 T cells downregulate the IL-18 receptor and become unresponsive to inflammatory cytokines and bacterial co-infections.

During many chronic infections virus-specific CD8 T cells succumb to exhaustion as they lose their ability to respond to antigenic activation. Combinations of IL-12, IL-18, and IL-21 have been shown to induce the antigen-independent production of interferon (IFN)-γ by effector and memory CD8 T cells. In this study we investigated whether exhausted CD8 T cells are sensitive to activation by these cytokines. We show that effector and memory, but not exhausted, CD8 T cells produce IFN-γ and upregulate CD25 following exposure to certain combinations of IL-12, IL-18, and IL-21. The unresponsiveness of exhausted CD8 T cells is associated with downregulation of the IL-18-receptor-α (IL-18Rα). Although IL-18Rα expression is connected with the ability of memory CD8 T cells to self-renew and efflux rhodamine 123, the IL-18Rα(lo) exhausted cells remained capable of secreting this dye. To further evaluate the consequences of IL-18Rα downregulation, we tracked the fate of IL-18Rα-deficient CD8 T cells in chronically infected mixed bone marrow chimeras and discovered that IL-18Rα affects the initial but not later phases of the response. The antigen-independent responsiveness of exhausted CD8 T cells was also investigated following co-infection with Listeria monocytogenes, which induces the expression of IL-12 and IL-18. Although IL-18Rα(hi) memory cells upregulated CD25 and produced IFN-γ, the IL-18Rα(lo) exhausted cells failed to respond. Collectively, these findings indicate that as exhausted T cells adjust to the chronically infected environment, they lose their susceptibility to antigen-independent activation by cytokines, which compromises their ability to detect bacterial co-infections.

Paleoenvironmental reconstruction of the coastal Monte Léon and Santa Cruz formations (Early Miocene) at Rincón del Buque, Southern Patagonia: A revisited locality

© 2015 Elsevier Ltd.Sedimentological, ichnological and paleontological analyses of the Early Miocene uppermost Monte León Formation and the lower part of the Santa Cruz Formation were carried out in Rincón del Buque (RDB), a fossiliferous locality north of Río Coyle in Santa Cruz Province, Patagonia, Argentina. This locality is of special importance because it contains the basal contact between the Monte Léon (MLF) and the Santa Cruz (SCF) formations and because it preserves a rich fossil assemblage of marine invertebrates and marine trace fossils, and terrestrial vertebrates and plants, which has not been extensively studied. A ~90m-thick section of the MLF and the SCF that crops out at RDB was selected for this study. Eleven facies associations (FA) are described, which are, from base to top: subtidal-intertidal deposits with Crassotrea orbignyi and bioturbation of the Skolithos-Cruziana ichnofacies (FA1); tidal creek deposits with terrestrial fossil mammals and Ophiomorpha isp. burrows (FA2); tidal flat deposits with Glossifungites ichnofacies (FA3); deposits of tidal channels (FA4) and tidal sand flats (FA5) both with and impoverish Skolithos ichnofacies associated; marsh deposits (FA6); tidal point bar deposits recording a depauperate mixture of both the Skolithos and Cruziana ichnofacies (FA7); fluvial channel deposits (FA8); fluvial point bar deposits (FA9); floodplain deposits (FA10); and pyroclastic and volcaniclastic deposits of the floodplain where terrestrial fossil mammal remains occur (FA11).The transition of the MLF-SCF at RDB reflects a changing depositional environment from the outer part of an estuary (FA1) through the central (FA2-6) to inner part of a tide-dominated estuary (FA7). Finally a fluvial system occurs with single channels of relatively low energy and low sinuosity enclosed by a broad, low-energy floodplain dominated by partially edaphized ash-fall, sheet-flood, and overbank deposits (FA8-11). Pyroclastic and volcaniclastic materials throughout the succession must have been deposited as ash-fall distal facies in a fluvial setting and also were carried by fluvial streams and redeposited in both estuarine and fluvial settings. These materials preserve most of the analyzed terrestrial fossil mammals that characterize the Santacrucian age of the RDB's succession. Episodic sedimentation under volcanic influence, high sedimentation rates and a relatively warm and seasonal climate are inferred for the MLF and SCF section.Lateral continuity of the marker horizons at RDB serve for correlation with other coastal localities such as the lower part of the coastal SCF south of Río Coyle (~17.6-17.4Ma) belonging to the Estancia La Costa Member of the SCF.