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

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

Isolation of a natural DNA virus of <i>Drosophila melanogaster</i>, and characterisation of host resistance and immune responses

<div><p><i>Drosophila melanogaster</i> has played a key role in our understanding of invertebrate immunity. However, both functional and evolutionary studies of host-virus interaction in <i>Drosophila</i> have been limited by a dearth of native virus isolates. In particular, despite a long history of virus research, DNA viruses of <i>D</i>. <i>melanogaster</i> have only recently been described, and none have been available for experimental study. Here we report the isolation and comprehensive characterisation of Kallithea virus, a large double-stranded DNA virus, and the first DNA virus to have been reported from wild populations of <i>D</i>. <i>melanogaster</i>. We find that Kallithea virus infection is costly for adult flies, reaching high titres in both sexes and disproportionately reducing survival in males, and movement and late fecundity in females. Using the <i>Drosophila</i> Genetic Reference Panel, we quantify host genetic variance for virus-induced mortality and viral titre and identify candidate host genes that may underlie this variation, including <i>Cdc42-interacting protein 4</i>. Using full transcriptome sequencing of infected males and females, we examine the transcriptional response of flies to Kallithea virus infection and describe differential regulation of virus-responsive genes. This work establishes Kallithea virus as a new tractable model to study the natural interaction between <i>D</i>. <i>melanogaster</i> and DNA viruses, and we hope it will serve as a basis for future studies of immune responses to DNA viruses in insects.</p></div

β-1,3-Glucan-Induced Host Phospholipase D Activation Is Involved in Aspergillus fumigatus Internalization into Type II Human Pneumocyte A549 Cells

The internalization of Aspergillus fumigatus into lung epithelial cells is a process that depends on host cell actin dynamics. The host membrane phosphatidylcholine cleavage driven by phospholipase D (PLD) is closely related to cellular actin dynamics. However, little is known about the impact of PLD on A. fumigatus internalization into lung epithelial cells. Here, we report that once germinated, A. fumigatus conidia were able to stimulate host PLD activity and internalize more efficiently in A549 cells without altering PLD expression. The internalization of A. fumigatus in A549 cells was suppressed by the downregulation of host cell PLD using chemical inhibitors or siRNA interference. The heat-killed swollen conidia, but not the resting conidia, were able to activate host PLD. Further, β-1,3-glucan, the core component of the conidial cell wall, stimulated host PLD activity. This PLD activation and conidia internalization were inhibited by anti-dectin-1 antibody. Indeed, dectin-1, a β-1,3-glucan receptor, was expressed in A549 cells, and its expression profile was not altered by conidial stimulation. Finally, host cell PLD1 and PLD2 accompanied A. fumigatus conidia during internalization. Our data indicate that host cell PLD activity induced by β-1,3-glucan on the surface of germinated conidia is important for the efficient internalization of A. fumigatus into A549 lung epithelial cells

Host-Adaptation of Francisella tularensis Alters the Bacterium's Surface-Carbohydrates to Hinder Effectors of Innate and Adaptive Immunity

The gram-negative bacterium Francisella tularensis survives in arthropods, fresh water amoeba, and mammals with both intracellular and extracellular phases and could reasonably be expected to express distinct phenotypes in these environments. The presence of a capsule on this bacterium has been controversial with some groups finding such a structure while other groups report that no capsule could be identified. Previously we reported in vitro culture conditions for this bacterium which, in contrast to typical methods, yielded a bacterial phenotype that mimics that of the bacterium's mammalian, extracellular phase.SDS-PAGE and carbohydrate analysis of differentially-cultivated F. tularensis LVS revealed that bacteria displaying the host-adapted phenotype produce both longer polymers of LPS O-antigen (OAg) and additional HMW carbohydrates/glycoproteins that are reduced/absent in non-host-adapted bacteria. Analysis of wildtype and OAg-mutant bacteria indicated that the induced changes in surface carbohydrates involved both OAg and non-OAg species. To assess the impact of these HMW carbohydrates on the access of outer membrane constituents to antibody we used differentially-cultivated bacteria in vitro to immunoprecipitate antibodies directed against outer membrane moieties. We observed that the surface-carbohydrates induced during host-adaptation shield many outer membrane antigens from binding by antibody. Similar assays with normal mouse serum indicate that the induced HMW carbohydrates also impede complement deposition. Using an in vitro macrophage infection assay, we find that the bacterial HMW carbohydrate impedes TLR2-dependent, pro-inflammatory cytokine production by macrophages. Lastly we show that upon host-adaptation, the human-virulent strain, F. tularensis SchuS4 also induces capsule production with the effect of reducing macrophage-activation and accelerating tularemia pathogenesis in mice.F. tularensis undergoes host-adaptation which includes production of multiple capsular materials. These capsules impede recognition of bacterial outer membrane constituents by antibody, complement, and Toll-Like Receptor 2. These changes in the host-pathogen interface have profound implications for pathogenesis and vaccine development

The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukaemia

Cytarabine (AraC) represents the most effective single agent treatment for AML. Nevertheless, overriding AraC resistance in AML remains an unmet medical need. Here we show that the CHK1 inhibitor (CHK1i) GDC-0575 enhances AraC-mediated killing of AML cells both in vitro and in vivo, thus abrogating any potential chemoresistance mechanisms involving DNA repair. Importantly, this combination of drugs does not affect normal long-term hematopoietic stem/progenitors. Moreover, the addition of CHK1i to AraC does not generate de novo mutations and in patients' samples where AraC is mutagenic, addition of CHK1i appears to eliminate the generation of mutant clones. Finally, we observe that persistent residual leukemic cells are quiescent and can become responsive to the treatment when forced into cycle via granulocyte colony-stimulating factor (G-CSF) administration. This drug combination (AraC+CHK1i+G-CSF) will open the doors for a more efficient treatment of AML in the clinic