Showing papers by "Vanderbilt University published in 1999"
TL;DR: The purpose of this study was to develop an equation from MDRD Study data that could improve the prediction of GFR from serum creatinine concentration, and major clinical decisions in general medicine, geriatrics, and oncology are made by using the Cockcroft-Gault formula and other formulas to predict the level of renal function.
Abstract: The serum creatinine concentration is widely used as an index of renal function, but this measure is affected by factors other than the glomerular filtration rate (GFR). This study examined an equa...
14,711 citations
TL;DR: Both practitioners and academics understand that consumer loyalty and satisfaction are linked inextricably. But they also understand that this relation is asymmetric as mentioned in this paper. Although loyal consumers are most...
Abstract: Both practitioners and academics understand that consumer loyalty and satisfaction are linked inextricably. They also understand that this relation is asymmetric. Although loyal consumers are most ...
8,021 citations
TL;DR: Research reveals that the reason more people have yet to shop online or even provide information to Web providers in exchange for access to information, is the fundamental lack of faith between most businesses and consumers on the Web today.
Abstract: M oving some Web consumers along to the purchase click is proving to be difficult, despite the impressive recent growth in online shopping. Consumer online shopping revenues and related corporate profits are still meager, though the industry is optimistic, thanks to bullish forecasts of cyberconsumer activity for the new millennium. In 1996, Internet shopping revenues for U.S. users, excluding cars and real estate, were estimated by Jupiter Communications , an e-commerce consulting firm in New York, at approximately $707 million but are expected to How merchants can win back lost consumer trust in the interests of e-commerce sales. reach nearly $37.5 billion by 2002 [1]. Meanwhile, the business-to-business side is taking off with more than $8 billion in revenues for 1997 and $327 billion predicted by 2002 just in the U.S., according to For-rester Research, an information consulting firm in Cambridge, Mass. [4]. On the consumer side, a variety of barriers are invoked to explain the continuing difficulties. There are, to be sure, numerous barriers. Such factors as the lack of standard technologies for secure payment, and the lack of profitable business models play important roles in the relative dearth of commercial activity by businesses and consumers on the Internet compared to what analysts expect in the near future. Granted, the commercial development of the Web is still in its infancy, so few expect these barriers to commercial development to persist. Still, commercial development of the Web faces a far more formidable barrier—consumers' fear of divulging their personal data—to its ultimate com-mercialization. The reason more people have yet to shop online or even provide information to Web providers in exchange for access to information, is the fundamental lack of faith between most businesses and consumers on the Web today. In essence, consumers simply do not trust most Web providers enough to engage in \" relationship exchanges \" involving money and personal information with them. Our research reveals that this lack of trust arises from the fact that cyberconsumers feel they lack control over the access that Web merchants have to their
2,210 citations
TL;DR: It is rare that FST can be translated into an accurate estimate of Nm, the number of migrants successfully entering a population per generation, and the mathematical model underlying this translation makes many biologically unrealistic assumptions.
Abstract: The difficulty of directly measuring gene flow has lead to the common use of indirect measures extrapolated from genetic frequency data. These measures are variants of FST, a standardized measure of the genetic variance among populations, and are used to solve for Nm, the number of migrants successfully entering a population per generation. Unfortunately, the mathematical model underlying this translation makes many biologically unrealistic assumptions; real populations are very likely to violate these assumptions, such that there is often limited quantitative information to be gained about dispersal from using gene frequency data. While studies of genetic structure per se are often worthwhile, and FST is an excellent measure of the extent of this population structure, it is rare that FST can be translated into an accurate estimate of Nm.
1,455 citations
TL;DR: In this article, computer assisted cell counting was used to reveal abnormal cytoarchitecture in left rostral and caudal orbitofrontal and dorsolateral prefrontal cortical regions in subjects with major depression as compared to psychiatrically normal controls.
1,412 citations
TL;DR: In this review the diversity of lipoxygenase expression will be highlighted and the several facets of lip oxygengenase function considered, concluding with a discussion of issues related to the acquisition of substrate in a cellular environment.
1,268 citations
TL;DR: These studies indicate that deficiencies in both β cell and hepatic GK contribute to the hyperglycemia of MODY-2, and suggest that heterozygous null for GK, either globally or just in the β cell, survive but are moderately hyperglycemic.
