bluuebunny/crossref_metadata_2025 huggingface dataset:
Caveolin-1 and -2 in airway epithelium: expression and in situ association as detected by FRET-CLSM
Authors: Krasteva Gabriela , Pfeil Uwe , Drab Marek , Kummer Wolfgang , König Peter
Published: August 2006

Background

Caveolae are involved in diverse cellular functions such as signal transduction, cholesterol homeostasis, endo- and transcytosis, and also may serve as entry sites for microorganisms. Hence, their occurrence in epithelium of the airways might be expected but, nonetheless, has not yet been examined.

Methods

Western blotting, real-time quantitative PCR analysis of abraded tracheal epithelium and laser-assisted microdissection combined with subsequent mRNA analysis were used to examine the expression of cav-1 and cav-2, two major caveolar coat proteins, in rat tracheal epithelium. Fluorescence immunohistochemistry was performed to locate caveolae and cav-1 and -2 in the airway epithelium of rats, mice and humans. Electron-microscopic analysis was used for the identification of caveolae. CLSM-FRET analysis determined the interaction of cav-1α and cav-2 in situ.

Results

Western blotting and laser-assisted microdissection identified protein and transcripts, respectively, of cav-1 and cav-2 in airway epithelium. Real-time quantitative RT-PCR analysis of abraded tracheal epithelium revealed a higher expression of cav-2 than of cav-1. Immunoreactivities for cav-1 and for cav-2 were co-localized in the cell membrane of the basal cells and basolaterally in the ciliated epithelial cells of large airways of rat and human. However, no labeling for cav-1 or cav-2 was observed in the epithelial cells of small bronchi. Using conventional double-labeling indirect immunofluorescence combined with CLSM-FRET analysis, we detected an association of cav-1α and -2 in epithelial cells. The presence of caveolae was confirmed by electron microscopy. In contrast to human and rat, cav-1-immunoreactivity and caveolae were confined to basal cells in mice. Epithelial caveolae were absent in cav-1-deficient mice, implicating a requirement of this caveolar protein in epithelial caveolae formation.

Conclusion

These results show that caveolae and caveolins are integral membrane components in basal and ciliated epithelial cells, indicating a crucial role in these cell types. In addition to their physiological role, they may be involved in airway infection.
Text mining of full-text journal articles combined with gene expression analysis reveals a relationship between sphingosine-1-phosphate and invasiveness of a glioblastoma cell line
Authors: Natarajan Jeyakumar , Berrar Daniel , Dubitzky Werner , Hack Catherine , Zhang Yonghong , DeSesa Catherine , Van Brocklyn James R , Bremer Eric G
Published: August 2006

Background

Sphingosine 1-phosphate (S1P), a lysophospholipid, is involved in various cellular processes such as migration, proliferation, and survival. To date, the impact of S1P on human glioblastoma is not fully understood. Particularly, the concerted role played by matrix metalloproteinases (MMP) and S1P in aggressive tumor behavior and angiogenesis remains to be elucidated.

Results

To gain new insights in the effect of S1P on angiogenesis and invasion of this type of malignant tumor, we used microarrays to investigate the gene expression in glioblastoma as a response to S1P administration in vitro. We compared the expression profiles for the same cell lines under the influence of epidermal growth factor (EGF), an important growth factor. We found a set of 72 genes that are significantly differentially expressed as a unique response to S1P. Based on the result of mining full-text articles from 20 scientific journals in the field of cancer research published over a period of five years, we inferred gene-gene interaction networks for these 72 differentially expressed genes. Among the generated networks, we identified a particularly interesting one. It describes a cascading event, triggered by S1P, leading to the transactivation of MMP-9 via neuregulin-1 (NRG-1), vascular endothelial growth factor (VEGF), and the urokinase-type plasminogen activator (uPA). This interaction network has the potential to shed new light on our understanding of the role played by MMP-9 in invasive glioblastomas.

