bluuebunny/crossref_metadata_2025_split huggingface dataset:
A preclinical pharmacokinetic/pharmacodynamic approach to determine a dose of GnRH, for treatment of ovarian follicular cyst in cattle
Authors: MONNOYER S. , GUYONNET J. , TOUTAIN P. L. 
Published: December 2004

The objective of this study was to explore the value of a preclinical PK/PD approach to determine a gonadotropin‐releasing hormone (GnRH) dose in cows using the pituitary LH response as a surrogate endpoint.Using an indirect effect model with stimulation of the LH entry rate, the in vivo basic pharmacodynamic parameters of GnRH were determined. The EC50 of GnRH was 51 ± 16 pg/mL, the EC50 being the GnRH plasma concentration able to produce 50% of the maximum possible stimulation (Smax) of the hypophysis (Smax = 48 ± 13). From individual PK/PD parameters, the ED50 of GnRH, i.e. the estimated dose of GnRH required to determine half the maximum possible stimulating effect on LH release, was calculated to 62 μg/h per cow. Using the PK/PD model, the GnRH dose required to achieve a selected breakpoint value of 5 ng/mL for maximum LH concentration (surrogate value for LH concentration predicting clinical efficacy for cystic conditions), was 52 ± 18 μg and for a standard GnRH dose of 100 μg, the mean maximum plasma LH concentration predicted by the model was 7.22 ± 0.98 ng/mL.
Deletion of the Dynein Heavy-Chain Gene
DYN1
Leads to Aberrant Nuclear Positioning and Defective Hyphal Development in
Candida albicans
Authors: Martin R. , Walther A. , Wendland J. 
Published: December 2004

ABSTRACT

Cytoplasmic dynein is a microtubule-associated minus-end-directed motor protein.
CaDYN1
encodes the single dynein heavy-chain gene of
Candida albicans
. The open reading frames of both alleles of
CaDYN1
were completely deleted via a PCR-based approach.
Cadyn1
mutants are viable but grow more slowly than the wild type. In vivo time-lapse microscopy was used to compare growth of wild-type (SC5314) and
dyn1
mutant strains during yeast growth and after hyphal induction. During yeast-like growth,
Cadyn1
strains formed chains of cells. Chromosomal
TUB1
-
GFP
and
HHF1
-
GFP
alleles were used both in wild-type and mutant strains to monitor the orientation of mitotic spindles and nuclear positioning in
C. albicans
. In vivo fluorescence time-lapse analyses with
HHF1-GFP
over several generations indicated defects in
dyn1
cells in the realignment of spindles with the mother-daughter axis of yeast cells compared to that of the wild type. Mitosis in the
dyn1
mutant, in contrast to that of wild-type yeast cells, was very frequently completed in the mother cells. Nevertheless, daughter nuclei were faithfully transported into the daughter cells, resulting in only a small number of multinucleate cells.
Cadyn1
mutant strains responded to hypha-inducing media containing
l
-proline or serum with initial germ tube formation. Elongation of the hyphal tubes eventually came to a halt, and these tubes showed a defect in the tipward localization of nuclei. Using a heterozygous
DYN1/dyn1
strain in which the remaining copy was controlled by the regulatable
MAL2
promoter, we could switch between wild-type and mutant phenotypes depending on the carbon source, indicating that the observed mutant phenotypes were solely due to deletion of
DYN1
.
Relaxed Primer Specificity Associated with Reverse Transcriptases Encoded by the pFOXC Retroplasmids of
Fusarium oxysporum
Authors: Simpson E. Barry , Ross Shannon L. , Marchetti Sarah E. , Kennell John C. 
Published: December 2004

ABSTRACT

The pFOXC mitochondrial retroplasmids are small, autonomously replicating linear DNAs that have a telomere-like repeat of a 5-bp sequence at their termini. The plasmids are possible evolutionary precursors of the ribonucleoprotein complex telomerase, as they encode an active reverse transcriptase (RT) that is involved in plasmid replication. Using an in vitro system to study reverse transcription, we show that the pFOXC RT is capable of copying in vitro-synthesized RNAs by use of cDNA primers or extension of snapped-back RNA templates. The ability of the pFOXC RT to use base-paired primers distinguishes it from the closely related RTs encoded by the Mauriceville and Varkud mitochondrial retroplasmids of
Neurospora
spp. Reaction products are similar, but not identical, to those obtained with conventional RTs, and differences reflect the ability of the pFOXC RT to initiate cDNA synthesis with loosely associated primers. The pFOXC RT can also copy DNA templates and extend 3′ mismatched DNA oligonucleotide primers. Analysis of pFOXC in vivo replication intermediates suggests that telomeric repeats are added during reverse transcription, and the ability to extend loosely associated primers could play a role in repeat formation by mechanisms similar to those associated with telomerase and certain non-long-terminal-repeat retrotransposons.
Snf7p, a Component of the ESCRT-III Protein Complex, Is an Upstream Member of the
RIM101
Pathway in
Candida albicans
Authors: Kullas Amy L. , Li Mingchun , Davis Dana A. 
Published: December 2004

