Home About us Contact
|
Home About us Contact | ||
|
|
||
Early Times (early + time)
Terms modified by Early Times Selected AbstractsAmphibolite and blueschist,greenschist facies metamorphism, Blue Mountain inlier, eastern JamaicaGEOLOGICAL JOURNAL, Issue 5 2008Richard N. Abbott Jr Abstract Cretaceous (possibly older) metamorphic rock occurs mainly in the Blue Mountain inlier in eastern Jamaica. Fault-bounded blocks reveal two styles of metamorphism, Westphalia Schist (upper amphibolite facies) and Mt. Hibernia Schist (blueschist (BS),greenschist (GS) facies). Both Westphalia Schist and Mt. Hibernia Schist preserve detailed records of retrograde P,T paths. The paths are independent, but consistent with different parts of the type-Sanbagawa metamorphic facies series in Japan. For each path, phase relationships and estimated P,T conditions support a two-stage P,T history involving residence at depth, followed by rapid uplift and cooling. Conditions of residence vary depending on the level in a tectonic block. For the critical mineral reaction (isograd) in Westphalia Schist, conditions were P ,7.5,kbars, T ,600°C (upper amphibolite facies). Retrograde conditions in Hibernia Schist were P,=,2.6,3.0,kbars, T,=,219,237°C for a(H2O),=,0.8,1.0 (GS facies). Mt. Hibernia Schist may represent a volume of rock that was separated and uplifted at an early time from an otherwise protracted P,T path of the sort that produced the Westphalia Schist. Reset K,Ar ages for hornblende and biotite indicate only that retrograde metamorphism of Westphalia Schist took place prior to 76.5,Ma (pre-Campanian). Uplift may have commenced with an Albian,Aptian (,112,Ma) orogenic event. Copyright © 2008 John Wiley & Sons, Ltd. [source] Modelling poroelastic hollow cylinder experiments with realistic boundary conditionsINTERNATIONAL JOURNAL FOR NUMERICAL AND ANALYTICAL METHODS IN GEOMECHANICS, Issue 12 2004S. Jourine Abstract A general poroelastic solution for axisymmetrical plane strain problems with time dependent boundary conditions is developed in Laplace domain. Time-domain results are obtained using numerical inversion of the Laplace transform. Previously published solutions can be considered as special cases of the proposed solution. In particular, we could reproduce numerical results for solid and hollow poroelastic cylinders with suddenly applied load/pressure (Rice and Cleary, Rev. Geophys. Space Phys. 1976; 14:227; Schmitt, Tait and Spann, Int. J. Rock Mech. Min. Sci. 1993; 30:1057; Cui and Abousleiman, ASCE J. Eng. Mech. 2001; 127:391). The new solution is used to model laboratory tests on thick-walled hollow cylinders of Berea sandstone subjected to intensive pressure drawdown. In the experiments, pressure at the inner boundary of the hollow cylinder is observed to decline exponentially with a decay constant of 3,5 1/s. It is found that solutions with idealized step-function type inner boundary conditions overestimate the induced tensile radial stresses considerably. Although basic poroelastic phenomena can be modelled properly at long time following a stepwise change in pressure, realistic time varying boundary conditions predict actual rock behaviour better at early time. Experimentally observed axial stresses can be matched but appear to require different values for , and , than are measured at long time. The proposed solution can be used to calculate the stress and pore pressure distributions around boreholes under infinite/finite boundary conditions. Prospective applications include investigating the effect of gradually changing pore pressure, modelling open-hole cavity completions, and describing the phenomenon of wellbore collapse (bridging) during oil or gas blowouts. Copyright © 2004 John Wiley & Sons, Ltd. [source] Predictive toxicogenomics approaches reveal underlying molecular mechanisms of nongenotoxic carcinogenicityMOLECULAR CARCINOGENESIS, Issue 12 2006Alex Y. Nie Toxicogenomics technology defines toxicity gene expression signatures for early predictions and hypotheses generation for mechanistic studies, which are important approaches for evaluating toxicity of drug candidate compounds. A large gene expression database built using cDNA microarrays and liver samples treated with over one hundred paradigm compounds was mined to determine gene