Conclusion

Automated extraction of information from biological literature promises to play an increasingly important role in biological knowledge discovery. This is particularly true for high-throughput approaches, such as microarrays, and for combining and integrating data from different sources. Text mining may hold the key to unraveling previously unknown relationships between biological entities and could develop into an indispensable instrument in the process of formulating novel and potentially promising hypotheses.
Trends in drop out, drug free discharge and rates of re-presentation: a retrospective cohort study of drug treatment clients in the North West of England
Authors: Beynon Caryl M , Bellis Mark A , McVeigh Jim
Published: August 2006

Background

Governments aim to increase treatment participation by problematic drug users. In the UK this has been achieved by fiscal investment, an expanded workforce, reduced waiting times and coercive measures (usually criminal justice (CJ) led). No assessment of these measures on treatment outcomes has been made. Using established monitoring systems we assessed trends in 'dropped out' and 'discharged drug free' (DDF), since the launch of the national drug strategy, and rates of treatment re-presentation for these cohorts.

Methods

A longitudinal dataset of drug users (1997 to 2004/05, n = 26,415) was used to identify people who dropped out of, and were DDF from, services for years 1998 to 2001/02, and re-presentations of these people in years to 2004/05. Trends in drop out and DDF, baseline comparisons of those DDF and those who dropped out and outcome comparisons for those referred from the CJ system versus other routes of referral were examined using chi square. Logistic regression analyses identified variables predicting drop out versus DDF and subsequent re-presentation versus no re-presentation.

Results

The proportion of individuals dropping out has increased from 7.2% in 1998 to 9.6% in 2001/02 (P < 0.001). The proportion DDF has fallen from 5.8% to 3.5% (P < 0.001). Drop out was more likely in later years, by those of younger age and by CJ referrals. The proportion re-presenting to treatment in the following year increased from 27.8% in 1998 to 44.5% in 2001/02 (P < 0.001) for those DDF, and from 22.9% to 48.6% (P < 0.001) for those who dropped out. Older age and prior treatment experience predicted re-presentation. Outcome (drop out or DDF) did not predict re-presentation.

Conclusion

Increasing numbers in treatment is associated with an increased proportion dropping out and an ever-smaller proportion DDF. Rates of drop out are significantly higher for those coerced into treatment via the CJ system. Rates of re-presentation are similar for those dropping out and those DDF. Encouragingly, those who need to re-engage with treatment, particularly those who drop out, are doing so more quickly. The impact of coercion on treatment outcomes and the appropriateness of aftercare provision require further consideration.
Impact of hormonal therapy on the detection of promoter hypermethylation of the detoxifying glutathione-S-transferase P1 gene (GSTP1) in prostate cancer
Authors: Kollermann Jens , Kempkensteffen Carsten , Helpap Burkhard , Schrader Mark , Krause Hans , Muller Markus , Miller Kurt , Schostak Martin
Published: August 2006

Background

In spite of excellent cure rates for prostate cancer patients with favorable tumor characteristics, patients with unfavorable characteristics after radical prostatectomy are still at a significantly increased risk of tumor progression. Early adjuvant hormonal therapy (AHT) has been shown to be of prognostic benefit in these patients. Unfortunately initiation and duration of early AHT in the individual patient is based on statistic data. PSA, as the standard prostate marker is neither able to reliably indicate minimal residual tumor disease in the early postoperative phase, nor can it be used for therapy monitoring due to the suppressive effect of hormonal therapy on PSA production. Promoter hypermethylation of the detoxifying glutathione-S-transferase P1 gene (GSTP1-HM) has been shown to be the most common DNA alteration of primary prostatic carcinoma which, when used as a marker, is supposed to be able to overcome some of the disadvantages of PSA. However until now information on the impact of hormonal therapy on the detection of GSTP1-HM is lacking. The purpose of our study was to assess the impact of endocrine therapy on the detection of GSTP1-HM by methylation-specific PCR (MSP) in prostate cancer.

Methods

Paraffin embedded tumor samples from the radical prostatectomy (RP) specimens from 15 patients after hormonal therapy (HT) (mean 8 months) were assessed by MSP. In 8 of the patients the GSTP-1 status of the tumors before HT was assessed on the corresponding initial diagnostic biopsies.

Results

Following HT MSP showed GSTP1-HM in 13/15 of the RP specimens. In two patients analysis of the RP specimens failed to show GSTP1-HM. All initial tumor samples (8/8 biopsy specimens) showed GSTP1-HM, including both patients negative for GSTP1 HM in the corresponding RP specimen.

