bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro
Activities of Quinine and Other Antimalarials and
pfnhe
Polymorphisms in
Plasmodium
Isolates from Kenya
Authors: Okombo John , Kiara Steven M. , Rono Josea , Mwai Leah , Pole Lewa , Ohuma Eric , Borrmann Steffen , Ochola Lynette Isabella , Nzila Alexis 
Published: June 2010

ABSTRACT

Resistance to the amino alcohol quinine has been associated with polymorphisms in
pfnhe
, a sodium hydrogen exchanger. We investigated the role of this gene in quinine resistance
in vitro
in isolates from Kenya. We analyzed
pfnhe
whole-gene polymorphisms, using capillary sequencing, and
pfcrt
at codon 76 (
pfcrt
-76) and
pfmdr1
at codon 86 (
pfmdr1
-86), using PCR-enzyme restriction methodology, in 29 isolates from Kilifi, Kenya, for association with the
in vitro
activities of quinine and 2 amino alcohols, mefloquine and halofantrine.
In vitro
activity was assessed as the drug concentration that inhibits 50% of parasite growth (IC
50
). The median IC
50
s of quinine, halofantrine, and mefloquine were 92, 22, and 18 nM, respectively. The presence of 2 DNNND repeats in microsatellite ms4760 of
pfnhe
was associated with reduced susceptibility to quinine (60 versus 227 nM for 1 and 2 repeats, respectively;
P
< 0.05), while 3 repeats were associated with restoration of susceptibility. The decrease in susceptibility conferred by the 2 DNNND repeats was more pronounced in parasites harboring the
pfmdr1
-86 mutation. No association was found between susceptibility to quinine and the
pfcrt
-76 mutation or between susceptibility to mefloquine or halofantrine and the
pfnhe
gene and the
pfcrt
-76 and
pfmdr1
-86 mutations. Using previously published data on the
in vitro
activities of chloroquine, lumefantrine, piperaquine, and dihydroartemisinin, we investigated the association of their activities with
pfnhe
polymorphism. With the exception of a modulation of the activity of lumefantrine by a mutation at position 1437,
pfnhe
did not modulate their activities. Two DNNND repeats combined with the
pfmdr1
-86 mutation could be used as an indicator of reduced susceptibility to quinine.
Effects of Four Different Meal Types on the Population Pharmacokinetics of Single-Dose Rifapentine in Healthy Male Volunteers
Authors: Zvada Simbarashe P. , Van Der Walt Jan-Stefan , Smith Peter J. , Fourie P. Bernard , Roscigno Giorgio , Mitchison Denis , Simonsson Ulrika S. H. , McIlleron Helen M. 
Published: June 2010

ABSTRACT
Rifapentine and its primary metabolite, 25-desacetyl rifapentine, are active against mycobacterium tuberculosis. The objectives of this study were to describe the population pharmacokinetics of rifapentine and 25-desacetyl rifapentine in fasting and fed states. Thirty-five male healthy volunteers were enrolled in an open-label, randomized, sequential, five-way crossover study. Participants received a single 900-mg dose of rifapentine after meals with high fat (meal A), bulk and low fat (meal B), bulk and high fat (meal C), high fluid and low fat (meal D), or 200 ml of water (meal E). Venous blood samples were collected over 72 h after each rifapentine dose, and plasma was analyzed for rifapentine and 25-desacetyl rifapentine using high-performance liquid chromatography. Pharmacokinetic data were analyzed by nonlinear mixed-effect modeling using NONMEM. Compared with the fasting state, meal A had the greatest effect on rifapentine oral bioavailability, increasing it by 86%. Meals B, C, and D resulted in 33%, 46%, and 49% increases in rifapentine oral bioavailability, respectively. Similar trends were observed for 25-desacetyl rifapentine. As meal behavior has a substantial impact on rifapentine exposure, it should be considered in the evaluation of optimal dosing approaches.
Population Dynamics of Antibiotic Treatment: a Mathematical Model and Hypotheses for Time-Kill and Continuous-Culture Experiments
Authors: Levin Bruce R. , Udekwu Klas I. 
Published: June 2010

