bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Antituberculosis Drug Pyrazinamide Affects the Course of Cutaneous Leishmaniasis In Vivo and Increases Activation of Macrophages and Dendritic Cells
Authors: Mendez Susana , Traslavina Ryan , Hinchman Meleana , Huang Lu , Green Patricia , Cynamon Michael H. , Welch John T. 
Published: September 2009

ABSTRACT

Antileishmanial therapy is suboptimal due to toxicity, high cost, and development of resistance to available drugs. Pyrazinamide (PZA) is a constituent of short-course tuberculosis chemotherapy. We investigated the effect of PZA on
Leishmania major
promastigote and amastigote survival. Promastigotes were more sensitive to the drug than amastigotes, with concentrations at which 50% of parasites were inhibited (MIC
50
) of 16.1 and 8.2 μM, respectively (48 h posttreatment). Moreover, 90% of amastigotes were eliminated at 120 h posttreatment, indicating that longer treatments will result in parasite elimination. Most strikingly, PZA treatment of infected C57BL/6 mice resulted in protection against disease and in a 100-fold reduction in the parasite burden. PZA treatment of J774 cells and bone marrow-derived dendritic cells and macrophages increased interleukin 12, tumor necrosis factor alpha, and activation marker expression, as well as nitric oxide production, suggesting that PZA enhances effective immune responses against the parasite. PZA treatment also activates dendritic cells deficient in Toll-like receptor 2 and 4 expression to initiate a proinflammatory response, confirming that the immunostimulatory effect of PZA is directly caused by the drug and is independent of Toll-like receptor stimulation. These results not only are strongly indicative of the promise of PZA as an alternative antileishmanial chemotherapy but also suggest that PZA causes collateral immunostimulation, a phenomenon that has never been reported for this drug.
Antiapoptotic Proteins Bcl-2 and Bcl-X
L
Inhibit
Clostridium difficile
Toxin A-Induced Cell Death in Human Epithelial Cells
Authors: Matte Isabelle , Lane Denis , Côté Élodie , Asselin Ann-Élise , Fortier Louis-Charles , Asselin Claude , Piché Alain 
Published: September 2009

ABSTRACT

It has been well established that
Clostridium difficile
toxin A (TcdA) induces cell death in human epithelial cells. However, the mechanism of TcdA-induced cell death remains to be fully characterized. Here, we show that TcdA induces dose-dependent cell death in ovarian carcinoma and colonic carcinoma cell lines. TcdA-mediated cell death, as well as caspase 8 and caspase 3 activation, were specifically abrogated by anti-toxin antibodies. Although caspase 8 and caspase 3 were activated by TcdA in OVCAR3 ovarian carcinoma and T84 colonic cancer cells, pancaspase and caspase 8, 3, and 9 inhibitors did not block TcdA-induced cell death. In contrast, tumor necrosis factor-related apoptosis-inducing ligand-induced cell death was nearly completely blocked by caspase inhibitors in OVCAR3 cells. In these cells, TcdA induces the mitochondrial pathway of apoptosis, as demonstrated by changes in mitochondrial outer membrane permeabilization (MOMP). Furthermore, overexpression of the antiapoptotic proteins Bcl-2 and Bcl-X
L
significantly inhibited TcdA-induced cell death, as well as TcdA-induced MOMP. Conversely, small interfering RNA-mediated inhibition of Bcl-X
L
in TcdA-resistant SKOV3ip1 cells enhanced TcdA-induced cell death. Overexpression of the antiapoptotic proteins Bcl-2 and Bcl-X
L
in T84 cells also inhibited TcdA-induced cell death. Altogether, our data demonstrate that TcdA induces cell death in both ovarian and colonic cancer cells preferentially via the mitochondrial pathway of apoptosis by a death receptor-independent and a caspase-independent mechanism. This process is regulated by antiapoptotic members of the Bcl-2 family.
Toll-Like Receptor Signaling in Airborne
Burkholderia thailandensis
Infection
Authors: West T. Eoin , Hawn Thomas R. , Skerrett Shawn J. 
Published: September 2009