Conclusion

In most cases hormonal therapy appears to not alter GSTP1 HM detection. However the change from a positive to a negative GSTP1 HM status in a subset of the patients may point to an, at least partial androgen dependency. Further studies on a larger cohort of patients are necessary to assess its frequency and the exact hormonal interactions.
UniPep - a database for human N-linked glycosites: a resource for biomarker discovery
Authors: Zhang Hui , Loriaux Paul , Eng Jimmy , Campbell David , Keller Andrew , Moss Pat , Bonneau Richard , Zhang Ning , Zhou Yong , Wollscheid Bernd , Cooke Kelly , Yi Eugene C , Lee Hookeun , Peskind Elaine R , Zhang Jing , Smith Richard D , Aebersold Ruedi
Published: August 2006

There has been considerable recent interest in proteomic analyses of plasma for the purpose of discovering biomarkers. Profiling N-linked glycopeptides is a particularly promising method because the population of N-linked glycosites represents the proteomes of plasma, the cell surface, and secreted proteins at very low redundancy and provides a compelling link between the tissue and plasma proteomes. Here, we describe UniPep http://www.unipep.org - a database of human N-linked glycosites - as a resource for biomarker discovery.
A genome-wide approach to identify genetic loci with a signature of natural selection in the Irish population
Authors: Mattiangeli Valeria , Ryan Anthony W , McManus Ross , Bradley Daniel G
Published: August 2006

Background

In this study we present a single population test (Ewens-Waterson) applied in a genomic context to investigate the presence of recent positive selection in the Irish population. The Irish population is an interesting focus for the investigation of recent selection since several lines of evidence suggest that it may have a relatively undisturbed genetic heritage.

Results

We first identified outlier single nucleotide polymorphisms (SNPs), from previously published genome-wide data, with high FST branch specification in a European-American population. Eight of these were chosen for further analysis. Evidence for selective history was assessed using the Ewens-Watterson's statistic calculated using Irish genotypes of microsatellites flanking the eight outlier SNPs. Evidence suggestive of selection was detected in three of these by comparison with a population-specific genome-wide empirical distribution of the Ewens-Watterson's statistic.

Conclusion

The cystic fibrosis gene, a disease that has a world maximum frequency in Ireland, was among the genes showing evidence of selection. In addition to the demonstrated utility in detecting a signature of natural selection, this approach has the particular advantage of speed. It also illustrates concordance between results drawn from alternative methods implemented in different populations.
Are Statewide Trauma Registries Comparable? Reaching for a National Trauma Dataset
Authors: Mann N. Clay , Guice Karen , Cassidy Laura , Wright Dagan , Koury Julie
Published: August 2006

Background:
Statewide trauma registries have proliferated in the last decade, suggesting that information could be aggregated to provide an accurate depiction of serious injury in the United States.

Objectives:
To determine whether variability exists in the composition and content of statewide trauma registries, specifically addressing case‐acquisition, case‐definition (inclusion criteria), and registry‐coding conventions.

Methods:
A cross‐sectional, two‐part survey was administered to managers of all statewide trauma registries. State trauma registrars also provided inclusion and exclusion criteria from their state registry and abstracted a clinical vignette designed to identify coding inconsistencies.

Results:
Thirty‐two states maintain a centralized registry, but requirements for data submission vary significantly. Inclusion and exclusion criteria also vary, particularly for nontraumatic injuries. Coding conventions adopted by states for vague or missing information are dissimilar. When abstractions of the clinical vignette are compared, only 19% and 47% of states provided similar quantity or content for injury e‐coding and diagnostic coding, respectively. Injury severity scores (based on diagnostic coding) demonstrated a range from 2 to 18.

Conclusions:
Statewide trauma registries are prevalent but vary significantly in composition and content. Standardizing inclusion criteria, variable definitions, and coding conventions would greatly enhance the usability of an aggregated, national trauma registry.
An Emergency Department–based Vaccination Program: Overcoming the Barriers for Adults at High Risk for Vaccine‐preventable Diseases
Authors: Rimple Diane , Weiss Steven J. , Brett Meghan , Ernst Amy A.
Published: August 2006

Background:
More than 10% of the population visit emergency departments (ED) every year. Many of these patients are not up‐to‐date on routine vaccinations that could prevent future illnesses. The ED could significantly impact these vaccination trends.

Objectives:
This study was a feasibility study to determine whether patients would be amenable to an ED‐based program that provided appropriate immunizations when they were at high risk for these diseases. In addition, the authors sought to identify barriers that predict high‐risk patients who did not receive immunizations before ED presentation and to identify barriers that predict those high‐risk unvaccinated patients who are unwilling to receive vaccinations when offered in the ED.