ABSTRACT
The objectives of the study were to develop a quantitative framework for generating hypotheses for and interpreting the results of time-kill and continuous-culture experiments designed to evaluate the efficacy of antibiotics and to relate the results of these experiments to MIC data. A mathematical model combining the pharmacodynamics (PD) of antibiotics with the population dynamics of bacteria exposed to these drugs in batch and continuous cultures was developed, and its properties were analyzed numerically (using computer simulations). These models incorporate details of (i) the functional form of the relationship between the concentrations of the antibiotics and rates of kill, (ii) the density of the target population of bacteria, (iii) the growth rate of the bacteria, (iv) byproduct resources generated from dead bacteria, (v) antibiotic-refractory subpopulations, persistence, and wall growth (biofilms), and (vi) density-independent and -dependent decay in antibiotic concentrations. Each of the factors noted above can profoundly affect the efficacy of antibiotics. Consequently, if the traditional (CLSI) MICs represent the sole pharmacodynamic parameter, PK/PD indices can fail to predict the efficacy of antibiotic treatment protocols. More comprehensive pharmacodynamic data obtained with time-kill and continuous-culture experiments would improve the predictive value of these indices. The mathematical model developed here can facilitate the design and interpretation of these experiments. The validity of the assumptions behind the construction of these models and the predictions (hypotheses) generated from the analysis of their properties can be tested experimentally. These hypotheses are presented, suggestions are made about how they can be tested, and the existing statuses of these tests are briefly discussed.
PSI-7851, a Pronucleotide of β-
d
-2′-Deoxy-2′-Fluoro-2′-
C
-Methyluridine Monophosphate, Is a Potent and Pan-Genotype Inhibitor of Hepatitis C Virus Replication
Authors: Lam Angela M. , Murakami Eisuke , Espiritu Christine , Steuer Holly M. Micolochick , Niu Congrong , Keilman Meg , Bao Haiying , Zennou Veronique , Bourne Nigel , Julander Justin G. , Morrey John D. , Smee Donald F. , Frick David N. , Heck Julie A. , Wang Peiyuan , Nagarathnam Dhanapalan , Ross Bruce S. , Sofia Michael J. , Otto Michael J. , Furman Phillip A. 
Published: June 2010

ABSTRACT

The hepatitis C virus (HCV) NS5B RNA polymerase facilitates the RNA synthesis step during the HCV replication cycle. Nucleoside analogs targeting the NS5B provide an attractive approach to treating HCV infections because of their high barrier to resistance and pan-genotype activity. PSI-7851, a pronucleotide of β-
d
-2′-deoxy-2′-fluoro-2′-
C
-methyluridine-5′-monophosphate, is a highly active nucleotide analog inhibitor of HCV for which a phase 1b multiple ascending dose study of genotype 1-infected individuals was recently completed (M. Rodriguez-Torres, E. Lawitz, S. Flach, J. M. Denning, E. Albanis, W. T. Symonds, and M. M. Berry, Abstr. 60th Annu. Meet. Am. Assoc. Study Liver Dis., abstr. LB17, 2009). The studies described here characterize the
in vitro
antiviral activity and cytotoxicity profile of PSI-7851. The 50% effective concentration for PSI-7851 against the genotype 1b replicon was determined to be 0.075 ± 0.050 μM (mean ± standard deviation). PSI-7851 was similarly effective against replicons derived from genotypes 1a, 1b, and 2a and the genotype 1a and 2a infectious virus systems. The active triphosphate, PSI-7409, inhibited recombinant NS5B polymerases from genotypes 1 to 4 with comparable 50% inhibitory concentrations. PSI-7851 is a specific HCV inhibitor, as it lacks antiviral activity against other closely related and unrelated viruses. PSI-7409 also lacked any significant activity against cellular DNA and RNA polymerases. No cytotoxicity, mitochondrial toxicity, or bone marrow toxicity was associated with PSI-7851 at the highest concentration tested (100 μM). Cross-resistance studies using replicon mutants conferring resistance to modified nucleoside analogs showed that PSI-7851 was less active against the S282T replicon mutant, whereas cells expressing a replicon containing the S96T/N142T mutation remained fully susceptible to PSI-7851. Clearance studies using replicon cells demonstrated that PSI-7851 was able to clear cells of HCV replicon RNA and prevent viral rebound.
Brain Microdialysis Study of Meropenem in Two Patients with Acute Brain Injury
Authors: Dahyot-Fizelier Claire , Timofeev Ivan , Marchand Sandrine , Hutchinson Peter , Debaene Bertrand , Menon David , Mimoz Olivier , Gupta Arun , Couet William 
Published: June 2010