expression signatures for nongenotoxic carcinogens (NGTCs). Data were obtained from male rats treated for 24 h. Training/testing sets of 24 NGTCs and 28 noncarcinogens were used to select genes. A semiexhaustive, nonredundant gene selection algorithm yielded six genes (nuclear transport factor 2, NUTF2; progesterone receptor membrane component 1, Pgrmc1; liver uridine diphosphate glucuronyltransferase, phenobarbital-inducible form, UDPGTr2; metallothionein 1A, MT1A; suppressor of lin-12 homolog, Sel1h; and methionine adenosyltransferase 1, alpha, Mat1a), which identified NGTCs with 88.5% prediction accuracy estimated by cross-validation. This six genes signature set also predicted NGTCs with 84% accuracy when samples were hybridized to commercially available CodeLink oligo-based microarrays. To unveil molecular mechanisms of nongenotoxic carcinogenesis, 125 differentially expressed genes (P,<,0.01) were selected by Student's t -test. These genes appear biologically relevant, of 71 well-annotated genes from these 125 genes, 62 were overrepresented in five biochemical pathway networks (most linked to cancer), and all of these networks were linked by one gene, c - myc. Gene expression profiling at early time points accurately predicts NGTC potential of compounds, and the same data can be mined effectively for other toxicity signatures. Predictive genes confirm prior work and suggest pathways critical for early stages of carcinogenesis. © 2006 Wiley-Liss, Inc. [source] Sonic and desert hedgehog signaling in human fetal prostate development,THE PROSTATE, Issue 6 2007Guodong Zhu Abstract Background Hedgehog signaling is thought to play an important role in rodent prostate organogenesis and morphogenesis. However, the role of this signaling pathway in human fetal prostate development has not been investigated. Methods Twenty-five human fetal prostates at various developmental stages (10,39 weeks) were included. Fifteen specimens were processed for H&E and immunohistochemical staining of the Hedgehog signaling components: Sonic Hedgehog (SHH), Desert Hedgehog (DHH), Patched-1(PTC1), Patched-2 (PTC2), Smoothened (SMO), GLI1, and proliferating cell nuclear antigen (PCNA). SHH, DHH, and GLI1 expression was also analyzed in ten snap-frozen specimens by Western blot. Results SHH, DHH, SMO, PTC1, GLI1, and PCNA expression, assessed by a semi-quantitative immunohistochemical method, was found mainly in the developing prostatic epithelial ducts, beginning at 10 weeks and peaking at 16 and 28 weeks with a dip occurring at 20 weeks, with the exception of PTC2. Conclusion Both SHH and DHH signaling components were detected during human fetal prostate development. Despite the high expression of PTC2 in the epithelium as well as the stroma in the early time of development, the expression of SHH, DHH, SMO, PTC1, and a SHH/DHH target transcription factor, GLI-1, were all largely restricted to epithelium in the developing prostate, suggesting that SHH/DHH signaling is primarily through an autocrine mechanism in human fetal prostate organogenesis. Prostate 67: 674,684, 2007. © 2007 Wiley-Liss, Inc. [source] High-Resolution Records of the Holocene Paleoenvironmental Variation Reflected by Carbonate and Its Isotopic Compositions in Bosten Lake and Response to Glacial ActivitiesACTA GEOLOGICA SINICA (ENGLISH EDITION), Issue 6 2009ZHANG Chengjun Abstract: The Early Holocene paleoclimate in Bosten Lake on the northern margin of the Tarim Basin, southern Xinjiang, is reconstructed through an analysis of a 953 cm long core (BSTC2000) taken from Bosten Lake. Multiple proxies of this core, including the mineral components of carbonate, carbonate content, stable isotopic compositions of carbonate, Ca/Sr, TOC and C/N and C/S of organic matter, are used to reconstruct the climatic change since 8500 a B.P. The chronology model is made by nine AMS 14C ages of leaves, seeds and organic matter contained in two parallel cores. The climate was cold and wet during 8500 to 8100 a B.P. Temperature increased from 8100 to 6400 a B.P., the climate was warm and humid, and the lake expanded. The lake level was highest during this stage. Then from 6400 to 5100 a B.P., the climate became cold and the lake level decreased slightly. During the late mid-Holocene, the climate was hot and dry from 