Showing papers by "Research Triangle Park published in 1999"
TL;DR: Results provide evidence for a nuclear bile acid signaling pathway that may regulate cholesterol homeostasis and modulated interaction of FXR with a peptide derived from steroid receptor coactivator 1.
Abstract: Bile acids regulate the transcription of genes that control cholesterol homeostasis through molecular mechanisms that are poorly understood. Physiological concentrations of free and conjugated chenodeoxycholic acid, lithocholic acid, and deoxycholic acid activated the farnesoid X receptor (FXR; NR1H4), an orphan nuclear receptor. As ligands, these bile acids and their conjugates modulated interaction of FXR with a peptide derived from steroid receptor coactivator 1. These results provide evidence for a nuclear bile acid signaling pathway that may regulate cholesterol homeostasis.
2,044 citations
TL;DR: This work has shown thatgenic animals suggest a complex role for NF-κB family members in immunity and development and interacts with multiple transcription factors and transcriptional co-factors.
Abstract: I. Introduction II. Nuclear Factor-κB (NF-κB) A. Introduction B. NF-κB is a dimeric transcription factor C. The regulatory subunit IκB is an inhibitor of NF-κB D. Activation and function of NF-κB E. The transcription factor NF-κB interacts with multiple transcription factors and transcriptional co-factors F. Transgenic animals suggest a complex role for NF-κB family members in immunity and development III. Steroid Hormones/Receptors: Glucocorticoids and the Glucocorticoid Receptor (GR) A. General background B. Glucocorticoid mechanism of action: the GR C. Glucocorticoid physiology D. GR/NF-κB interactions E. GR interacts with other transcription factors and transcriptional cofactors IV. NF-κB and GR Antagonism: Physiological Significance? V. Interactions Between NF-κB and Other Steroid Hormone Receptors A. Androgen receptor (AR) B. Estrogen receptor (ER) C. Progesterone receptor (PR) VI. Summary/Conclusions
826 citations
TL;DR: The Mini Asthma Quality of Life Questionnaire has good measurement properties but they are not quite as strong as those of the original Asthma quality of life Questionnaire.
Abstract: The 32-item Asthma Quality of Life Questionnaire (AQLQ) has shown good responsiveness, reliability and construct validity; properties that are essential for use in clinical trials, clinical practice and surveys. However, to meet the needs of large clinical trials and long-term monitoring, where efficiency may take precedent over precision of measurement, the 15-item self-administered MiniAQLQ has been developed. The MiniAQLQ was tested in a 9-week observational study of 40 adults with symptomatic asthma. Patients completed the MiniAQLQ, the AQLQ, the Short Form (SF)-36, the Asthma Control Questionnaire and spirometry at baseline, 1, 5 and 9 weeks. In patients whose asthma was stable between clinic visits, reliability was very acceptable for the MiniAQLQ (intraclass correlation coefficient (ICC)=0.83), but not quite as good as for the AQLQ (ICC=0.95). Similarly, responsiveness in the MiniAQLQ (p=0.0007) was good but not quite so good as for the AQLQ (p<0.0001). Construct validity (correlation with other indices of health status) was strong for both the MiniAQLQ and the AQLQ. Criterion validity showed that there was no bias between the instruments (p=0.61) and the correlation between them was high (r=0.90). The Mini Asthma Quality of Life Questionnaire has good measurement properties but they are not quite as strong as those of the original Asthma Quality of Life Questionnaire. The choice of questionnaire should depend on the task at hand.
688 citations
TL;DR: The analysis indicates that the chemicals discussed here can be clustered into three or four separate groups, based on the resulting profiles of reproductive effects, and suggests that L may display several mechanisms of endocrine toxicity, one of which involves AR binding.