ABSTRACT

Melioidosis is a tropical disease endemic in southeast Asia and northern Australia caused by the gram-negative soil saprophyte
Burkholderia pseudomallei
. Although infection is often systemic, the lung is frequently involved.
B. thailandensis
is a closely related organism that at high doses causes lethal pneumonia in mice. We examined the role of Toll-like receptors (TLRs), essential components of innate immunity, in vitro and in vivo during murine
B. thailandensis
pneumonia. TLR2, TLR4, and TLR5 mediate NF-κB activation by
B. thailandensis
in transfected HEK293 or CHO cells. In macrophages, TLR4 and the adaptor molecule MyD88, but not TLR2 or TLR5, are required for tumor necrosis factor alpha production induced by
B. thailandensis
. In low-dose airborne infection, TLR4 is needed for early, but not late, bacterial containment, and MyD88 is essential for control of infection and host survival. TLR2 and TLR5 are not necessary to contain low-dose infection. In high-dose airborne infection, TLR2 deficiency confers a slight survival advantage. Lung and systemic inflammatory responses are induced by low-dose inhaled
B. thailandensis
independently of individual TLRs or MyD88. These findings suggest that redundancy in TLR signaling or other MyD88-dependent pathways may be important in pneumonic
B. thailandensis
infection but that MyD88-independent mechanisms of inflammation are also activated. TLR signaling in
B. thailandensis
infection is substantially comparable to signaling induced by virulent
B. pseudomallei
. These studies provide additional insights into the host-pathogen interaction in pneumonic
Burkholderia
infection.
OmpA of Uropathogenic
Escherichia coli
Promotes Postinvasion Pathogenesis of Cystitis
Authors: Nicholson Tracy F. , Watts Kristin M. , Hunstad David A. 
Published: September 2009

ABSTRACT

Type 1 pilus directs bladder epithelial binding and invasion by uropathogenic
Escherichia coli
(UPEC) in the initial stage of cystitis, but the bacterial determinants of postinvasion events in the pathogenesis of cystitis are largely undetermined. We show here that the UPEC outer membrane protein A (OmpA), a monomeric, major, integral protein component of the bacterial outer membrane, functions as a critical determinant of intracellular virulence for UPEC, promoting persistent infection within bladder epithelium. Using a murine urinary tract infection (UTI) model, we demonstrate that whereas deletion of the UPEC
ompA
gene did not disrupt initial epithelial binding and invasion by UPEC, it did preclude completion of the intracellular bacterial community (IBC) pathway, accompanied by diminishing bacterial loads in the bladder. This defect in epithelial persistence of the
ompA
mutant was enhanced in competitive infections with wild-type UPEC. Microscopic examinations revealed that the
ompA
mutant formed significantly fewer IBCs, and those that were initiated were unable to progress past the early stages of maturation. These defects could be corrected by complementation of
ompA
. In addition, expression of
ompA
during wild-type UTI was sharply increased at time points correlated with IBC development and the arrival of host immune effector cells. Our findings establish OmpA as a key UPEC virulence factor that functions after epithelial invasion to facilitate IBC maturation and chronic bacterial persistence.
Bacterial Growth Rate and Host Factors as Determinants of Intracellular Bacterial Distributions in SystemicSalmonella entericaInfections
Authors: Grant Andrew J. , Foster Gemma L. , McKinley Trevelyan J. , Brown Sam P. , Clare Simon , Maskell Duncan J. , Mastroeni Pietro 
Published: September 2009

ABSTRACTBacteria of the speciesSalmonella entericacause a range of life-threatening diseases in humans and animals worldwide. The within-host quantitative, spatial, and temporal dynamics ofS. entericainteractions are key to understanding how immunity acts on these infections and how bacteria evade immune surveillance. In this study, we test hypotheses generated from mathematical models of in vivo dynamics ofSalmonellainfections with experimental observation of bacteria at the single-cell level in infected mouse organs to improve our understanding of the dynamic interactions between host and bacterial mechanisms that determine net growth rates ofS. entericawithin the host. We show that both bacterial and host factors determine the numerical distributions of bacteria within host cells and thus the level of dispersiveness of the infection.
Rhodococcus equiVirulence-Associated Protein A Is Required for Diversion of Phagosome Biogenesis but Not for Cytotoxicity
Authors: von Bargen Kristine , Polidori Marco , Becken Ulrike , Huth Gitta , Prescott John F. , Haas Albert 
Published: September 2009