1,260 citations
TL;DR: M1G appears to be a major endogenous DNA adduct in human beings that may contribute significantly to cancer linked to lifestyle and dietary factors and high throughput methods for its detection and quantitation will be extremely useful for screening large populations.
Abstract: Malondialdehyde is a naturally occurring product of lipid peroxidation and prostaglandin biosynthesis that is mutagenic and carcinogenic. It reacts with DNA to form adducts to deoxyguanosine and deoxyadenosine. The major adduct to DNA is a pyrimidopurinone called M1G. Site-specific mutagenesis experiments indicate that M1G is mutagenic in bacteria and is repaired by the nucleotide excision repair pathway. M1G has been detected in liver, white blood cells, pancreas, and breast from healthy human beings at levels ranging from 1–120 per 108 nucleotides. Several different assays for M1G have been described that are based on mass spectrometry, 32 P -postlabeling, or immunochemical techniques. Each technique offers advantages and disadvantages based on a combination of sensitivity and specificity. Application of each of these techniques to the analysis of M1G is reviewed and future needs for improvements are identified. M1G appears to be a major endogenous DNA adduct in human beings that may contribute significantly to cancer linked to lifestyle and dietary factors. High throughput methods for its detection and quantitation will be extremely useful for screening large populations.
1,219 citations
TL;DR: Several issues remain to be resolved regarding the catalytic activity of the P-450 3A4 protein, including rate-limiting steps and the need for cytochrome b5, divalent cations, and acidic phospholipid systems for optimal activity.
Abstract: Cytochrome P-450 (P-450) 3A4 is the most abundant P-450 expressed in human liver and small intestine. P-450 3A4 contributes to the metabolism of approximately half the drugs in use today, and variations in its catalytic activity are important in issues of bioavailability and drug-drug interactions. The gene is known to be inducible by barbiturates, glucocorticoids, and rifampicin in humans and in isolated hepatocytes, although the mechanism remains unclear. The 5'-untranslated region includes putative basal transcription element, hepatocyte nuclear factor, p53, AP-3, glucocorticoid regulatory element, pregnane X receptor, and estrogen receptor element sequences. Recently, the GRE element has been shown to act in a classic glucocorticoid response. Several issues remain to be resolved regarding the catalytic activity of the P-450 3A4 protein, including rate-limiting steps and the need for cytochrome b5, divalent cations, and acidic phospholipid systems for optimal activity. Another issue involves the basis of the homotropic and heterotropic cooperativity seen with the enzyme. The in vivo significance of these findings remains to be further established. In addition to more basic studies on P-450 3A4, several areas of practical interest to the pharmaceutical industry require development.
1,202 citations
TL;DR: An important functional role for the insulin receptor in glucose sensing by the pancreatic beta cell is indicated and it is suggested that defects in insulin signaling at the level of the beta cell may contribute to the observed alterations in insulin secretion in type 2 diabetes.
1,140 citations
TL;DR: This article showed that matrilysin functions in intestinal mucosal defense by regulating the activity of defensins, which may be a common role for this metalloproteinase in its numerous epithelial sites of expression.
Abstract: Precursors of α-defensin peptides require activation for bactericidal activity. In mouse small intestine, matrilysin colocalized with α-defensins (cryptdins) in Paneth cell granules, and in vitro it cleaved the pro segment from cryptdin precursors. Matrilysin-deficient (MAT−/−) mice lacked mature cryptdins and accumulated precursor molecules. Intestinal peptide preparations from MAT−/− mice had decreased antimicrobial activity. Orally administered bacteria survived in greater numbers and were more virulent in MAT−/− mice than in MAT+/+ mice. Thus, matrilysin functions in intestinal mucosal defense by regulating the activity of defensins, which may be a common role for this metalloproteinase in its numerous epithelial sites of expression.
TL;DR: Atypical antipsychotic drugs as a group appear to be superior to typical neuroleptics with regard to cognitive function, however, available data suggest that these drugs produce significant differences in specific cognitive functions.