5100 to 3100 a B.P., but there was a short cold period during 4400 to 3800 a B.P. At this temporal interval, a mass of ice and snow melting water supplied the lake at the early time and made the lake level rise. The second highest lake level stage occurred during 5200 to 3800 a B.P. The climate was cool and wet during 3100 to 2200 a B.P., when the lake expanded with decreasing evaporation. The lake had the last short-term high level during 3100 to 2800 a B.P. After this short high lake level period, the lake shrank because of the long-term lower temperature and reduced water supply. From 2200 to 1200 a B.P., the climate was hot and dry, and the lake shrank greatly. Although the temperature decreased somewhat from 1200 a B.P. to the present, the climate was warm and dry. The lake level began to rise a little again, but it did not reach the river bed altitude of the Konqi River, an outflow river of the Bosten Lake. [source] EARLY ACTIVATION OF INTERNAL MEDIAL SMOOTH MUSCLE CELLS IN THE RABBIT AORTA AFTER MECHANICAL INJURY: RELATIONSHIP WITH INTIMAL THICKENING AND PHARMACOLOGICAL APPLICATIONSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2006Huguette Louis SUMMARY 1Smooth muscle cells (SMC) participate in both inflammatory and dedifferentiation processes during atherosclerosis, as well as during mechanical injury following angioplasty. In the latter, we studied medial SMC differentiation and inflammation processes implicated early after de-endothelialization in relation to mechanical stresses. We hypothesized that activation of a subpopulation of SMC within the media plays a crucial role in the early phase of neointimal formation. 2For this purpose, we used a rabbit model of balloon injury to study activation and differentiation of medial SMC in the early time after denudation and just before neointima thickening. Inflammation was evaluated by the expression of vascular cell adhesion molecule (VCAM)-1, integrin a4b1 and nuclear factor (NF)-kB. Myosin isoforms and 2P1A2 antigen, a membrane protein expressed by rabbit dedifferentiated SMC, were used as markers of differentiation. 3On day 2 after de-endothelialization, VCAM-1, a4b1 and NF-kB were coexpressed by a well-defined subpopulation of SMC of the internal part of the media, in the vicinity of the blood stream. At the same time, the majority of SMC throughout the media expressed non-muscle myosin heavy chain-B (nm-MHC-B) and 2P1A2 antigen. On day 7, when intimal thickening appeared, SMC of the media were no longer activated, whereas some intimal SMC expressed the activation markers. Thus, after de-endothelialization, early dedifferentiation occurs in most of the medial SMC, whereas activation concerned only a subpopulation of SMC located in the internal media. Using the T-type voltage-operated calcium channel blocker mibefradil (0.1,1 mmol/L) in SMC culture, we showed that this agent exhibited an antiproliferative effect in a dose-dependant manner only on undifferentiated cells. 4In conclusion, the results suggest that the activated SMC represent cells that are potentially able to migrate and participate in the intimal thickening process. Thus, the medial SMC inflammatory process, without any contribution of inflammatory cells, may represent a major mechanism underlying the development of intimal thickening following mechanical stress. In humans, inhibition of T-type calcium channels may be a tool to prevent the early proliferation step leading to neointimal formation. [source] Proteolytic activation of internalized cholera toxin within hepatic endosomes by cathepsin DFEBS JOURNAL, Issue 17 2005Clémence Merlen We have defined the in vivo and in vitro metabolic fate of internalized cholera toxin (CT) in the endosomal apparatus of rat liver. In vivo, CT was internalized and accumulated in endosomes where it underwent degradation in a pH-dependent manner. In vitro proteolysis of CT using an endosomal lysate required an acidic pH and was sensitive to pepstatin A, an inhibitor of aspartic acid proteases. By nondenaturating immunoprecipitation, the acidic CT-degrading activity was attributed to the luminal form of endosomal cathepsin D. The rate of toxin hydrolysis using an endosomal lysate or pure cathepsin D was found to be high for native CT and free CT-B subunit, and low for free CT-A