Protein Kinase C and Toll-Like Receptor Signaling

Protein kinase C (PKC) is a family of kinases that are implicated in a plethora of diseases, including cancer and cardiovascular disease. PKC isoforms can have different, and sometimes opposing, effects in these disease states. Toll-like receptors (TLRs) are a family of pattern recognition receptors that bind pathogens and stimulate the secretion of cytokines. It has long been known that PKC inhibitors reduce LPS-stimulated cytokine secretion by macrophages, linking PKC activation to TLR signaling. Recent studies have shown that PKC-α, -δ, -ε, and -ζ are directly involved in multiple steps in TLR pathways. They associate with the TLR or proximal components of the receptor complex. These isoforms are also involved in the downstream activation of MAPK, RhoA, TAK1, and NF-κB. Thus, PKC activation is intimately involved in TLR signaling and the innate immune response

Distribution and origin of natural gas leakage in the Colorado Basin, offshore Argentina Margin, South America : seismic interpretation and 3D basin modelling

The detailed analysis of a dense 2D seismic reflection dataset and data from 8 exploration wells, allowed us to identify, map out and characterize possible indications of past and present-day hydrocarbon leakage (i.e. gas chimneys, gas pockets, and seafloor mounds and pockmarks) on the continental shelf and slope of the Colorado Basin, offshore Argentina, where Permian, Jurassic and Early Cretaceous source rocks are potentially present and may be currently mature. Identified gas leakage features, developed both in the syn-rift and post-rift successions, were also analysed in relation to the structural the stratigraphic elements of the basin. A family of seabed pockmarks, located close to an array of submarine channels, was identified on the distal slope of the basin. These pockmarks are overlying a series of sub-vertical to vertical seismic chimneys in the subsurface. A calibrated basin-wide 3D petroleum system model comprising generation and migration of hydrocarbons was carried out and compared with the observations from the seismic analysis. Preliminary results from this model indicate that although synrift and early Cretaceous source rock (SR) intervals may be depleted in the central areas of the basin, an active kitchen from the Aptian SR may be present below the slope areas. Hydrocarbon migration pathways predicted by the 3D model (Hybrid method) coincide with the interpreted seismic chimneys underlying the observed seabed slope pockmarks. Hence, our results indicate that thermogenic gas may be currently generated in the distal slope of the basin from mature early post-rift source rocks within the Early Cretaceous (Aptian) sequences and migrates vertically, due to seal failure, through the stratigraphic column. This migrating thermogenic gas is feeding the seafloor pockmarks identified in the distal slope of the basin, although up-dip lateral migration along stratigraphic layers to the more proximal slope areas cannot be ruled out. The present work represents the first published study integrating detailed seismic analysis and 3D basin modelling linking observed gas-leakage indicators and associated seepage pathways, to their relative abundance, distribution and feeding systems offshore Argentina's continental margin

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Protein kinase C (PKC) is a family of kinases that are implicated in a plethora of diseases, including cancer and cardiovascular disease. PKC isoforms can have different, and sometimes opposing, effects in these disease states. Toll-like receptors (TLRs) are a family of pattern recognition receptors that bind pathogens and stimulate the secretion of cytokines. It has long been known that PKC inhibitors reduce LPS-stimulated cytokine secretion by macrophages, linking PKC activation to TLR signaling. Recent studies have shown that PKC-α, -δ, -ε, and -ζ are directly involved in multiple steps in TLR pathways. They associate with the TLR or proximal components of the receptor complex. These isoforms are also involved in the downstream activation of MAPK, RhoA, TAK1, and NF-κB. Thus, PKC activation is intimately involved in TLR signaling and the innate immune response

Tectonic evolution of the Colorado Basin, offshore Argentina, inferred from seismo-stratigraphy and depositional rates analysis

International audienceBased on a dense 2D seismic reflection dataset and information from 8 exploration wells, we reinterpreted the stratigraphic evolution of the Colorado Basin. The basin is located on the continental shelf and slope within 50 to 2250 m of bathymetry. The total sediment fill can be up to 16,000 m. Seismic-to-well log correlations provide a chrono-stratigraphic framework for the interpreted seismic sequences. We show that the Colorado Basin records the development of a Permian pre-rift period, a Triassic/Jurassic to Early Cretaceous rift phase and a Lower Cretaceous to Tertiary drift phase. This passive margin represents the evolution of lithospheric extension from active rifting to the thermal subsidence/drift stage. Several Cretaceous to Cenozoic slumping episodes were identified and related to progradation of the sequences and sediment build-up in the slope, as well as to the development of seaward dipping extensional faults

Colorado Basin 3D structure and evolution, Argentine passive margin

International audienceThis 3D structural model of the Colorado Basin provides new insights into the crustal geometry of the basin and its evolution in relation with the Argentine passive margin. Three NW-SE segments (oblique to the N30°E-trending margin) structure the basin. The oldest infill is generally thought to be coeval with the rifting of the South Atlantic margins in Late Jurassic-Early Cretaceous. This coeval development of the Colorado Basin and of the passive margin is still under debate and gives rise to several hypotheses that we investigate in the light of our observations. We propose that reactivation of inherited structures is predominant in the evolution of the Colorado Basin: (1) the Western segment follows the continental continuation of the Colorado transfer zone; (2) the Central segment consists in the continental continuation of the Tona deformation zone; (3) the Eastern segment is superimposed over the Palaeozoic Claromecó Basin. In addition to the 3 segments, the Central High, separating the Central segment to the Eastern segment, corresponds to the Palaeozoic Sierras Australes Fold Belt. The direction of extension responsible for the South Atlantic opening cannot explain the syn-rift infill and thinning of the basin. The structural analysis shows two phases of syn-rift deformation with different directions. Thus, we suggest that the Colorado Basin and the South Atlantic margin are not coeval but that a first extensional event, probably oblique, predates the extension responsible for the South Atlantic opening. This event is then followed by the formation of the N30°-trending distal margin and the reactivation of Palaeozoic N70°-trending faults occurs under the NW-SE opening of the South Atlantic. This two-phase evolution is consistent with the fault chronology and the two directions of thinned crust observed in the distal margin