Abstract: Cognitive function is markedly impaired in most patients with schizophrenia. Antecedents of this impairment are evident in childhood. The cognitive disability is nearly fully developed at the first episode of psychosis in most patients. The contribution of cognitive impairment to outcome in schizophrenia, especially work function, has been established. Preliminary results indicate that cognitive function, along with disorganization symptoms, discriminate schizophrenia patients who are able to work full-time from those who are not. Typical neuroleptic drugs lack the ability to improve the various domains of cognitive function impaired in schizophrenia. Atypical antipsychotic drugs pharmacologically related to clozapine-quetiapine, olanzapine, risperidone, sertindole, and ziprasidone--share the ability to produce fewer extrapyramidal symptoms than typical neuroleptic drugs and more potent antagonism of serotonin2a relative to dopamine2 receptors. However, they have a number of different clinical effects. We have identified all the studies of clozapine, olanzapine, and risperidone that provide data on their effects on cognition in schizophrenia. Data for each drug are reviewed separately in order to identify differences among them in their effects on cognition. Twelve studies that report cognitive effects of clozapine are reviewed. These studies provide (1) strong evidence that clozapine improves attention and verbal fluency and (2) moderate evidence that clozapine improves some types of executive function. However, results of the effects of clozapine on working memory and secondary verbal and spatial memory were inconclusive. Risperidone has relatively consistent positive effects on working memory, executive functioning, and attention, whereas improvement in verbal learning and memory was inconsistent. Preliminary evidence presented here suggests that olanzapine improves verbal learning and memory, verbal fluency, and executive function, but not attention, working memory, or visual learning and memory. Thus, atypical antipsychotic drugs as a group appear to be superior to typical neuroleptics with regard to cognitive function. However, available data suggest that these drugs produce significant differences in specific cognitive functions. These differences may be valuable adjunctive guides for their use in clinical practice if cognitive improvements reach clinical significance. The effects of the atypical antipsychotic drugs on cholinergic and 5-HT2a-mediated neurotransmission as the possible basis for their ability to improve cognition are discussed. It is suggested that the development of drugs for schizophrenia should focus on improving the key cognitive deficits in schizophrenia: executive function, verbal fluency, working memory, verbal and visual learning and memory, and attention.
TL;DR: In this paper, the authors compared the 24-month intervention effects of a lifestyle physical activity program with traditional structured exercise on improving physical activity, cardiorespiratory fitness, and cardiovascular disease risk factors.
Abstract: ContextEven though the strong association between physical
inactivity and ill health is well documented, 60% of the population is
inadequately active or completely inactive. Traditional methods of
prescribing exercise have not proven effective for increasing and
maintaining a program of regular physical activity.ObjectiveTo compare the 24-month intervention effects of a
lifestyle physical activity program with traditional structured
exercise on improving physical activity, cardiorespiratory fitness, and
cardiovascular disease risk factors.DesignRandomized clinical trial conducted from August
1, 1993, through July 31, 1997.ParticipantsSedentary men (n = 116) and women (n = 119) with
self-reported physical activity of less than 36 and 34 kcal/kg per day,
respectively.InterventionsSix months of intensive and 18 months of maintenance
intervention on either a lifestyle physical activity or a traditional
structured exercise program.Main Outcome MeasuresPrimary outcomes were physical activity
assessed by the 7-Day Physical Activity Recall and peak oxygen
consumption (VO2peak) by a maximal exercise
treadmill test. Secondary outcomes were plasma lipid and lipoprotein
cholesterol concentrations, blood pressure, and body composition. All
measures were obtained at baseline and at 6 and 24 months.ResultsBoth the lifestyle and structured activity groups
had significant and comparable improvements in physical activity and
cardiorespiratory fitness from baseline to 24 months. Adjusted mean
changes (95% confidence intervals [CIs]) were 0.84 (95% CI,
0.42-1.25 kcal/kg per day; P<.001) and 0.69 (95% CI,
0.25-1.12 kcal/kg day; P = .002) for activity, and 0.77 (95%
CI, 0.18-1.36 mL/kg per minute; P = .01) and 1.34 (95% CI,
0.72-1.96 mL/kg per minute; P<.001) for
VO2peak for the lifestyle and structured
activity groups, respectively. There were significant and comparable
reductions in systolic blood pressure (−3.63 [95% CI, −5.54 to
−1.72 mm Hg; P<.001] and −3.26 [95% CI, −5.26 to
−1.25 mm Hg; P = .002]) and diastolic blood pressure (−5.38
[95% CI, −6.90 to −3.86 mm Hg; P<.001] and −5.14
[95% CI, −6.73 to −3.54 mm Hg; P<.001) for the lifestyle
and structured activity groups, respectively. Neither group
significantly changed their weight (−0.05 [95% CI, −1.05 to 0.96
kg; P = .93] and 0.69 [95% CI, −0.37 to 1.74 kg;
P = .20]), but each group significantly reduced their
percentage of body fat (−2.39% [95% CI, −2.92% to −1.85%;
P<.001] and −1.85% [95% CI, −2.41% to −1.28%;
P<.001]) in the lifestyle and structured activity groups,
respectively.ConclusionsIn previously sedentary healthy adults, a
lifestyle physical activity intervention is as effective as a
structured exercise program in improving physical activity,
cardiorespiratory fitness, and blood pressure.