subunit. On the basis of IC50 values, competition studies revealed that CT-A and CT-B subunits share a common binding site on the cathepsin D enzyme, with native CT and free CT-B subunit displaying the highest affinity for the protease. By immunofluorescence, partial colocalization of internalized CT with cathepsin D was confirmed at early times of endocytosis in both hepatoma HepG2 and intestinal Caco-2 cells. Hydrolysates of CT generated at low pH by bovine cathepsin D displayed ADP-ribosyltransferase activity towards exogenous Gs, protein suggesting that CT cytotoxicity, at least in part, may be related to proteolytic events within endocytic vesicles. Together, these data identify the endocytic apparatus as a critical subcellular site for the accumulation and proteolytic degradation of endocytosed CT, and define endosomal cathepsin D an enzyme potentially responsible for CT cytotoxic activation. [source] Supraspinatus tendon repair into a bony trough in the rabbit: Mechanical restoration and correlative imagingJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2010Guy Trudel Abstract Recurrence of tears is a common complication after rotator cuff surgery. Retearing seems to occur early after surgery and may be attributed to too early or too vigorous exercises. We found no experimental data correlating the strength of the rotator cuff early after surgery and imaging. Our objectives were to measure the peak load to failure of rabbit supraspinatus tendon,bone constructs at early times postoperatively, to determine their mode of failure, and to determine whether computed tomography (CT) can predict their strength. We divided one supraspinatus tendon of 40 adult female white New Zealand rabbits and, after resection of the enthesis, sutured the tendon into a bony trough. Ten rabbits were killed immediately and 10 each at 1, 2, and 6 weeks postoperatively. The explanted tendons of both shoulders were imaged on CT and tested to failure. Compared to normal tendons (mean 210,±,42 N), the mean strength was very low at 0 weeks (57,±,21 N) and 1 week (86,±,33 N) (both p,<,0.05); it had recovered by 6 weeks (324,±,66 N). Early on, suture pullout was the most common mode of failure, whereas at 6 weeks, mid-substance tears predominated (p,<,0.05). Hypoattenuation on CT was associated with increased strength of the tendon,bone construct (p,<,0.05). The strength of the surgical construct is very low in the early postoperative period. Therefore, the shoulder should be submitted only to loads not interfering with healing. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:710,715, 2010 [source] A Determination of Hydration Mechanisms for Tricalcium Silicate Using a Kinetic Cellular Automaton ModelJOURNAL OF THE AMERICAN CERAMIC SOCIETY, Issue 7 2008Jeffrey W. Bullard Reaction mechanisms for the early stages of hydration of tricalcium silicate (Ca3SiO5) have not been agreed upon, although theories have appeared in the literature. In this paper, a mechanistic description is proposed that is consistent with a wide range of reported experimental observations, and which is supported quantitatively by simulations using HydratiCA, a new three-dimensional microstructure model of chemical kinetics. Rate processes are quantitatively modeled using probabilistic cellular automaton algorithms that are based on the principles of transition state theory. The model can test alternate assumptions about the reaction paths and rate-controlling steps, making it a kind of experimental tool for investigating kinetics and interpreting experimental observations. It is used here to show that hydration of Ca3SiO5 is most likely controlled by nucleation and growth of a compositionally variable calcium silicate hydrate solid, mediated at very early times by a transient, thermodynamically metastable solid that rapidly covers and sharply reduces the dissolution rate of Ca3SiO5. This proposed mechanism involves important elements of two leading theories of Ca3SiO5 hydration, neither of which alone has been able to capture the full range of experimental data when tested by the model. [source] Cosmological simulations of intergalactic medium enrichment from galactic outflowsMONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 4 2006Benjamin D. Oppenheimer ABSTRACT We investigate