Abstract: Antiandrogenic chemicals alter sexual differentiation by a variety of mechanisms, and as a consequence, they induce different profiles of effects. For example, in utero treatment with the androgen receptor (AR) antagonist, flutamide, produces ventral prostate agenesis and testicular nondescent, while in contrast, finasteride, an inhibitor of 5 alpha-dihydrotestosterone (DHT) synthesis, rarely, if ever, induces such malformations. In this regard, it was recently proposed that dibutyl phthalate (DBP) alters reproductive development by a different mechanism of action than flutamide or vinclozolin (V), which are AR antagonists, because the male offsprings display an unusually high incidence of testicular and epididymal alterations--effects rarely seen after in utero flutamide or V treatment. In this study, we present original data describing the reproductive effects of 10 known or suspected anti-androgens, including a Leydig cell toxicant ethane dimethane sulphonate (EDS, 50 mg kg-1 day-1), linuron (L, 100 mg kg-1 day-1), p,p'-DDE (100 mg kg-1 day-1), ketoconazole (12-50 mg kg-1 day-1), procymidone (P, 100 mg kg-1 day-1), chlozolinate (100 mg kg-1 day-1), iprodione (100 mg kg-1 day-1), DBP (500 mg kg-1 day-1), diethylhexyl phthalate (DEHP, 750 mg kg-1 day-1), and polychlorinated biphenyl (PCB) congener no. 169 (single dose of 1.8 mg kg-1). Our analysis indicates that the chemicals discussed here can be clustered into three or four separate groups, based on the resulting profiles of reproductive effects. Vinclozolin, P, and DDE, known AR ligands, produce similar profiles of toxicity. However, p,p'-DDE is less potent in this regard. DBP and DEHP produce a profile distinct from the above AR ligands. Male offsprings display a higher incidence of epididymal and testicular lesions than generally seen with flutamide, P, or V even at high dosage levels. Linuron treatment induced a level of external effects consistent with its low affinity for AR [reduced anogenital distance (AGD), retained nipples, and a low incidence of hypospadias]. However, L treatment also induced an unanticipated degree of malformed epididymides and testis atrophy. In fact, the profile of effects induced by L was similar to that seen with DBP. These results suggest that L may display several mechanisms of endocrine toxicity, one of which involves AR binding. Chlozolinate and iprodione did not produce any signs of maternal or fetal endocrine toxicity at 100 mg kg-1 day-1. EDS produced severe maternal toxicity and a 45% reduction in size at birth, which resulted in the death of all neonates by 5 days of age. However, EDS only reduced AGD in male pups by 15%. Ketoconazole did not demasculinize or feminize males but rather displayed anti-hormonal activities, apparently by inhibiting ovarian hormone synthesis, which resulted in delayed delivery and whole litter loss. In summary, the above in vivo data suggest that the chemicals we studied alter male sexual differentiation via different mechanisms. The anti-androgens V, P, and p,p'-DDE produce flutamide-like profiles that are distinct from those seen with DBP, DEHP, and L. The effects of PCB 169 bear little resemblance to those of any known anti-androgen. Only in depth in vitro studies will reveal the degree to which one can rely upon in vivo studies, like those presented here, to predict the cellular and molecular mechanisms of developmental toxicity.
667 citations
TL;DR: Activation of the repressed nuclear receptor CAR appears to be a versatile mediator that regulates PB induction of the CYP2B and other genes.
664 citations
TL;DR: The AQLQ(S) has strong measurement properties and is valid for measuring health-related quality of life in asthma and the choice of instrument should depend on the task at hand.
640 citations
TL;DR: In this paper, a four-decade-long field study of carbon accumulation by pine ecosystems established on previously cultivated soils in South Carolina, USA is presented, where newly accumulated carbon is tracked by its distinctive 14C signature, acquired around the onset of forest growth from thermonuclear bomb testing that nearly doubled atmospheric 14CO2 in the 1960s.
Abstract: Present understanding of the global carbon cycle is limited by uncertainty over soil-carbon dynamics. The clearing of the world's forests, mainly for agricultural uses, releases large amounts of carbon to the atmosphere (up to 2 x 1015 gyr-1), much of which arises from the cultivation driving an accelerated decomposition of soil organic matter. Although the effects of cultivation on soil carbon are well studied, studies of soil-carbon recovery after cultivation are limited. Here we present a four-decade-long field study of carbon accumulation by pine ecosystems established on previously cultivated soils in South Carolina, USA. Newly accumulated carbon is tracked by its distinctive 14C signature, acquired around the onset of forest growth from thermonuclear bomb testing that nearly doubled atmospheric 14CO2 in the 1960s. Field data combined with model simulations indicate that the young aggrading forest rapidly incorporated bomb radiocarbon into the forest floor and the upper 60 cm of underlying mineral soil. By the 1990s, however, carbon accumulated only in forest biomass, forest floor, and the upper 7.5 cm of the mineral soil. Although the forest was a strong carbon sink, trees accounted for about 80%, the forest floor 20%, and mineral soil <1%, of the carbon accretion. Despite high carbon inputs to the mineral soil, carbon sequestration was limited by rapid decomposition, facilitated by the coarse soil texture and low-activity clay mineralogy.