ABSTRACTRhodococcus equiis a gram-positive facultative intracellular pathogen that can cause severe bronchopneumonia in foals and AIDS patients. Virulence is plasmid regulated and is accompanied by phagosome maturation arrest and host cell necrosis. A replacement mutant in the gene for VapA (virulence-associated protein A), a major virulence factor ofR. equi, was tested for its activities during macrophage infection. Early in infection, phagosomes containing thevapAmutant did not fuse with lysosomes and did not stain with the acidotropic fluor LysoTracker similar to those containing virulent wild-typeR. equi. However,vapAmutant phagosomes had a lower average pH. Late in infection, phagosomes containing thevapAmutant were as frequently positive for LysoTracker as phagosomes containing plasmid-cured, avirulent bacteria, whereas those with virulent wild-typeR. equiwere still negative for the fluor. Macrophage necrosis after prolonged infection with virulent bacteria was accompanied by a loss of organelle staining with LysoTracker, suggesting that lysosome proton gradients had collapsed. ThevapAmutant still killed the macrophages and yet did not affect the pH of host cell lysosomes. Hence, VapA is not required for host cell necrosis but is required for neutralization of phagosomes and lysosomes or their disruption. This is the first report of anR. equimutant with altered phagosome biogenesis.
Tropopause-Level Waveguides
Authors: Martius O. , Schwierz C. , Davies H. C. 
Published: September 2009

Abstract
Jet streams located on the dynamical tropopause are accompanied by coaligned bands of enhanced potential vorticity (PV) gradients, and these bands can serve as space–time evolving waveguides for synoptic and larger-scale flow. Consideration is given to the detection and examination of the along-flow extent and lateral confinement of the waveguides on the dynamic tropopause (i.e., iso-PV surface) and on tropopause-cutting isentropic surfaces. Thereafter a two-part study is undertaken of the possible interaction between such waveguides (i.e., jet streams). First, a highly idealized theoretical model points to the nature of the dynamical linkage that can exist between perturbations on coaligned waveguides. Second, diagnostic analysis of two observed events helps identify the contemporaneous space–time evolution of the jets and serves to illustrate the nature of the transfer of wave activity from the extratropical waveguide onto a subtropical and a polar waveguide, respectively.
Diagnosis of the Downstream Ridging Associated with Extratropical Transition Using Short-Term Ensemble Forecasts
Authors: Torn Ryan D. 
Published: September 2009

Abstract
The dynamical mechanisms that led to downstream ridging during the extratropical transition (ET) of Typhoons Tokage and Nabi are evaluated using data drawn from a cycling ensemble Kalman filter coupled with the Weather Research and Forecasting Model (WRF). During both transitions, the ensemble covariances indicate that the 350-K potential vorticity (PV) at the apex of the ridge, which is used to define the ridge structure, is proportional to the amount of precipitation along the baroclinic zone to the northeast of the tropical cyclone (TC), and at some times to the upper-tropospheric divergence above the tropical cyclone. Multivariate regression calculations indicate that the frontal precipitation has the largest impact on the ridge amplitude and area during Tokage’s transition, while the TC divergence has roughly equal impact during some times of Nabi’s transition. The amount of precipitation along the baroclinic zone is modulated by the lower-tropospheric frontogenesis and moisture flux on the east side of the tropical cyclone, both of which are related to the TC winds. Although both of these metrics covary with the PV at the ridge apex, a one standard deviation perturbation to the moisture flux is associated with a larger change in the ridge PV.
Diagnostic perturbations to the initial conditions confirm that increasing (decreasing) the initial moisture flux leads to comparatively lower (higher) PV at the ridge apex 12 h later. Assimilating a single hypothetical wind or moisture observation within the large moisture flux region leads to a 0.3 standard deviation change in the 12-h PV forecast when the observation innovation is comparable to the observation error. Overall, these results suggest that better wind and moisture analyses at the periphery of the TC could improve forecasts of the downstream ridging during ET.
Plastic deformations in kyanites by tectonometamorphic processes: a single-crystal X-ray diffraction study
Authors: Gatta G. D. , Rotiroti N. , M. Zucali  
Published: September 2009