TL;DR: In this article, the authors discuss transfer from both a retrospective and a prospective perspective: what has past transfer research taught us that is especially important for education? What might research on transfer look like in the future? Our discussion of past research is brief, not because it is unimportant but because of space limitations and the fact that our primary emphasis is on the future.
Abstract: A belief in transfer lies at the heart of our educational system. Most educators want learning activities to have positive effects that extend beyond the exact conditions of initial learning. They are hopeful that students will show evidence of transfer in a variety of situations: from one problem to another within a course, from one course to another, from one school year to the next, and from their years in school to their years in the workplace. Beliefs about transfer often accompany the claim that it is better to ' 'educate'' people broadly than simply to \"train\" them to perform particular tasks (e.g., Broudy, 1977). In this chapter, we discuss research on transfer from both a retrospective and a prospective perspective. What has past transfer research taught us that is especially important for education? What might research on transfer look like in the future? Our discussion of past research is brief, not because it is unimportant but because of space limitations and the fact that our primary emphasis is on the future. We argue that prevailing theories and methods of measuring transfer are limited in scope; we propose an alternative that complements and extends current approaches; and we sketch this alternative's implications for education. Our discussion is organized into five sections. First, we briefly summarize some of the key findings from the literature on transfer—both the successes and the disappointments. Second, we contrast the \"traditional\" view of transfer with an alternative that emphasizes the ability to learn during transfer. Third, we discuss mechanisms for transfer that emphasize Broudy's analysis of \"knowing with\" (which he adds to the more familiar replicative \"knowing that\" and applicative \"knowing how\"). Fourth, we show how our alternate view of transfer affects assumptions about what is valuable for students to learn. Finally, we show
University of California, Irvine1, New York Medical College2, University of North Carolina at Chapel Hill3, University of Chicago4, University of Washington5, Johns Hopkins University6, Yeshiva University7, University of Texas Health Science Center at San Antonio8, University of Pennsylvania9, University of Pittsburgh10, Brown University11, University of Colorado Denver12, Vanderbilt University13, University of Miami14, Yale University15
TL;DR: Specific detailed recommendations for each level have been established in this document, which are intended to improve the rate of early suspicion and diagnosis of, and therefore early intervention for, autism.
Abstract: The Child Neurology Society and American Academy of Neurology recently proposed to formulate Practice Parameters for the Diagnosis and Evaluation of Autism for their memberships. This endeavor was expanded to include representatives from nine professional organizations and four parent organizations, with liaisons from the National Institutes of Health. This document was written by this multidisciplinary Consensus Panel after systematic analysis of over 2,500 relevant scientific articles in the literature. The Panel concluded that appropriate diagnosis of autism requires a dual-level approach: (a) routine developmental surveillance, and (b) diagnosis and evaluation of autism. Specific detailed recommendations for each level have been established in this document, which are intended to improve the rate of early suspicion and diagnosis of, and therefore early intervention for, autism.
TL;DR: The death rates in some subgroups of patients with sepsis-induced organ failure have decreased, even though there is no specific therapy for sepsi, and the reduced mortality may be .
Abstract: Sepsis is an infection-induced syndrome defined as the presence of two or more of the following features of systemic inflammation: fever or hypothermia, leukocytosis or leukopenia, tachycardia, and tachypnea or a supranormal minute ventilation.1 When an organ system begins to fail because of sepsis, the sepsis is considered severe. Each year, sepsis develops in more than 500,000 patients in the United States, and only 55 to 65 percent survive.2,3 Fortunately, the death rates in some subgroups of patients with sepsis-induced organ failure have decreased, even though there is no specific therapy for sepsis.3,4 The reduced mortality may be . . .
TL;DR: In this paper, the authors report the results of a consensus conference on the diagnosis of multiple system atrophy (MSA), which includes four domains: autonomic failure/urinary dysfunction, parkinsonism and cerebellar ataxia, and corticospinal dysfunction.