models of self-consistent chemical enrichment of the intergalactic medium (IGM) from z= 6.0 , 1.5, based on hydrodynamic simulations of structure formation that explicitly incorporate outflows from star-forming galaxies. Our main result is that outflow parametrizations derived from observations of local starburst galaxies, in particular momentum-driven wind scenarios, provide the best agreement with observations of C iv absorption at z, 2,5. Such models sufficiently enrich the high- z IGM to produce a global mass density of C iv absorbers that is relatively invariant from z= 5.5 , 1.5, in agreement with observations. This occurs despite continual IGM enrichment causing an increase in volume-averaged metallicity by ,× 5,10 over this redshift range, because energy input accompanying the enriching outflows causes a drop in the global ionization fraction of C iv. Comparisons to observed C iv column density and linewidth distributions and C iv -based pixel optical depth ratios provide significant constraints on wind models. Our best-fitting outflow models show mean IGM temperatures only slightly above our no-outflow case, metal filling factors of just a few per cent with volume-weighted metallicities around 10,3 at z, 3, significant amounts of collisionally ionized C iv absorption and a metallicity,density relationship that rises rapidly at low overdensities and flattens at higher ones. In general, we find that outflow speeds must be high enough to enrich the low-density IGM at early times but low enough not to overheat it, and concurrently must significantly suppress early star formation while still producing enough early metals. It is therefore non-trivial that locally calibrated momentum-driven wind scenarios naturally yield the desired strength and evolution of outflows, and suggest that such models represent a significant step towards understanding the impact of galactic outflows on galaxies and the IGM across cosmic time. [source] Cosmic evolution of metal densities: the enrichment of the intergalactic mediumMONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 1 2006F. Calura ABSTRACT By means of chemo-photometric models for galaxies of different morphological types, we have carried out a detailed study of the history of element production by spheroidal and dwarf irregular galaxies. Spheroidal galaxies suffer a strong and intense star formation episode at early times. In dwarf irregulars, the star formation rate (SFR) proceeds at a low regime but continuously. Both galactic types enrich the intergalactic medium (IGM) with metals by means of galactic winds. We have assumed that the galaxy number density is fixed and normalized to the value of the optical luminosity function observed in the local Universe. Our models allow us to investigate in detail how the metal fractions locked up in stars in spheroids and dwarf irregulars, those present in the interstellar medium (ISM) and those ejected into the IGM have changed with cosmic time. By relaxing the instantaneous recycling approximation and taking into account stellar lifetimes, for the first time we have studied the evolution of the chemical abundance ratios in the IGM and compared our predictions with a set of observations by various authors. Our results indicate that the bulk of the IGM enrichment is due to spheroids, with dwarf irregular galaxies playing a negligible role. Our predictions grossly account for the [O/H] observed in the IGM at high redshift, but overestimate the [C/H]. Furthermore, it appears hard to reproduce the abundance ratios observed in the high-redshift IGM. Some possible explanations are discussed in the text. This is the first attempt to study the abundance ratios in the IGM by means of detailed chemical evolution models which take into account the stellar lifetimes. Numerical simulations adopting our chemical evolution prescriptions could be useful to improve our understanding of the IGM chemical enrichment. [source] Testing linear-theory predictions of galaxy formationMONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 4 2000Ben Sugerman The angular momentum of galaxies is routinely ascribed to a process of tidal torques acting during the early stages of gravitational collapse, and is predicted from the initial mass distribution using second-order