AbstractThe crystalch emistry and crystal structure of naturalky anite crystals from the Eclogitic Micaschists Complex of the Sesia-Lanzo Zone, Western Italian Alps, have been investigated by means of optical microscopy, wavelength dispersive X-ray microanalysis, and single-crystal X-ray diffraction. The association of kyanite + garnet + phengitic-mica + chloritoid suggests that the eclogite-facies stages occurred at P ≤ 2.1 GPa and T ≤ 650ºC. Kyanite grains are large (cm-sized) porphyroblasts grown dynamically during one of the deformational events related to the subduction of the Austroalpine continentalcr ust. Under the polarizing microscope, kyanite grains show almost homogeneous cores, whereas rims are sometimes symplectitic aggregates of quartz and kyanite, confirming at least two stages of growth most likely related to the multistage deformational history of these rocks. Chemical analysis shows that Fe3+ is the major substituting cation for Al3+, ranging between 0.038 and 0.067 a.p.f.u.The single-crystal X-ray diffraction investigation of the kyanites shows severely textured patterns on the (h0l)*-plane. Such evidence is not observed in the unwarped diffraction patterns on (0kl)* and (hk0)*. The most significant difference between the structuralp arameters refined in this study, with respect to those of previously published unstrained gem-quality crystals, concerns the displacement parameters. The anisotropic displacement ellipsoids of all the atomic sites are significantly larger than those previously described, and systematically oriented with the largest elliptical section almost perpendicular to [010]. The larger ellipsoids in the kyanite crystal investigated here reflect the displacement of the centre of gravity of the electron distribution, rather than an anomalous atomic thermal motion. The magnitude and orientation of the displacement parameters and the textured/strained diffraction pattern may be the result of two combined effects: (1) that the kyanite crystals are actually composed of several blocks; (2) the crystals are affected by a pervasive residual strain, as a result of tectonometamorphic plastic deformations and re-crystallization.
H2O and CO2in minerals of the haüyne-sodalite group: an FTIR spectroscopy study
Authors: Bellatreccia F. , Della Ventura G. , Piccinini M. , Cavallo A. , Brilli M. 
Published: September 2009

AbstractThis paper reports an infrared spectroscopic study of a set of sodalite-group minerals. The specimens have been identified using a combination of X-ray diffraction and microchemical analysis. As expected, the Si/Al ratio is ~1; the extra framework cation content is characterized by a well-defined Na ⇌ (Ca+K) substitution. The lattice parameters of the studied samples range from sodalite (sample LM11) with a = 8.889(2) Å, to haüyne (sample HR3S) with a = 9.1265(2) Å. The specimens, having the SO2–group as a dominant anion, show a clear correlation between the a cell edge and the K content. Singlecrystal FTIR spectroscopy shows that haüyne and nosean typically contain enclathrated CO2molecules, inadditionto H2O and minor carbonate, while sodalite is virtually CO2-free. Detailed microspectrometric mappings show a non-homogeneous distribution of volatile constituents across the crystals, which may be related to the presence of fractures in the crystals. Because of such zoning, a relatively wide variation is observed when calibrating extinction coefficients on the basis of a bulk analytical method such as CHN elemental analysis.
High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia
Authors: Herling Marco , Patel Kaushali A. , Weit Nicole , Lilienthal Nils , Hallek Michael , Keating Michael J. , Jones Dan 
Published: September 2009

AbstractAlthough activation of the B-cell receptor (BCR) signaling pathway is implicated in the pathogenesis of chronic lymphocytic leukemia (CLL), its clinical impact and the molecular correlates of such response are not clearly defined. T-cell leukemia 1 (TCL1), the AKT modulator and proto-oncogene, is differentially expressed in CLL and linked to its pathogenesis based on CD5+ B-cell expansions arising in TCL1-transgenic mice. We studied here the association of TCL1 levels and its intracellular dynamics with the in vitro responses to BCR stimulation in 70 CLL cases. The growth kinetics after BCR engagement correlated strongly with the degree and timing of induced AKT phospho-activation. This signaling intensity was best predicted by TCL1 levels and the kinetics of TCL1-AKT corecruitment to BCR membrane activation complexes, which further included the kinases LYN, SYK, ZAP70, and PKC. High TCL1 levels were also strongly associated with aggressive disease features, such as advanced clinical stage, higher white blood cell counts, and shorter lymphocyte doubling time. Higher TCL1 levels independently predicted an inferior clinical outcome (ie, shorter progression-free survival, P < .001), regardless of therapy regimen, especially for ZAP70+ tumors. We propose TCL1 as a marker of the BCR-responsive CLL subset identifying poor prognostic cases where targeting BCR-associated kinases may be therapeutically useful.
A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis
Authors: Tremmel Martina , Matzke Alexandra , Albrecht Imke , Laib Anna M. , Olaku Vivienne , Ballmer-Hofer Kurt , Christofori Gerhard , Héroult Mélanie , Augustin Hellmut G. , Ponta Helmut , Orian-Rousseau Véronique 
Published: September 2009