TL;DR: As marketing gains increasing prominence as an orientation that everyone in the organization shares and as a process that all functions participate in deploying, a critical issue that arises is the issue of the...
Abstract: As marketing gains increasing prominence as an orientation that everyone in the organization shares and as a process that all functions participate in deploying, a critical issue that arises is the...
TL;DR: The authors argue that the contrast between the two perspectives cannot be reduced to that of choosing between the individual and the social collective as the primary unit of analysis, and compare the situated viewpoint they find useful in their work with the cognitive approach advocated by Anderson et al. by focusing on their treatments of meaning and instructional goals.
Abstract: In their recent exchange, Anderson, Reder, and Simon (1996 Anderson, Reder, and Simon (1997) and Greeno (1997) frame the conflicts between cognitive theory and situated learning theory in terms of issues that are primarily of interest to educational psychologists. We attempt to broaden the debate by approaching this discussion of perspectives against the background of our concerns as educators who engage in classroom-based research and instructional design in collaboration with teachers. We first delineate the underlying differences between the two perspectives by distinguishing their central organizing metaphors. We then argue that the contrast between the two perspectives cannot be reduced to that of choosing between the individual and the social collective as the primary unit of analysis. Against this background, we compare the situated viewpoint we find useful in our work with the cognitive approach advocated by Anderson et al. by focusing on their treatments of meaning and instructional goals. Finall...
TL;DR: It is proposed that regulation of matrilysin production by β-catenin accumulation is a contributing factor to intestinal tumorigenesis.
Abstract: Matrilysin is a matrix metalloproteinase expressed in the tumor cells of greater than 80% of intestinal adenomas. The majority of these intestinal tumors are associated with the accumulation of β-catenin, a component of the cadherin adhesion complex and, through its association with the T Cell Factor (Tcf) DNA binding proteins, a regulator in the Wnt signal transduction pathway. In murine intestinal tumors, matrilysin transcripts show striking overlap with the accumulation of β-catenin protein. The matrilysin promoter is upregulated as much as 12-fold by β-catenin in colon tumor cell lines in a manner inversely proportional to the endogenous levels of β-catenin/Tcf complex and is dependent upon a single optimal Tcf-4 recognition site. Coexpression of the E-cadherin cytoplasmic domain blocked this induction and reduced basal promoter activity in every colon cancer cell line tested. Inactivation of the Tcf binding site increased promoter activity and overexpression of the Tcf factor, LEF-1, significantly downregulated matrilysin promoter activity, suggesting that β-catenin transactivates the matrilysin promoter by virtue of its ability to abrogate Tcf-mediated repression. Because genetic ablation of matrilysin decreases tumor formation in multiple intestinal neoplasia (Min) mice, we propose that regulation of matrilysin production by β-catenin accumulation is a contributing factor to intestinal tumorigenesis.
TL;DR: Future antipsychotic drug development can include targeting multiple serotonin receptor subtypes, some, or all of which, may contribute to their differences in efficacy and side effect profile.
TL;DR: This paper reports a new approach to the template-directed synthesis of inorganic±organic nanotubes using tobacco mosaic virus (TMV), and shows that TMV is a suitable template for reactions such as co-crystallization, oxidative hydrolysis, and sol-gel condensation.
Abstract: The use of biological molecules, assemblies and systems in the development of inorganic materials synthesis continues to offer new and exciting alternatives to conventional synthetic strategies. Biological templates, such as protein cages, viroid capsules, bacterial rhapidosomes, S-layers, multicellular superstructures, biolipid cylinders, and DNA, have been utilized to direct the deposition, assembly, and patterning of inorganic nanoparticles and microstructures. In this paper, we report a new approach to the template-directed synthesis of inorganic±organic nanotubes using tobacco mosaic virus (TMV). TMV is a remarkably stable virion, remaining intact at temperatures up to 60 C and at pH values between 2 and 10. Each viral particle consists of 2130 identical protein subunits arranged in a helical motif around a single strand of RNA to produce a hollow protein tube, 300 18 nm in size, with a 4 nm-wide central channel. The internal and external surfaces of the protein consist of repeated patterns of charged amino acid residues, such as glutamate, aspartate, arginine, and lysine. In principle, these functionalities should offer a wide variety of nucleation sites for surface-controlled inorganic deposition, which, in association with the high thermal and pH stability, could be exploited in the synthesis of unusual materials such as high-aspect-ratio composites and protein-confined inorganic nanowires. Here we show that TMV is a suitable template for reactions such as co-crystallization (CdS and PbS), oxidative hydrolysis (iron oxides), and sol-gel condensation (SiO2) (Fig. 1).