Methods:
This study was a prospective cross‐sectional study of all patients arriving in the ED at one inner‐city trauma center between 10 am and 10 pm over the course of a three‐week intervention period. The subjects completed a survey that included information about their risk of influenza (flu) and pneumococcal disease, their immunization history, and their perceptions of their need for immunization. Demographic information collected included insurance status, age, gender, and primary language. All high‐risk patients who were not current with their immunizations were offered vaccination. The primary outcome was improvement in vaccination coverage based on an ED surveillance and treatment system for vaccinations. The secondary outcomes were barriers to successful vaccination before ED presentation and barriers to acceptance of vaccination in the ED. Results were compared using chi‐square test and confidence interval analysis. Characteristics of barriers to immunization were determined using a logistic regression model. A p‐value < 0.05 was considered significant.

Results:
A total of 674 subjects were entered into the study. Vaccination of subjects at high risk for flu increased significantly from 16% before to 83% after ED evaluation and treatment, and vaccination of subjects at high risk for pneumococcal disease increased significantly from 18% before to 84% after ED evaluation and treatment. Significant barriers to vaccination before ED presentation were lack of insurance (odds ratio [OR] = 0.31 for flu, 0.22 for pneumococcal disease), age younger than 50 years (OR = 0.18 for flu, 0.24 for pneumococcal disease), and no perceived need for vaccination (OR = 0.07 for flu). The sole significant barrier to vaccine administration in the ED was perceived need for vaccination (OR = 0.32 for flu).

Conclusions:
An ED‐based vaccination program is both feasible and successful. Other than a shortage of vaccine, the only ED barrier to vaccination (perceived need) might be overcome with patient education.
Emergency Department Treatment of Viral Gastritis Using Intravenous Ondansetron or Dexamethasone in Children
Authors: Stork Christine M. , Brown Kathleen M. , Reilly Tracey H. , Secreti LaLaina , Brown Lawrence H.
Published: August 2006

Objectives To compare the efficacy of intravenous ondansetron or dexamethasone compared with intravenous fluid therapy alone in children presenting to the emergency department with refractory vomiting from viral gastritis who had failed attempts at oral hydration.

Methods This double‐blind, randomized, controlled trial was performed in a tertiary care pediatric emergency department. Children aged 6 months to 12 years presenting with more than three episodes of vomiting in the past 24 hours, mild/moderate dehydration, and failed oral hydration were included. Patients with other medical causes were excluded. Subjects were randomized to dexamethasone 1 mg/kg (15 mg maximum), ondansetron 0.15 mg/kg, or placebo (normal saline [NS], 10 mL). All subjects also received intravenous NS at 10–20 mL/kg/hr. Oral fluid tolerance was evaluated at two and four hours. Those not tolerating oral fluids at four hours were admitted. Discharged patients were evaluated at 24 and 72 hours for vomiting and repeat health care visits. The primary study outcome was hospitalization rates between the groups. Data were analyzed using chi‐square test, Kruskal–Wallis test, Mantel–Haenszel test, and analysis of variance, with p < 0.05 considered significant.

Results A total of 166 subjects were enrolled; data for analysis were available for 44 NS‐treated patients, 46 ondansetron‐treated patients, and 47 dexamethasone‐treated patients. Hospital admission occurred in nine patients (20.5%) receiving placebo (NS alone), two patients (4.4%) receiving ondansetron, and seven patients (14.9%) receiving dexamethasone, with ondansetron significantly different from placebo (p = 0.02). Similarly, at two hours, more ondansetron‐treated patients (39 [86.6%]) tolerated oral hydration than NS‐treated patients (29 [67.4%]; relative risk, 1.28; 95% confidence interval = 1.02 to 1.68). There were no differences in number of mean episodes of vomiting or repeat visits to health care at 24 and 72 hours in the ondansetron, dexamethasone, or NS groups.