perturbation theory and the Zel'dovich approximation. We test this theory for a flat hierarchical cosmogony using a large N -body simulation with sufficient dynamic range to include tidal fields, allow resolution of individual galaxies, and thereby expand on previous studies. The predictions of linear collapse, linear tidal torque, and biased-peaks galaxy formation are applied to the initial conditions and compared with results for evolved bound objects. We find relatively good correlation between the predictions of linear theory and actual galaxy evolution. Collapse is well described by an ellipsoidal model within a shear field, which results primarily in triaxial objects that do not map directly to the initial density field. While structure formation from early times is a complex history of hierarchical merging, salient features are well described by the simple spherical-collapse model. Most notably, we test several methods for determining the turnaround epoch, and find that turnaround is successfully described by the spherical-collapse model. The angular momentum of collapsing structures grows linearly until turnaround, as predicted, and continues quasi-linearly until shell crossing. The predicted angular momentum for well-resolved galaxies at turnaround overestimates the true turnaround and final values by a factor of ,3, with a scatter of ,70 per cent, and only marginally yields the correct direction of the angular momentum vector. We recover the prediction that final angular momentum scales as mass to the 5/3 power. We find that mass and angular momentum also vary proportionally with peak height. In view of the fact that the observed galaxy collapse is a stochastic hierarchical and non-linear process, it is encouraging that the linear theory can serve as an effective predictive and analytic tool. [source] Dark adaptation recovery of human rod bipolar cell response kinetics estimated from scotopic b -wave measurementsTHE JOURNAL OF PHYSIOLOGY, Issue 22 2008A. M. Cameron We recorded ganzfeld scotopic ERGs to examine the responses of human rod bipolar cells in vivo, during dark adaptation recovery following bleaching exposures, as well as during adaptation to steady background lights. In order to be able to record responses at relatively early times in recovery, we utilized a ,criterion response amplitude' protocol in which the test flash strength was adjusted to elicit responses of nearly constant amplitude. In order to provide accurate and unbiased measures of response kinetics, we utilized a curve-fitting procedure to fit a smooth function to the measured responses in the vicinity of the peak, thereby extracting both the time-to-peak and the amplitude of the responses. Following bleaching exposures, the responses exhibited both desensitization and accelerated kinetics. During early post-bleach recovery, the flash sensitivity and time-to-peak varied according to a power-law expression (with an exponent of 6), as found in the presence of steady background light. This light-like phenomenon, however, appeared to be set against the backdrop of a second, more slowly recovering ,pure' desensitization, most clearly evident at late post-bleach times. The post-bleach ,equivalent background intensity' derived from measurements of flash sensitivity faded initially with an S2 slope of ,0.24 decades min,1, and later as a gentle S3 tail. When calculated from kinetics, the results displayed only the S2 slope. While the recovery of rod bipolar cell response kinetics can be described accurately by a declining level of opsin in the rods, the sensitivity of these cells is reduced further than expected by this mechanism alone. [source] Pharmacokinetics of E-6087, a new anti-inflammatory agent, in rats and dogsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2001Raquel F. Reinoso Abstract The pharmacokinetics of E-6087, a newly developed cyclooxygenase-2 inhibitor, was studied in rats and dogs after single oral and intravenous doses. In both animal species, E-6087 was characterized by a long elimination half-life (20,35 h), a low plasma clearance (0.10,0.22 l h,1 kg,1) and a relatively large volume of distribution (2,6 l kg,1). Oral bioavailability was lower in dogs than in rats whereas a faster elimination was found in rats. Multiple peaks were present