TL;DR: This article reviewed rational choice theories in the sociology of religion and the controversies surrounding applications of these perspectives, and investigated the influence of religion on politics, the family, health and well-being, and on free space and social capital.
Abstract: The sociology of religion is experiencing a period of substantial organizational and intellectual growth. Recent theoretical and empirical papers on the sociology of religion appearing in top journals in sociology have generated both interest and controversy. We begin with a selective overview of research on religious beliefs and commitments. Second, we investigate the influence of religion on politics, the family, health and well-being, and on free space and social capital. Finally, we review rational choice theories in the sociology of religion and the controversies surrounding applications of these perspectives.
TL;DR: Mutations in human NKX2.5 cause a variety of cardiac anomalies and may account for a clinically significant portion of tetralogy of Fallot and idiopathic AV block.
Abstract: Heterozygous mutations in NKX2.5, a homeobox transcription factor, were reported to cause secundum atrial septal defects and result in atrioventricular (AV) conduction block during postnatal life. To further characterize the role of NKX2.5 in cardiac morphogenesis, we sought additional mutations in groups of probands with cardiac anomalies and first-degree AV block, idiopathic AV block, or tetralogy of Fallot. We identified 7 novel mutations by sequence analysis of the NKX2.5-coding region in 26 individuals. Associated phenotypes included AV block, which was the primary manifestation of cardiac disease in nearly a quarter of affected individuals, as well as atrial septal defect and ventricular septal defect. Ventricular septal defect was associated with tetralogy of Fallot or double-outlet right ventricle in 3 individuals. Ebstein’s anomaly and other tricuspid valve abnormalities were also present. Mutations in human NKX2.5 cause a variety of cardiac anomalies and may account for a clinically significant portion of tetralogy of Fallot and idiopathic AV block. The coinheritance of NKX2.5 mutations with various congenital heart defects suggests that this transcription factor contributes to diverse cardiac developmental pathways.
J. Clin. Invest. 104:1567–1573 (1999).
TL;DR: The BRET technique is used to demonstrate that the clock protein KaiB interacts to form homodimers, and should be particularly useful for testing protein interactions within native cells, especially with integral membrane proteins or proteins targeted to specific organelles.
Abstract: We describe a method for assaying protein interactions that offers some attractive advantages over previous assays. This method, called bioluminescence resonance energy transfer (BRET), uses a bioluminescent luciferase that is genetically fused to one candidate protein, and a green fluorescent protein mutant fused to another protein of interest. Interactions between the two fusion proteins can bring the luciferase and green fluorescent protein close enough for resonance energy transfer to occur, thus changing the color of the bioluminescent emission. By using proteins encoded by circadian (daily) clock genes from cyanobacteria, we use the BRET technique to demonstrate that the clock protein KaiB interacts to form homodimers. BRET should be particularly useful for testing protein interactions within native cells, especially with integral membrane proteins or proteins targeted to specific organelles.
TL;DR: In this article, the authors report further theoretical development of Lee and Mitchell's (1994) unfolding model of voluntary turnover, which describes different psychological paths that people take when quitting or...
Abstract: This work reports further theoretical development of Lee and Mitchell's (1994) unfolding model of voluntary turnover, which describes different psychological paths that people take when quitting or...
TL;DR: C‐Jun protects cells from UV‐induced cell death and cooperates with NF‐κB to prevent apoptosis induced by tumor necrosis factor alpha (TNFα), and shows that different extracellular stimuli can target c‐Jun by distinct biochemical mechanisms.
Abstract: c-Jun is a component of the transcription factor AP-1, which is activated by a wide variety of extracellular stimuli. The regulation of c-Jun is complex and involves both increases in the levels of c-Jun protein as well as phosphorylation of specific serines (63 and 73) by Jun N-terminal kinase (JNK). We have used fibroblasts derived from c-Jun null embryos to define the role of c-Jun in two separate processes: cell growth and apoptosis. We show that in fibroblasts, c-Jun is required for progression through the G1 phase of the cell cycle; c-Jun-mediated G1 progression occurs by a mechanism that involves direct transcriptional control of the cyclin D1 gene, establishing a molecular link between growth factor signaling and cell cycle regulators. In addition, c-Jun protects cells from UV-induced cell death and cooperates with NF-kappaB to prevent apoptosis induced by tumor necrosis factor alpha (TNFalpha). c-Jun mediated G1 progression is independent of phosphorylation of serines 63/73; however, protection from apoptosis in response to UV, a potent inducer of JNK/SAP kinase activity, requires serines 63/73. The results reveal critical roles for c-Jun in two different cellular processes and show that different extracellular stimuli can target c-Jun by distinct biochemical mechanisms.