ABSTRACT

The success of
Candida albicans
as an opportunistic pathogen is based in part on its ability to adapt to diverse environments. The
RIM101
pathway governs adaptation to neutral-alkaline environments and is required for virulence. Analysis of a genomic two-hybrid study conducted with
Saccharomyces cerevisiae
revealed that components involved in multivesicular bodies (MVB) transport may interact with
RIM101
pathway members. Thus, we hypothesized that these proteins may function in the
RIM101
pathway in
C. albicans
. We identified
C. albicans
homologs to
S. cerevisiae
Snf7p, Vps4p, and Bro1p and generated mutants in the cognate gene. We found that
snf7
Δ/Δ mutants, but not
vps4
Δ/Δ nor
bro1
Δ/Δ mutants, had phenotypes similar to, but more severe than, those of
RIM101
pathway mutants. We found that the constitutively active
RIM101-405
allele partially rescued
snf7
Δ/Δ mutant phenotypes. The
vps4
Δ/Δ mutant had subtle phenotypes, but these were not rescued by the
RIM101-405
allele. Further, we found that the
snf7
Δ/Δ,
vps4
Δ/Δ, and
bro1
Δ/Δ mutants did not efficiently localize the vital dye FM4-64 to the vacuole and that it was often accumulated in an MVB-like compartment. This phenotype was not rescued by
RIM101-405
or observed in
RIM101
pathway mutants. These results suggest that Snf7p may serve two functions in the cell: one as a
RIM101
pathway member and one for MVB transport to the vacuole.
Control of rRNA Synthesis in
Escherichia coli
: a Systems Biology Approach
Authors: Dennis Patrick P. , Ehrenberg Mans , Bremer Hans 
Published: December 2004

SUMMARY

The first part of this review contains an overview of the various
contributions and models relating to the control of rRNA synthesis
reported over the last 45 years. The second part describes a systems
biology approach to identify the factors and effectors that control the
interactions between RNA polymerase and rRNA (
rrn
) promoters
of
Escherichia coli
bacteria during exponential growth in
different media. This analysis is based on measurements of absolute
rrn
promoter activities as transcripts per minute per promoter
in bacterial strains either deficient or proficient in the synthesis of
the factor Fis and/or the effector ppGpp. These absolute promoter
activities are evaluated in terms of
rrn
promoter strength
(
V
max
/

K
m

) and free RNA
polymerase concentrations. Three major conclusions emerge from this
evaluation. First, the
rrn
promoters are not saturated with
RNA polymerase. As a consequence, changes in the concentration of free
RNA polymerase contribute to changes in
rrn
promoter
activities. Second,
rrn
P2 promoter strength is not
specifically regulated during exponential growth at different rates;
its activity changes only when the concentration of free RNA polymerase
changes. Third, the effector ppGpp reduces the strength of the
rrn
P1 promoter both directly and indirectly by reducing
synthesis of the stimulating factor Fis. This control of
rrn
P1 promoter strength forms part of a larger feedback loop that adjusts
the synthesis of ribosomes to the availability of amino acids via amino
acid-dependent control of ppGpp
accumulation.
Metagenomics: Application of Genomics to Uncultured Microorganisms
Authors: Handelsman Jo 
Published: December 2004