regardless of administration route and animal species, suggesting the existence of enterohepatic circulation. Gender effect on the pharmacokinetics of E-6087 was only found in rats, with greater exposure and longer elimination in females than in males. Food intake reduced the bioavailability (,22%) with no apparent changes in the absorption rate. After oral dosing of 1, 5 and 25 mg kg,1 to rats, linearity was lost at the highest dose due to the low aqueous solubility of E-6087. Drug absorption was improved by micronization. E-6087 and E-6132, (a pharmacologically active metabolite), showed different pharmacokinetics. The higher percentage of E-6087 at early times suggests that E-6087 is the main compound responsible for in vivo activity, although E-6132 would contribute to the activity at later times. Copyright © 2001 John Wiley & Sons, Ltd. [source] Sorting nexin 3 (SNX3) is a component of a tubular endosomal network induced by Salmonella and involved in maturation of the Salmonella -containing vacuoleCELLULAR MICROBIOLOGY, Issue 9 2010Virginie Braun Summary Salmonella enterica serovar Typhimurium is an intracellular pathogen that grows within a modified endomembrane compartment, the Salmonella -containing vacuole (SCV). Maturation of nascent SCVs involves the recruitment of early endosome markers and the remodelling of phosphoinositides at the membrane of the vacuole, in particular the production of phosphatidylinositol 3-phosphate [PI(3)P]. Sorting nexins (SNXs) are a family of proteins characterized by the presence of a phox homology (PX) domain that binds to phosphoinositides and are involved in intracellular trafficking in eukaryotic cells. We therefore studied whether sorting nexins, particularly sorting nexin 3 (SNX3), play a role in Salmonella infection. We found that SNX3 transiently localized to SCVs at early times post invasion (10 min) and presented a striking tubulation phenotype in the vicinity of SCVs at later times (30,60 min). The bacterial effector SopB, which is known to promote PI(3)P production on SCVs, was required for the formation of SNX3 tubules. In addition, RAB5 was also required for the formation of SNX3 tubules. Depletion of SNX3 by siRNA impaired RAB7 and LAMP1 recruitment to the SCV. Moreover, the formation of Salmonella -induced filaments (Sifs) was altered by SNX3 knock-down. Therefore, SNX3 plays a significant role in regulating the maturation of SCVs. [source] Differences in human macrophage receptor usage, lysosomal fusion kinetics and survival between logarithmic and metacyclic Leishmania infantum chagasi promastigotesCELLULAR MICROBIOLOGY, Issue 12 2009Norikiyo Ueno Summary The obligate intracellular protozoan, Leishmania infantum chagasi (Lic) undergoes receptor-mediated phagocytosis by macrophages followed by a transient delay in phagolysosome maturation. We found differences in the pathway through which virulent Lic metacyclic promastigotes or avirulent logarithmic promastigotes are phagocytosed by human monocyte-derived macrophages (MDMs). Both logarithmic and metacyclic promastigotes entered MDMs through a compartment lined by the third complement receptor (CR3). In contrast, many logarithmic promastigotes entered through vacuoles lined by mannose receptors (MR) whereas most metacyclic promastigotes did not (P < 0.005). CR3-positive vacuoles containing metacyclic promastigotes stained for caveolin-1 protein, suggesting CR3 localizes in caveolae during phagocytosis. Following entry, the kinetics of phagolysosomal maturation and intracellular survival also differed. Vacuoles containing metacyclic parasites did not accumulate lysosome-associated membrane protein-1 (LAMP-1) at early times after phagocytosis, whereas vacuoles with logarithmic promastigotes did. MDMs phagocytosed greater numbers of logarithmic than metacyclic promastigotes, yet metacyclics ultimately replicated intracellularly with greater efficiency. These data suggest that virulent metacyclic Leishmania promastigotes fail to ligate macrophage MR, and enter through a path that ultimately enhances intracellular survival. The relatively quiescent entry of virulent Leishmania spp. into macrophages may be accounted for by the ability of metacyclic promastigotes to selectively bypass deleterious entry pathways. [source] | ||||||||||||||||