TL;DR: Observations indicate that RNA editing can serve as a mechanism for regulating alternative splicing and they suggest a novel strategy by which ADAR2 can modulate its own expression.
Abstract: The enzyme ADAR2 is a double-stranded RNA-specific adenosine deaminase which is involved in the editing of mammalian messenger RNAs by the site-specific conversion of adenosine to inosine. Here we identify several rat ADAR2 mRNAs produced as a result of two distinct alternative splicing events. One such splicing event uses a proximal 3' acceptor site, adding 47 nucleotides to the ADAR2 coding region, changing the predicted reading frame of the mature ADAR2 transcript. Nucleotide-sequence analysis of ADAR2 genomic DNA revealed the presence of adenosine-adenosine (AA) and adenosine-guanosine (AG) dinucleotides at these proximal and distal alternative 3' acceptor sites, respectively. Use of the proximal 3' acceptor depends upon the ability of ADAR2 to edit its own pre-mRNA, converting the intronic AA to an adenosine-inosine (AI) dinucleotide which effectively mimics the highly conserved AG sequence normally found at 3' splice junctions. Our observations indicate that RNA editing can serve as a mechanism for regulating alternative splicing and they suggest a novel strategy by which ADAR2 can modulate its own expression.
TL;DR: It is demonstrated herein that COX2-derived prostacyclin (PGI2) is the primary PG that is essential for implantation and decidualization, and several lines of evidence suggest that the effects of PGI2 are mediated by its activation of the nuclear hormone receptor PPARdelta, demonstrating the first reported biologic function of this receptor signaling pathway.
Abstract: We have demonstrated previously that cyclo-oxygenase-2 (COX2), the rate-limiting enzyme in the biosynthesis of prostaglandins (PGs), is essential for blastocyst implantation and decidualization. However, the candidate PG(s) that participates in these processes and the mechanism of its action remain undefined. Using COX2-deficient mice and multiple approaches, we demonstrate herein that COX2-derived prostacyclin (PGI2) is the primary PG that is essential for implantation and decidualization. Several lines of evidence suggest that the effects of PGI2 are mediated by its activation of the nuclear hormone receptor PPARdelta, demonstrating the first reported biologic function of this receptor signaling pathway.
Journal Article•
TL;DR: OATP transporters and P-gp colocalize in organs of importance to drug disposition such as the liver, their activity provides an explanation for the heretofore unknown mechanism(s) responsible for fexofenadine's disposition and suggests potentially similar roles in the disposition of other xenobiotics.
Abstract: Fexofenadine, a nonsedating antihistamine, does not undergo significant metabolic biotransformation. Accordingly, it was hypothesized that uptake and efflux transporters could be importantly involved in the drug's disposition. Utilizing a recombinant vaccinia expression system, members of the organic anion transporting polypeptide family, such as the human organic anion transporting polypeptide (OATP) and rat organic anion transporting polypeptides 1 and 2 (Oatp1 and Oatp2), were found to mediate [(14)C]fexofenadine cellular uptake. On the other hand, the bile acid transporter human sodium taurocholate cotransporting polypeptide (NTCP) and the rat organic cation transporter rOCT1 did not exhibit such activity. P-glycoprotein (P-gp) was identified as a fexofenadine efflux transporter, using the LLC-PK1 cell, a polarized epithelial cell line lacking P-gp, and the derivative cell line (L-MDR1), which overexpresses P-gp. In addition, oral and i.v. administration of [(14)C]fexofenadine to mice lacking mdr1a-encoded P-gp resulted in 5- and 9-fold increases in the drug's plasma and brain levels, respectively, compared with wild-type mice. Also, a number of drug inhibitors of P-gp were found to be effective inhibitors of OATP. Because OATP transporters and P-gp colocalize in organs of importance to drug disposition such as the liver, their activity provides an explanation for the heretofore unknown mechanism(s) responsible for fexofenadine's disposition and suggests potentially similar roles in the disposition of other xenobiotics.