Variables associated with nest survival of Golden-winged Warblers (Vermivora chrysoptera) among vegetation communities commonly used for nesting

Among shrubland- and young forest-nesting bird species in North America, Golden-winged Warblers (Vermivora chrysoptera) are one of the most rapidly declining partly because of limited nesting habitat. Creation and management of high quality vegetation communities used for nesting are needed to reduce declines. Thus, we examined whether common characteristics could be managed across much of the Golden-winged Warbler’s breeding range to increase daily survival rate (DSR) of nests. We monitored 388 nests on 62 sites throughout Minnesota, Wisconsin, New York, North Carolina, Pennsylvania, Tennessee, and West Virginia. We evaluated competing DSR models in spatial-temporal (dominant vegetation type, population segment, state, and year), intraseasonal (nest stage and time-within-season), and vegetation model suites. The best-supported DSR models among the three model suites suggested potential associations between daily survival rate of nests and state, time-within-season, percent grass and Rubus cover within 1 m of the nest, and distance to later successional forest edge. Overall, grass cover (negative association with DSR above 50%) and Rubus cover (DSR lowest at about 30%) within 1 m of the nest and distance to later successional forest edge (negative association with DSR) may represent common management targets across our states for increasing Golden-winged Warbler DSR, particularly in the Appalachian Mountains population segment. Context-specific adjustments to management strategies, such as in wetlands or areas of overlap with Blue-winged Warblers (Vermivora cyanoptera), may be necessary to increase DSR for Golden-winged Warblers

Ligation of Macrophage Fcγ Receptors Recapitulates the Gene Expression Pattern of Vulnerable Human Carotid Plaques

Stroke is a leading cause of death in the United States. As ∼60% of strokes result from carotid plaque rupture, elucidating the mechanisms that underlie vulnerability is critical for therapeutic intervention. We tested the hypothesis that stable and vulnerable human plaques differentially express genes associated with matrix degradation. Examination established that femoral, and the distal region of carotid, plaques were histologically stable while the proximal carotid plaque regions were vulnerable. Quantitative RT-PCR was used to compare expression of 22 genes among these tissues. Distal carotid and femoral gene expression was not significantly different, permitting the distal carotid segments to be used as a paired control for their corresponding proximal regions. Analysis of the paired plaques revealed differences in 16 genes that impact plaque stability: matrix metalloproteinases (MMP, higher in vulnerable), MMP modulators (inhibitors: lower, activators: higher in vulnerable), activating Fc receptors (FcγR, higher in vulnerable) and FcγR signaling molecules (higher in vulnerable). Surprisingly, the relative expression of smooth muscle cell and macrophage markers in the three plaque types was not significantly different, suggesting that macrophage distribution and/or activation state correlates with (in)stability. Immunohistochemistry revealed that macrophages and smooth muscle cells localize to distinct and non-overlapping regions in all plaques. MMP protein localized to macrophage-rich regions. In vitro, treatment of macrophages with immune complexes, but not oxidized low density lipoprotein, C-reactive protein, or TNF-α, induced a gene expression profile similar to that of the vulnerable plaques. That ligation of FcγR recapitulates the pattern of gene expression in vulnerable plaques suggests that the FcγR → macrophage activation pathway may play a greater role in human plaque vulnerability than previously appreciated

Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example

Idiosyncratic drug reactions (IDRs) are poorly understood, unpredictable, and not detected in preclinical studies. Although the cause of these reactions is likely multi-factorial, one hypothesis is that an underlying inflammatory state lowers the tolerance to a xenobiotic. Previously used in an inflammation IDR model, bacterial lipopolysaccharide (LPS) is heterogeneous in nature, making development of standardized testing protocols difficult. Here, the use of rat tumor necrosis factor-α (TNFα) to replace LPS as an inflammatory stimulus was investigated. Sprague-Dawley rats were treated with separate preparations of LPS or TNFα, and hepatic transcriptomic effects were compared. TNFα showed enhanced consistency at the transcriptomic level compared to LPS. TNFα and LPS regulated similar biochemical pathways, although LPS was associated with more robust inflammatory signaling than TNFα. Rats were then codosed with TNFα and trovafloxacin (TVX), an IDR-associated drug, and evaluated by liver histopathology, clinical chemistry, and gene expression analysis. TNFα/TVX induced unique gene expression changes that clustered separately from TNFα/levofloxacin, a drug not associated with IDRs. TNFα/TVX cotreatment led to autoinduction of TNFα resulting in potentiation of underlying gene expression stress signals. Comparison of TNFα/TVX and LPS/TVX gene expression profiles revealed similarities in the regulation of biochemical pathways. In conclusion, TNFα could be used in lieu of LPS as an inflammatory stimulus in this model of IDRs