ABSTRACT
Concentrations of unbound meropenem in the cerebral extracellular fluid (ECF) of two patients with acute brain injury were assessed by microdialysis. Brain ECF unbound-meropenem concentrations were lower than serum unbound-meropenem concentrations, with brain-to-serum area under the concentration-time curve ratios of 0.73 and 0.14. A pharmacokinetic model was developed to fit the experimental data adequately.
Extracellular ATP and P2Y Receptor Activation Induce a Proinflammatory Host Response in the Human Urinary Tract
Authors: Säve Susanne , Persson Katarina 
Published: June 2010

ABSTRACTExtracellular ATP can be released by many cell types under conditions of cellular stress and signals through activation of purinergic receptors. Bladder uroepithelial cells grownin vitrohave previously been shown to release ATP in response to stretch. In the present study, we investigated ATP release from uroepithelial cells infected with bacteria and the effect of ATP on the host cell proinflammatory interleukin 8 (IL-8) response. The human kidney epithelial cell line A498 and the human uroepithelial cell line UROtsa were grown in culture and stimulated by the uropathogenicEscherichia coli(UPEC) IA2 strain or the stable ATP analogue ATP-γ-S. ATP and IL-8 levels were measured in cell culture medium with a luciferin-luciferase assay and enzyme-linked immunosorbent assay (ELISA), respectively. The results showed that UPEC infection of uroepithelial cells for 1 h significantly increased (P< 0.01) the extracellular ATP levels. ATP-γ-S (10 and 100 μM) stimulated release of IL-8 from UROtsa and A498 cells after 6 and 24 h. Experiments with different purinoceptor agonists suggested that P2Y receptors, and not P2X receptors, were responsible for the ATP-γ-S-induced IL-8 release. The potency profile further suggested involvement of P2Y1, P2Y2, and/or P2Y11receptors, and reverse transcription-PCR (RT-PCR) studies confirmed that the cells expressed these receptors. The amount of IL-8 released increased 12-fold in UPEC-infected cells, and apyrase, an enzyme that degrades ATP, reduced this increase by approximately 50%. The present study suggests that enhanced ATP release and P2Y receptor activation during urinary tract infection may represent a novel, non-TLR4-mediated mechanism for production of proinflammatory IL-8 in human urinary tract epithelial cells.
Identification of Lipoprotein MslA as a Neoteric Virulence Factor ofMycoplasma gallisepticum
Authors: Szczepanek S. M. , Frasca S. , Schumacher V. L. , Liao X. , Padula M. , Djordjevic S. P. , Geary S. J. 
Published: June 2010

ABSTRACTMany lipoproteins are expressed on the surfaces of mycoplasmas, and some have been implicated as playing roles in pathogenesis. Family 2 lipoproteins ofMycoplasma pneumoniaehave a conserved “mycoplasma lipoprotein X” central domain and a “mycoplasma lipoprotein 10” C-terminal domain and are differentially expressed in response to environmental conditions. Homologues of family 2 lipoproteins areMycoplasmaspecific and include the lipoprotein ofMycoplasma gallisepticum, encoded by the MGA0674 gene. Comparative transcriptomic analysis of theM. gallisepticumlive attenuated vaccine strain F and the virulent strain Rlow, reported in this study, indicated that MGA0674 is one of several differentially expressed genes. The MGA0674-encoded lipoprotein is a proteolytically processed, immunogenic, TX-114 detergent-phase protein which appears to have antigenic divergence between field strains Rlowand S6. We examined the virulence of an RlowΔMGA0674 mutant (P1H9)in vivoand observed reduced recovery and attenuated virulence in the tracheas of experimentally infected chickens. The virulence of two additional RlowΔMGA0674 mutants, 2162 and 2204, was assessed in a secondin vivovirulence experiment. These mutants exhibited partial to complete attenuationin vivo, but recovery was observed more frequently. Since onlyMycoplasmaspecies harbor homologues of MGA0674, the gene product has been renamed “Mycoplasma-specific lipoprotein A” (MslA). Collectively, these data indicate that MslA is an immunogenic lipoprotein exhibiting reduced expression in an attenuated strain and plays a role inM. gallisepticumvirulence.
Salmonella entericaReplication in Hemophagocytic Macrophages Requires Two Type Three Secretion Systems
Authors: Silva-Herzog Eugenia , Detweiler Corrella S. 
Published: June 2010