602 citations
TL;DR: Loss of both receptors leads to an ovarian phenotype that is distinct from that of the individual ERKO mutants, which indicates that both receptors are required for the maintenance of germ and somatic cells in the postnatal ovary.
Abstract: Mice lacking estrogen receptors α and β were generated to clarify the roles of each receptor in the physiology of estrogen target tissues. Both sexes of αβ estrogen receptor knockout (αβERKO) mutants exhibit normal reproductive tract development but are infertile. Ovaries of adult αβERKO females exhibit follicle transdifferentiation to structures resembling seminiferous tubules of the testis, including Sertoli-like cells and expression of Mullerian inhibiting substance, sulfated glycoprotein-2, and Sox9. Therefore, loss of both receptors leads to an ovarian phenotype that is distinct from that of the individual ERKO mutants, which indicates that both receptors are required for the maintenance of germ and somatic cells in the postnatal ovary.
568 citations
TL;DR: The most widely quoted number of new sexually transmitted disease (STD) cases each year is 12 million as discussed by the authors, however, this figure has not changed in more than a half century.
Abstract: Background:Accurate, updated estimates of the incidence and prevalence of sexually transmitted infections in the United States remain elusive. The most widely quoted number of new sexually transmitted disease (STD) cases each year is 12 million. However, this figure has not changed in more than a de
563 citations
TL;DR: PICK1 (protein interacting with C kinase), a PDZ domain-containing protein, interacts with the C termini of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptors in vitro and in vivo and suggests that PICK1 may play an important role in the modulation of synaptic transmission by regulating the synaptic targeting of AMPA receptors.
520 citations
TL;DR: These collective data support the use of salmeterol as first-line bronchodilator therapy for the long-term treatment of airflow obstruction in patients with COPD.
TL;DR: A "reverse endocrinology" strategy has resulted in the discovery of unanticipated nuclear signaling pathways for retinoids, fatty acids, eicosanoids, and steroids with important physiological and pharmacological ramifications.
Abstract: Steroid and thyroid hormones and vitamin A metabolites (retinoids) regulate the expression of complex gene programs by binding to members of the nuclear receptor family of ligand-activated transcription factors. The nuclear receptor family also includes many "orphan" members that currently lack known ligands but that represent candidate receptors for new hormones. Recently, natural and synthetic ligands have been identified for several orphan receptors and used to dissect their biological roles. This "reverse endocrinology" strategy has resulted in the discovery of unanticipated nuclear signaling pathways for retinoids, fatty acids, eicosanoids, and steroids with important physiological and pharmacological ramifications.
TL;DR: The results indicate that Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability and may contribute to the aneuploidy.
Abstract: Gadd45a-null mice generated by gene targeting exhibited several of the phenotypes characteristic of p53-deficient mice, including genomic instability, increased radiation carcinogenesis and a low frequency of exencephaly. Genomic instability was exemplified by aneuploidy, chromosome aberrations, gene amplification and centrosome amplification, and was accompanied by abnormalities in mitosis, cytokinesis and growth control. Unequal segregation of chromosomes due to multiple spindle poles during mitosis occurred in several Gadd45a -/- cell lineages and may contribute to the aneuploidy. Our results indicate that Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability.
TL;DR: The results suggest that formation of transcriptionally impaired hGRalpha-hGRbeta heterodimers is an important component of the mechanism responsible for the dominant negative activity of hGRbeta.
TL;DR: The next challenge is to develop technology that minimizes or eliminates the tissue culture steps, and provides predictable transgene expression.
TL;DR: Stably transduced derivatives have been selected from a substantial number of different cell types, suggesting that stable lines can be derived from any cell type that exhibits transient expression.