SUMMARY

Metagenomics (also referred to as environmental and community genomics) is the genomic analysis of microorganisms by direct extraction and cloning of DNA from an assemblage of microorganisms. The development of metagenomics stemmed from the ineluctable evidence that as-yet-uncultured microorganisms represent the vast majority of organisms in most environments on earth. This evidence was derived from analyses of 16S rRNA gene sequences amplified directly from the environment, an approach that avoided the bias imposed by culturing and led to the discovery of vast new lineages of microbial life. Although the portrait of the microbial world was revolutionized by analysis of 16S rRNA genes, such studies yielded only a phylogenetic description of community membership, providing little insight into the genetics, physiology, and biochemistry of the members. Metagenomics provides a second tier of technical innovation that facilitates study of the physiology and ecology of environmental microorganisms. Novel genes and gene products discovered through metagenomics include the first bacteriorhodopsin of bacterial origin; novel small molecules with antimicrobial activity; and new members of families of known proteins, such as an Na
+
(Li
+
)/H
+
antiporter, RecA, DNA polymerase, and antibiotic resistance determinants. Reassembly of multiple genomes has provided insight into energy and nutrient cycling within the community, genome structure, gene function, population genetics and microheterogeneity, and lateral gene transfer among members of an uncultured community. The application of metagenomic sequence information will facilitate the design of better culturing strategies to link genomic analysis with pure culture studies.
Metabolic Interdependence of Obligate Intracellular Bacteria and Their Insect Hosts
Authors: Zientz Evelyn , Dandekar Thomas , Gross Roy 
Published: December 2004

SUMMARYMutualistic associations of obligate intracellular bacteria and insects have attracted much interest in the past few years due to the evolutionary consequences for their genome structure. However, much less attention has been paid to the metabolic ramifications for these endosymbiotic microorganisms, which have to compete with but also to adapt to another metabolism—that of the host cell. This review attempts to provide insights into the complex physiological interactions and the evolution of metabolic pathways of several mutualistic bacteria of aphids, ants, and tsetse flies and their insect hosts.
Contribution of capsaicin-sensitive sensory neurons to antithrombin-induced reduction of ischemia/reperfusion-induced liver injury in rats
Authors: Harada Naoaki , Yuksel Mehtap , Isobe Hirotaka , Okajima Kenji 
Published: December 2004

SummaryWe previously reported that antithrombin (AT) reduced ischemia/ reperfusion (I/R)-induced liver injury in rats by increasing endothelial production of prostacyclin (PGI2). However, the mechanism(s) underlying this phenomenon remains to be fully elucidated. We also demonstrated that activation of capsaicinsensitive sensory neurons increased endothelial production of PGI2 by releasing calcitonin gene-related peptide (CGRP) in rats subjected to hepatic I/R. In the present study, we investigated whether AT increases endothelial production of PGI2 through activation of the sensory neurons in rats subjected to hepatic I/R. AT significantly enhanced the I/R-induced increases in hepatic tissue levels of CGRP in rats. Increases in hepatic tissue levels of 6-keto-PGF1α, a stable metabolite of PGI2 , the increase in hepatic-tissue blood flow, and attenuation of both hepatic local inflammatory responses and liver injury in rats administered AT were completely reversed by administration of capsazepine, an inhibitor of sensory neuron activation and CGRP(8–37), a CGRP antagonist.AT did not show any protective effect on liver injury in animals undergoing functional denervation by administration of a large amount of capsaicin.AT significantly increased CGRP release from cultured dorsal root ganglion neurons isolated from rats in the presence of capsaicin.Taken together,these observations strongly suggested that AT might increase hepatic tissue levels of PGI2 via enhancement of hepatic I/R-induced activation of capsaicin-sensitive sensory neurons,thereby reducing liver injury in rats. In this process, CGRP-induced activation of both endothelial nitric oxide synthase and cyclooxygenase-1 might be critically involved.
Haemostatic abnormalities and thrombotic disorders in malignant lymphoma
Authors: Sase Tomohiro , Yamaguchi Motoko , Ogawa Shoko , Kamikura Yuko , Nishikawa Masakatsu , Kaneko Toshihiro , Abe Yasunori , Nishioka Junji , Nobori Tsutomu , Shiku Hiroshi , Wada Hideo 
Published: December 2004

SummaryWe examined haemostatic abnormalities and thrombotic disorders in 217 patients with malignant lymphoma. Plasma levels of fibrinogen and D-dimer were significantly higher in patients with malignant lymphoma than in healthy subjects.The incidence of severe complications, such as disseminated intravascular coagulation (DIC) and interstitial pneumonia (IP), differed with each clinical stage or histological type, but they occurred frequently in stage IV or natural killer (NK) cell lymphoma. Plasma levels of fibrinogen degradation products (FDP) and D-dimer, leukocyte tissue factor (TF) mRNA and plasma TF antigen were significantly higher in stage IV than in stage I, II or III. Plasma levels of FDP, D-dimer, and leukocyte TF mRNA in NK cell lymp homa were markedly higher than in other types of lymphoma. Immunohistochemical staining of NK cell lymphoma revealed that granulocyte macrophage colony-stimulating factor was positive in tumour cells, whereas von Willebrand factor and TF were positive in vascular endothelial cells of surrounding tissue. Our results suggested that patients with stage IV disease and NK cell lymphoma were in abnormal thrombotic and haemostatic state, and may frequently develop DIC and IP. One of the mechanisms of DIC and IP may involve elevated cytokine production by lymphoma cells, which can stimulate the expression of TF in blood cells or surrounding tissue.
High incidence of thrombosis in African-American and Latin-American patients with Paroxysmal Nocturnal Haemoglobinuria
Authors: Thaler Howard , Luzzatto Lucio , Araten David 
Published: December 2004