ABSTRACTSalmonella entericaserotype Typhimurium is a natural pathogen of mice, which acquire the bacteria orally and develop systemic acute infections that can become subacute to chronic infections.S.Typhimurium can reside within hemophagocytic macrophages (HMs) in SV129S6 mice, an Slc11a1/Nramp1+/+inbred strain. HMs are activated macrophages which have ingested viable hematopoietic cells and are a key characteristic of infectious and inflammatory diseases. Here we show that modestS.Typhimurium replication in HMs begins at 18 h postinfection, while activated macrophages kill the bacteria. For bacterial replication to occur, the phagocytosed viable cells must be grown to a low cell density and the multiplicity of infection must be low. HMs are able to kill phagocytosedEscherichia coli, produce reactive nitrogen species, and retainS.Typhimurium within membrane-bound vesicles.S.Typhimurium does not rescueE. coliupon coinfection of HMs. This indicates thatS.Typhimurium does not cause HMs to become permissive for other microbes; rather,S.Typhimurium is especially equipped to survive within HMs. Two type three secretion systems (T3SS) encoded byS.Typhimurium are required for replication within HMs. While the T3SS withinSalmonellapathogenicity island 2 (SPI-2) has been previously shown to be important for bacterial survival in cells, a role for SPI-1 in replication in macrophages has not been reported. The requirement for SPI-1 in HMs may help explain the role of SPI-1 during long-term colonization of mice.
Signaling through C/EBP Homologous Protein and Death Receptor 5 and Calpain Activation Differentially Regulate THP-1 Cell Maturation-Dependent Apoptosis Induced by Shiga Toxin Type 1
Authors: Lee Moo-Seung , Cherla Rama P. , Lentz Erin K. , Leyva-Illades Dinorah , Tesh Vernon L. 
Published: June 2010

ABSTRACTShiga toxins (Stxs) induce apoptosis via activation of the intrinsic and extrinsic pathways in many cell types. Toxin-mediated activation of the endoplasmic reticulum (ER) stress response was shown to be instrumental in initiating apoptosis in THP-1 myeloid leukemia cells. THP-1 cells responded to Shiga toxin type 1 (Stx1) in a cell maturation-dependent manner, undergoing rapid apoptosis in the undifferentiated state but reduced and delayed apoptosis in differentiated cells. The onset of apoptosis was associated with calpain activation and changes in expression of C/EBP homologous protein (CHOP), Bcl-2 family members, and death receptor 5 (DR5). Ligation of DR5 by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) activates the extrinsic pathway of apoptosis. We show here that expression of TRAIL and DR5 is increased by Stx1 treatment. Addition of exogenous TRAIL enhances, and anti-TRAIL antibodies inhibit, Stx1-induced apoptosis of THP-1 cells. Silencing of CHOP or DR5 expression selectively prevented caspase activation, loss of mitochondrial membrane potential, and Stx1-induced apoptosis of macrophage-like THP-1 cells. In contrast, the rapid kinetics of apoptosis induction in monocytic THP-1 cells correlated with rates of calpain cleavage. The results suggest that CHOP-DR5 signaling and calpain activation differentially contribute to cell maturation-dependent Stx1-induced apoptosis. Inhibition of these signaling pathways may protect cells from Stx cytotoxicity.
Microbial Electrosynthesis: Feeding Microbes Electricity To Convert Carbon Dioxide and Water to Multicarbon Extracellular Organic Compounds
Authors: Nevin Kelly P. , Woodard Trevor L. , Franks Ashley E. , Summers Zarath M. , Lovley Derek R. 
Published: June 2010

ABSTRACT

The possibility of providing the acetogenic microorganism
Sporomusa ovata
with electrons delivered directly to the cells with a graphite electrode for the reduction of carbon dioxide to organic compounds was investigated. Biofilms of
S. ovata
growing on graphite cathode surfaces consumed electrons with the reduction of carbon dioxide to acetate and small amounts of 2-oxobutyrate. Electrons appearing in these products accounted for over 85% of the electrons consumed. These results demonstrate that microbial production of multicarbon organic compounds from carbon dioxide and water with electricity as the energy source is feasible.

IMPORTANCE
Reducing carbon dioxide to multicarbon organic chemicals and fuels with electricity has been identified as an attractive strategy to convert solar energy that is harvested intermittently with photovoltaic technology and store it as covalent chemical bonds. The organic compounds produced can then be distributed via existing infrastructure. Nonbiological electrochemical reduction of carbon dioxide has proven problematic. The results presented here suggest that microbiological catalysts may be a robust alternative, and when coupled with photovoltaics, current-driven microbial carbon dioxide reduction represents a new form of photosynthesis that might convert solar energy to organic products more effectively than traditional biomass-based strategies.
Spatial and temporal diagenetic evolution of syntectonic sediments in a pulsatory uplifted coastal escarpment, evidenced from the Plio-Pleistocene, Makran subduction zone, Iran
Authors: Hosseini-Barzi Mahboubeh 
Published: June 2010