Abstract: Recombinant baculoviruses can serve as gene-transfer vehicles for transient expression of recombinant proteins in a wide range of mammalian cell types. Furthermore, by inclusion of a dominant selectable marker in the viral vector, cell lines can be derived that stably express recombinant genes. A virus was constructed containing two expression cassettes controlled by constitutive mammalian promoters: the cytomegalovirus immediate early promoter/enhancer directing expression of green fluorescent protein and the simian virus 40 (SV40) early promoter controlling neomycin phosphotransferase II. Using this virus, efficient gene delivery and expression was observed and measured in numerous cell types of human, primate, and rodent origin. In addition to commonly used transformed cell lines such as HeLa, CHO, Cos-7, and 293, this list includes primary human keratinocytes and bone marrow fibroblasts. In all cases, addition of butyrate or trichostatin A (a selective histone deacetylase inhibitor) to transduced cells markedly enhanced the levels of reporter protein expression observed. When transduced cells are put under selection with the antibiotic G418, cell lines can be obtained at high frequency that stably maintain the expression cassettes of the vector DNA and exhibit stable, high-level expression of the reporter gene. Stably transduced derivatives have been selected from a substantial number of different cell types, suggesting that stable lines can be derived from any cell type that exhibits transient expression.
TL;DR: In this article, a review examines the potential for γ-hexachlorocyclohexane (HCH) to be transformed into other isomers of HCH.
Abstract: This review examines the potential for γ-hexachlorocyclohexane (HCH) to be transformed into other isomers of HCH. HCH residues are among the most widely distributed and frequently detected organochlorine contaminants in the environment. The potential environmental and human health risks associated with these residues have prompted Canada, the United States, and Mexico to consider the development of a North American Regional Action Plan (NARAP) to assess and mitigate HCH pollution. More information on the propensity of γ-HCH to transform into other isomers is essential to the development of an effective regional management program. The high relative concentrations of α-HCH in the Arctic suggest that γ-HCH may be transformed into other isomers in the environment. Laboratory studies show that significant photoisomerization of γ-HCH to α-HCH is possible. However, field studies do not find evidence for significant isomerization of γ-HCH, and recent environmental samples suggest that α-HCH residues are declinin...
TL;DR: A good correlation was found between the fraction of dose absorbed and the effective permeability for ten drugs covering a wide range of absorption characteristics, and the model was able to explain the oral plasma concentration profiles of atenolol.
TL;DR: DBP is an example of an environmental antiandrogen that disrupts androgen-regulated male sexual differentiation without interacting directly with the androgen receptor (AR) in vitro, as does flutamide.
TL;DR: CLA is a high affinity ligand and activator of peroxisome proliferator-activated receptor alpha (PPARalpha) and induces accumulation of PPAR-responsive mRNAs in a rat hepatoma cell line and its effects on lipid metabolism may be attributed to transcriptional events associated with this nuclear receptor.
TL;DR: The effective proinflammatory effects of endotoxin on macrophages may upset lung homeostasis while metals-induced cytotoxicity/necrosis may set up inflammation independent of macrophage-derived cytokines.
TL;DR: FXR is a physiological BA sensor that is likely to play an essential role in BA homeostasis through the regulation of genes involved in their enterohepatic circulation.
TL;DR: This work has shown that independent signal transduction pathways regulate cellular turgor during hyperosmotic stress and appressorium-mediated plant infection in Magnaporthe grisea, and that Δosm1 mutants showed a dramatically reduced ability to accumulate arabitol in the mycelium.
Abstract: The phytopathogenic fungus Magnaporthe grisea elaborates a specialized infection cell called an appressorium with which it mechanically ruptures the plant cuticle. To generate mechanical force, appressoria produce enormous hydrostatic turgor by accumulating molar concentrations of glycerol. To investigate the genetic control of cellular turgor, we analyzed the response of M. grisea to hyperosmotic stress. During acute and chronic hyperosmotic stress adaptation, M. grisea accumulates arabitol as its major compatible solute in addition to smaller quantities of glycerol. A mitogen-activated protein kinase–encoding gene OSM1 was isolated from M. grisea and shown to encode a functional homolog of HIGH-OSMOLARITY GLYCEROL1 ( HOG1 ), which encodes a mitogen-activated protein kinase that regulates cellular turgor in yeast. A null mutation of OSM1 was generated in M. grisea by targeted gene replacement, and the resulting mutants were sensitive to osmotic stress and showed morphological defects when grown under hyperosmotic conditions. M. grisea Δ osm1 mutants showed a dramatically reduced ability to accumulate arabitol in the mycelium. Surprisingly, glycerol accumulation and turgor generation in appressoria were unaltered by the Δ osm1 null mutation, and the mutants were fully pathogenic. This result indicates that independent signal transduction pathways regulate cellular turgor during hyperosmotic stress and appressorium-mediated plant infection. Consistent with this, exposure of M. grisea appressoria to external hyperosmotic stress induced OSM1 -dependent production of arabitol.