SummaryParoxysmal Nocturnal Haemoglobinuria (PNH) results in a marked thrombophilic state by unknown mechanisms. Geographic differences in thrombosis incidence in PNH have been observed. We have reviewed 64 patients with “Classic PNH” from a single institution in order to determine the rate of thrombosis in different ethnic groups.When we compared African- Americans (n=11) and Latin-Americans (n=8) with other patients (n= 45), we found that African-American and Latin-American patients are at increased risk [Hazard ratio 3.66 (p=0.005) and 3.52, (p= 0.035) respectively by Cox regression]. Our data also suggest that this difference in the rate of thrombosis has an impact on length of survival.These findings demonstrate that ethnicity is a risk factor for thrombosis in PNH and have implications for decision-making regarding the management of these patients,including the prevention of thrombosis.
Tissue factor pathway inhibitor on circulating microparticles in acute myocardial infarction
Authors: Steppich Birgit , Mattisek Christoph , Sobczyk Dean , Kastrati Adnan , Schömig Albert , Ott Ilka 
Published: December 2004

SummaryIn acute myocardial infarction (AMI), increased Tissue Factor (TF) expression on circulating monocytes and microparticles (MP) may contribute to thrombotic events. Because surfaceboundTissue Factor Pathway Inhibitor-1 (TFPI) inhibitsTF activity on monocytes and endothelial cells decreased TFPI expression may reinforce the procoagulant activity of circulating MP.Aim of the study was to analyze TFPI expression and TF activity after stenting and thrombolysis inAMI.Thirty-nine patients of a randomized study comparing intravenous thrombolysis (n = 19) and stenting (n = 20) were included. Before and after therapy blood samples for analysis of MPs, TF antigen and activity, prothrombin fragment F1+2 and D-dimer were obtained.TFPI expression on TF positive MPs was decreased after thrombolysis but not after stenting. In contrast, TF plasma levels and TF positive MP remained unchanged in both treatment groups. After thrombolysis increased D-dimer and F1+2 plasma concentrations indicated activation of fibrinolysis and coagulation. Significance of MPTFPI for inhibition ofTF activity was measured using inhibitory TFPI antibodies. Membrane-associated TFPI inhibited TF activity on circulating MPs. After thrombolysis inhibition of TF activity by TFPI was decreased as compared to stenting. Correlation of circulating TF with F1+2 only after thrombolysis, suggests a role forTF-induced activation of coagulation after thrombolysis. Enhanced TF activity on circulating MPs inAMI is inhibited by endogenous surface-boundTFPI.After thrombolysis but not after stenting MPTFPI is degraded and may induce thrombin generation due to unopposed tissue factor activity. Anti-TF therapies during thrombolysis may reduce thrombin generation in AMI.
Regulation of chemotaxis by the cytoplasmic domain of tissue factor
Authors: Johnell Matilda , Sorensen Brit , Petersen Lars , Heldin Carl-Henrik , Siegbahn Agneta 
Published: December 2004