Conclusions In children with dehydration secondary to vomiting from acute viral gastritis, ondansetron with intravenous rehydration improves tolerance of oral fluids after two hours and reduces the hospital admission rate when compared with intravenous rehydration with or without dexamethasone.
An Independent Evaluation of Four Quantitative Emergency Department Crowding Scales
Authors: Jones Spencer S. , Allen Todd L. , Flottemesch Thomas J. , Welch Shari J.
Published: August 2006

Background

Emergency department (ED) overcrowding has become a frequent topic of investigation. Despite a significant body of research, there is no standard definition or measurement of ED crowding. Four quantitative scales for ED crowding have been proposed in the literature: the Real‐time Emergency Analysis of Demand Indicators (READI), the Emergency Department Work Index (EDWIN), the National Emergency Department Overcrowding Study (NEDOCS) scale, and the Emergency Department Crowding Scale (EDCS). These four scales have yet to be independently evaluated and compared.

Objectives

The goals of this study were to formally compare four existing quantitative ED crowding scales by measuring their ability to detect instances of perceived ED crowding and to determine whether any of these scales provide a generalizable solution for measuring ED crowding.

Methods

Data were collected at two‐hour intervals over 135 consecutive sampling instances. Physician and nurse agreement was assessed using weighted κ statistics. The crowding scales were compared via correlation statistics and their ability to predict perceived instances of ED crowding. Sensitivity, specificity, and positive predictive values were calculated at site‐specific cut points and at the recommended thresholds.

Results

All four of the crowding scales were significantly correlated, but their predictive abilities varied widely. NEDOCS had the highest area under the receiver operating characteristic curve (AROC) (0.92), while EDCS had the lowest (0.64). The recommended thresholds for the crowding scales were rarely exceeded; therefore, the scales were adjusted to site‐specific cut points. At a site‐specific cut point of 37.19, NEDOCS had the highest sensitivity (0.81), specificity (0.87), and positive predictive value (0.62).

Conclusions

At the study site, the suggested thresholds of the published crowding scales did not agree with providers' perceptions of ED crowding. Even after adjusting the scales to site‐specific thresholds, a relatively low prevalence of ED crowding resulted in unacceptably low positive predictive values for each scale. These results indicate that these crowding scales lack scalability and do not perform as designed in EDs where crowding is not the norm. However, two of the crowding scales, EDWIN and NEDOCS, and one of the READI subscales, bed ratio, yielded good predictive power (AROC >0.80) of perceived ED crowding, suggesting that they could be used effectively after a period of site‐specific calibration at EDs where crowding is a frequent occurrence.
Epithelial-Specific and Stage-Specific Functions of Insulin-Like Growth Factor-I during Postnatal Mammary Development
Authors: Loladze Aimee V. , Stull Malinda A. , Rowzee Anne M. , DeMarco Jean , Lantry James H. , Rosen Clifford J. , LeRoith Derek , Wagner Kay-Uwe , Hennighausen Lothar , Wood Teresa L.
Published: August 2006

Postnatal development of the mammary gland requires interactions between the epithelial and stromal compartments, which regulate actions of hormones and growth factors. IGF-I is expressed in both epithelial and stromal compartments during postnatal development of the mammary gland. However, little is known about how local expression of IGF-I in epithelium or stroma regulates mammary growth and differentiation during puberty and pregnancy-induced alveolar development. The goal of this study was to investigate the mechanisms of IGF-I actions in the postnatal mammary gland and test the hypothesis that IGF-I expressed in stromal and epithelial compartments has distinct functions. We established mouse lines with inactivation of the igf1 gene in mammary epithelium by crossing igf1/loxP mice with mouse lines expressing Cre recombinase under the control of either the mouse mammary tumor virus long-terminal repeat or the whey acidic protein gene promoter. Epithelial-specific loss of IGF-I during pubertal growth resulted in deficits in ductal branching. In contrast, heterozygous reduction of IGF-I throughout the gland decreased expression of cyclins A2 and B1 during pubertal growth and resulted in alterations in proliferation of the alveolar epithelium and milk protein levels during pregnancy-induced differentiation. Reduction in epithelial IGF-I at either of these stages had no effect on these indices. Taken together, our results support distinct roles for IGF-I expressed in epithelial and stromal compartments in mediating growth of the postnatal mammary gland.
The Orphan Nuclear Receptor, NOR-1, Is a Target of β-Adrenergic Signaling in Skeletal Muscle
Authors: Pearen Michael A. , Ryall James G. , Maxwell Megan A. , Ohkura Naganari , Lynch Gordon S. , Muscat George E. O.
Published: August 2006