TL;DR: It is suggested that P450 2E1 is possibly the only cytochrome P450 enzyme involved in the metabolism of AM and AN in mice, that inhibiting total P450 activity does not result in new pathways of non-P450 metabolism of aminobenzotriazole, and that mice devoid of P4502E1 do not excrete metabolites of AM or AN that would be produced by oxidation by other cyto Chrome P450s.
Abstract: Acrylonitrile (AN) and acrylamide (AM) are commonly used in the synthesis of plastics and polymers. In rodents, AM and AN are metabolized to the epoxides glycidamide and cyanoethylene oxide, respectively. The aim of this study was to determine the role of cytochrome P450 in the metabolism of AM and AN in vivo. Wild-type (WT) mice, WT mice pretreated with aminobenzotriazole (ABT, 50 mg/kg ip, 2 h pre-exposure), and mice devoid of cytochrome P450 2E1 (P450 2E1-null) were treated with 50 mg/kg [13C]AM po. WT mice and P450 2E1-null mice were treated with 2.5 or 10 mg/kg [13C]AN po. Urine was collected for 24 h, and metabolites were characterized using 13C NMR. WT mice excreted metabolites derived from the epoxides and from direct GSH conjugation with AM or AN. Only metabolites derived from direct GSH conjugation with AM or AN were observed in the urine from ABT-pretreated WT mice and P450 2E1-null mice. On the basis of evaluation of urinary metabolites at these doses, these data suggest that P450 2E1 is possi...
TL;DR: The analysis of the intracellular maturation and catalytic activity of the widely expressed metalloprotease disintegrin MDC9 suggests that removal of the inhibitory pro-domain of M DC9 by a furin-type pro-protein convertase in the secretory pathway is a prerequisite for protease activity.
TL;DR: The hepatocarcinogenic response of rodents to DEHP is not relevant to human cancer risk at any anticipated exposure level, and DEHP should be classified an unlikely human carcinogen with a margin of exposure (MOE) approach to risk assessment.
TL;DR: The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate glucose and lipid homeostasis as mentioned in this paper and play a central role in the regulation of adipogenesis and is the molecular target for the 2,4-thiazolidinedione class of antidiabetic drugs.
Abstract: The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate glucose and lipid homeostasis. The PPARγ subtype plays a central role in the regulation of adipogenesis and is the molecular target for the 2,4-thiazolidinedione class of antidiabetic drugs. Structural studies have revealed that agonist ligands activate the PPARs through direct interactions with the C-terminal region of the ligand-binding domain, which includes the activation function 2 helix. GW0072 was identified as a high-affinity PPARγ ligand that was a weak partial agonist of PPARγ transactivation. X-ray crystallography revealed that GW0072 occupied the ligand-binding pocket by using different epitopes than the known PPAR agonists and did not interact with the activation function 2 helix. In cell culture, GW0072 was a potent antagonist of adipocyte differentiation. These results establish an approach to the design of PPAR ligands with modified biological activities.
TL;DR: It is suggested that normal amounts of phytoestrogens in natural-ingredient rodent diets may affect one developmental parameter, the female AGD, and that higher doses can affect several other parameters in both males and females.
TL;DR: For combined oral contraceptives and progestin-only methods, the main mechanisms are ovulation inhibition and changes in the cervical mucus that inhibit sperm penetration as discussed by the authors, but no scientific evidence indicates that prevention of implantation actually results from the use of these methods.
TL;DR: A novel signal processing strategy for cochlear implants designed to emphasize stochastic independence across the excited neural population is described, based on the observation that high rate pulse trains may produce random spike patterns in auditory nerve fibers that are statistically similar to those produced by spontaneous activity in the normal cochlea.