Abstract

Plio-Pleistocene sediments in coastal escarpments of Makran in SE Iran shows different patterns of diagenetic features in diverse depositional facies and therefore implies a facies-controlled diagenetic evolution mainly related to different porosity patterns. Although geochemical characteristics of various cements in this sediment are masked by pervasive meteoric diagenesis, remnants of primary geochemical characteristics (Mg, Mn, Fe and Sr concentrations, and δ
18
O and δ
13
C values), cathodoluminescence of these cements and paragenetic sequences of diagenetic features help us to unravel the diagenetic history and to reconstruct the history of exposures. The correlation of diagenetic features between rock units in each sedimentary column, inferred by using two distinct dolomite cementation phases, suggests pulsatory changes in the fluid chemistry related to eight episodes of seaward and landward migration of fluids as a result of relative sea-level fluctuation during eight episodes of uplift and relaxation and/or eustactic sea-level fluctuation. Moreover, lateral correlation of paragenetic sequences (eastward increase in the number of phases of cementation and dissolution) implies that pulsation in fluid migration has developed toward the eastern part of each fault-limited block as uplift and erosion rate increased. In the last stage, a net seaward migration of fluids seems to have occurred as relative sea level fell (as a result of regional uplift and/or eustacy). In the last two stages of uplift, reverse fault activities enhanced methane seepage, as indicated by the geochemistry of dolomite cements (δ
13
C−16.15‰ to 20.16‰).
The geomagnetic polarity timescale for the Triassic: linkage to stage boundary definitions
Authors: Hounslow Mark W. , Muttoni Giovanni 
Published: June 2010

Abstract

Studies of Triassic magnetostratigraphy began in the 1960s, with focus on poorly fossilferous nonmarine red-beds. Construction of the Triassic geomagnetic polarity timescale was not consolidated until the 1990s, when access to magnetometers of sufficient sensitivity became widely available to measure specimens from marine successions. The biostratigraphically-calibrated magnetostratigraphy for the Lower Triassic is currently largely based on ammonoid zonations from Boreal successions. Exceptions are the Permian–Triassic and Olenekian–Anisian boundaries, which have more extensive magnetostratigraphic studies calibrated by conodont zonations. Extensive magnetostratigraphic studies of nonmarine Lower Triassic successions allow a validation and cross-calibration of the marine-based ages into some nonmarine successions. The Middle Triassic magnetostratigraphic timescale is strongly age-constrained by conodont and ammonoid zonations from multiple Tethyan carbonate successions, the conclusions of which are supported by detailed work on several nonmarine Anisian successions. The mid Carnian is the only extensive interval in the Triassic in which biostratigraphic-based age calibration of the magnetostratigraphy is not well resolved. Problems remain with the Norian and early Rhaetian in properly constraining the magnetostratigraphic correlation between the well-validated nonmarine successions, such as the Newark Supergroup, and the marine-section-based polarity timescale. The highest time-resolution available from magnetozone correlations should be about 20–30 ka, with an average magnetozone duration of
c
. 240 ka, for the Lower and Middle Triassic, and about twice this for the Upper Triassic.
The Triassic isotope record
Authors: Tanner Lawrence H. 
Published: June 2010

Abstract

A variety of stable isotope measurements have been found useful in studying processes of environmental change. Measurements of δ
13
C, δ
18
O, δ
34
S and
87
Sr/
86
Sr all can provide information about the conditions of the water column in which sediment deposition occurred, but the most widely applied of these is δ
13
C. The carbon isotope record for the Triassic System is a complex one; a pronounced negative excursion begins below the base of the Triassic System and continues into the basal Triassic. The succeeding 4 to 6 Ma Lower Triassic interval is marked by isotopic instability, with positive and negative excursions, continuing through the basal Middle Triassic. In contrast to the Lower Triassic, most of the Middle and Upper Triassic display relative isotopic stability, with rising values of δ
13
C likely reflecting environmental recovery and increasing storage of organic carbon in terrestrial environments. The uppermost Triassic is marked by a pronounced negative excursion near the system boundary that has been linked to significant biotic turnover. The causes of the various excursions remain under investigation, particularly those at the system boundaries, with outgassing during volcanic activity, changes in productivity, ocean anoxia, and seafloor methane releases all suggested as mechanisms both for perturbing the global carbon cycle and for forcing biotic extinction.