SummaryWe previously demonstrated that FVIIa bound to tissue factor (TF) induces a hyperchemotactic response towards PDGF-BB. The aim of the present study was to investigate the role of the cytoplasmic domain of TF in cell migration. Porcine aortic endothelial (PAE) cells expressing human PDGF β -receptors (PAE/ PDGFR β ) were transfected for expression of human wildtype TF (PAE/PDGFRβ ,TF), a construct lacking the cytoplasmic domain (PAE/PDGFRβ ,TF ∆ cyto), a construct with alanine replacement of serine 258 (PAE/PDGFRβ ,TFS258A), or a construct with alanine replacement of serine 253, 258 and 263 in the cytoplasmic domain (PAE/PDGFRβ ,TF3SA). All stably transfected cell lines expressed functional TF. Chemotaxis was analyzed in a modified Boyden chamber assay. PAE/PDGFRβ ,TF cells stinulated with FVIIa migrated towards a 100-fold lower concentration of PDGF-BB than in the absence of FVIIa,however,hyperchemotaxis was not seen in PAE/PDGFRβ ,TF ∆ cyto cells. PAE/ PDGFR β /TFS258A and PAE/PDGFRβ ,TF3SA cells responded to low levels of PDGF-BB, but migrated a significantly shorter distance than PAE/PDGFRβ ,TF cells. Thus, hyperchemotaxis towards PDGF-BB is likely to depend in part on phosphorylation of the cytoplasmic domain of TF.We conclude that the cytoplasmic domain of TF plays a pivotal role in modulating cellular migration response.Our results suggest that the FVIIa/TF complex mediates intracellular signaling by alternative signal transduction pathway(s).
Model Describing the Relationship Between Pharmacokinetics and Hematologic Toxicity of the Epirubicin-Docetaxel Regimen in Breast Cancer Patients
Authors: Sandström M. , Lindman H. , Nygren P. , Lidbrink E. , Bergh J. , Karlsson M.O. 
Published: December 2004

Purpose The aims of the present study were (1) to characterize the pharmacokinetics of both component drugs and (2) to describe the relationship between the pharmacokinetics and the dose-limiting hematologic toxicity for the epirubicin (EPI)/docetaxel (DTX) regimen in breast cancer patients. Patients and Methods Forty-four patients with advanced disease received EPI and DTX every 3 weeks for up to nine cycles. The initial doses (EPI/DTX) were 75/70 mg/m2. Based on leukocyte (WBC) and platelet counts, the subsequent doses were, stepwise, either escalated (maximum, 120/100 mg/m2) or reduced (minimum, 40/50 mg/m2). Hematologic toxicity was monitored in all patients, whereas pharmacokinetics was studied in 16 patients. A semiphysiological model, including physiological parameters as well as drug-specific parameters, was used to describe the time course of WBC count following treatment. Results In the final pharmacokinetic model, interoccasion variability was estimated to be less than interindividual variability in the clearances for both drugs. The sum of the individual EPI and DTX areas under concentration-time curve correlated stronger to WBC survival fraction than did the corresponding sum of doses. A pharmacokinetic-pharmacodynamic (PK-PD) model with additive effects of EPI and DTX could adequately describe the data. Conclusion The final PK-PD model might provide a tool for calculation of WBC time course, and hence, for prediction of nadir day and duration of leukopenia in breast cancer patients treated with the EPI/DTX regimen.
The Declining Value‐relevance of Accounting Information and Non‐Information‐based Trading: An Empirical Analysis*
Authors: DONTOH ALEX , RADHAKRISHNAN SURESH , RONEN JOSHUA 
Published: December 2004

AbstractRecently, a growing body of literature has suggested that financial statements have lost their value‐relevance because of a shift from a traditional capital‐intensive economy to a high‐technology, service‐oriented economy. These conclusions are based on studies that find a temporal decline in the association between stock prices and accounting information (earnings and book values). This paper empirically tests a theoretical prediction arising from the noisy rational expectations equilibrium model that suggests that the decline could be driven by non‐information‐based (NIB) trading activity, because such trading reduces the ability of stock prices to reflect accounting information. Specifically, Dontoh, Radhakrishnan, and Ronen (2004) show that when NIB trading increases, the R2s of a regression of stock price on accounting information declines. Our empirical tests confirm this prediction; that is, the decline in the association between stock prices and accounting information as measured by R2s is driven by an increase in NIB trading.
The Walk‐down to Beatable Analyst Forecasts: The Role of Equity Issuance and Insider Trading Incentives*
Authors: RICHARDSON SCOTT , TEOH SIEW HONG , WYSOCKI PETER D. 
Published: December 2004

AbstractIt has been alleged that firms and analysts engage in an "earnings‐guidance game" where analysts first issue optimistic earnings forecasts and then "walk down" their estimates to a level that firms can beat at the official earnings announcement. We examine whether the walk‐down to beatable targets is associated with managerial incentives to sell stock after earnings announcements on the firm's behalf (through new equity issuance) or from their personal accounts (through option exercises and stock sales). Consistent with these hypotheses, we find that the walk‐down to beatable targets is most pronounced when firms or insiders are net sellers of stock after an earnings announcement. These findings provide new insights on the impact of capital‐market incentives on communications between managers and analysts.