Abstract
A specific splice variant of the CD44 cell- surface protein family, CD44v6, has been shown to act as a coreceptor for the receptor tyrosine kinase c-Met on epithelial cells. Here we show that also on endothelial cells (ECs), the activity of c-Met is dependent on CD44v6. Furthermore, another receptor tyrosine kinase, VEGFR-2, is also regulated by CD44v6. The CD44v6 ectodomain and a small peptide mimicking a specific extracellular motif of CD44v6 or a CD44v6-specific antibody prevent CD44v6-mediated receptor activation. This indicates that the extracellular part of CD44v6 is required for interaction with c-Met or VEGFR-2. In the cytoplasm, signaling by activated c-Met and VEGFR-2 requires association of the CD44 carboxy-terminus with ezrin that couples CD44v6 to the cytoskeleton. CD44v6 controls EC migration, sprouting, and tubule formation induced by hepatocyte growth factor (HGF) or VEGF-A. In vivo the development of blood vessels from grafted EC spheroids and angiogenesis in tumors is impaired by CD44v6 blocking reagents, suggesting that the coreceptor function of CD44v6 for c-Met and VEGFR-2 is a promising target to block angiogenesis in pathologic conditions.
Monitoring compartment-specific substrate cleavage by cathepsins B, K, L, and S at physiological pH and redox conditions
Authors: Jordans Silvia , Jenko-Kokalj Saša , Kühl Nicole M , Tedelind Sofia , Sendt Wolfgang , Brömme Dieter , Turk Dušan , Brix Klaudia 
Published: September 2009

Abstract

Background
Cysteine cathepsins are known to primarily cleave their substrates at reducing and acidic conditions within endo-lysosomes. Nevertheless, they have also been linked to extracellular proteolysis, that is, in oxidizing and neutral environments. Although the impact of reducing or oxidizing conditions on proteolytic activity is a key to understand physiological protease functions, redox conditions have only rarely been considered in routine enzyme activity assays. Therefore we developed an assay to test for proteolytic processing of a natural substrate by cysteine cathepsins which accounts for redox potentials and pH values corresponding to the conditions in the extracellular space in comparison to those within endo-lysosomes of mammalian cells.

Results
The proteolytic potencies of cysteine cathepsins B, K, L and S towards thyroglobulin were analyzed under conditions simulating oxidizing versus reducing environments with neutral to acidic pH values. Thyroglobulin, the precursor molecule of thyroid hormones, was chosen as substrate, because it represents a natural target of cysteine cathepsins. Thyroglobulin processing involves thyroid hormone liberation which, under physiological circumstances, starts in the extracellular follicle lumen before being continued within endo-lysosomes. Our study shows that all cathepsins tested were capable of processing thyroglobulin at neutral and oxidizing conditions, although these are reportedly non-favorable for cysteine proteases. All analyzed cathepsins generated distinct fragments of thyroglobulin at extracellular versus endo-lysosomal conditions as demonstrated by SDS-PAGE followed by immunoblotting or N-terminal sequencing. Moreover, the thyroid hormone thyroxine was liberated by the action of cathepsin S at extracellular conditions, while cathepsins B, K and L worked most efficiently in this respect at endo-lysosomal conditions.

Conclusion
The results revealed distinct cleavage patterns at all conditions analyzed, indicating compartment-specific processing of thyroglobulin by cysteine cathepsins. In particular, proteolytic activity of cathepsin S towards the substrate thyroglobulin can now be understood as instrumental for extracellular thyroid hormone liberation. Our study emphasizes that the proteolytic functions of cysteine cathepsins in the thyroid are not restricted to endo-lysosomes but include pivotal roles in extracellular substrate utilization. We conclude that understanding of the interplay and fine adjustment of protease networks in vivo is better approachable by simulating physiological conditions in protease activity assays.