β-Adrenergic receptor (β-AR) agonists induce Nur77 mRNA expression in the C2C12 skeletal muscle cell culture model and elicit skeletal muscle hypertrophy. We previously demonstrated that Nur77 (NR4A1) is involved in lipolysis and gene expression associated with the regulation of lipid homeostasis. Subsequently it was demonstrated by another group that β-AR agonists and cold exposure-induced Nur77 expression in brown adipocytes and brown adipose tissue, respectively. Moreover, NOR-1 (NR4A3) was hyperinduced by cold exposure in the nur77−/− animal model. These studies underscored the importance of understanding the role of NOR-1 in skeletal muscle. In this context we observed 30–480 min of β-AR agonist treatment significantly and transiently increased expression of the orphan nuclear receptor NOR-1 in both mouse skeletal muscle tissue (plantaris) and C2C12 skeletal muscle cells. Specific β2- and β3-AR agonists had similar effects as the pan-agonist and were blocked by the β-AR antagonist propranolol. Moreover, in agreement with these observations, isoprenaline also significantly increased the activity of the NOR-1 promoter. Stable exogenous expression of a NOR-1 small interfering RNA (but not the negative control small interfering RNA) in skeletal muscle cells significantly repressed endogenous NOR-1 mRNA expression and led to changes in the expression of genes involved in the control of lipid use and muscle mass underscored by a dramatic increase in myostatin mRNA expression. Concordantly the myostatin promoter was repressed by NOR-1 expression. In conclusion, NOR-1 is highly responsive to β-adrenergic signaling and regulates the expression of genes controlling fatty acid use and muscle mass.
Low-Dose Dopamine Agonist Administration Blocks Vascular Endothelial Growth Factor (VEGF)-Mediated Vascular Hyperpermeability without Altering VEGF Receptor 2-Dependent Luteal Angiogenesis in a Rat Ovarian Hyperstimulation Model
Authors: Gomez Raul , Gonzalez-Izquierdo Miguel , Zimmermann Ralf C. , Novella-Maestre Edurne , Alonso-Muriel Isabel , Sanchez-Criado Jose , Remohi Jose , Simon Carlos , Pellicer Antonio
Published: August 2006

No specific treatment is available for ovarian hyperstimulation syndrome (OHSS), the most important complication in infertile women treated with gonadotropins. OHSS is caused by increased vascular permeability (VP) through ovarian hypersecretion of vascular endothelial growth factor (VEGF)-activating VEGF receptor 2 (VEGFR-2). We previously demonstrated in an OHSS rodent model that increased VP was prevented by inactivating VEGFR-2 with a receptor antagonist (SU5416). However, due to its toxicity (thromboembolism) and disruption of VEGFR-2-dependent angiogenic processes critical for pregnancy, this kind of compound cannot be used clinically to prevent OHSS. Dopamine receptor 2 (Dp-r2) agonists, used in the treatment of human hyperprolactinemia including pregnancy, inhibit VEGFR-2-dependent VP and angiogenesis when administered at high doses in animal cancer models. To test whether VEGFR-2-dependent VP and angiogenesis could be segregated in a dose-dependent fashion with the Dp-r2 agonist cabergoline, a well-established OHSS rat model supplemented with prolactin was used. A 100 μg/kg low-dose Dp-r2 agonist cabergoline reversed VEGFR-2-dependent VP without affecting luteal angiogenesis through partial inhibition of ovarian VEGFR-2 phosphorylation levels. No luteolytic effects (serum progesterone levels and luteal apoptosis unaffected) were observed. Cabergoline administration also did not affect VEGF/VEGFR-2 ovarian mRNA levels. Results in the animal model and the safe clinical profile of Dp-r2 agonists encouraged us to administer cabergoline to oocyte donors at high risk for developing the syndrome. Prophylactic administration of cabergoline (5–10 μg/kg·d) decreased the occurrence of OHSS from 65% (controls) to 25% (treatment). Therefore, a specific, safe treatment for OHSS is now available.
Mineralocorticoid Receptor Antagonist Reduces Renal Injury in Rodent Models of Types 1 and 2 Diabetes Mellitus
Authors: Guo Christine , Martinez-Vasquez Diego , Mendez Gonzalo P. , Toniolo Maria F. , Yao Tham M. , Oestreicher Eveline M. , Kikuchi Taisuke , Lapointe Nathalie , Pojoga Luminita , Williams Gordon H. , Ricchiuti Vincent , Adler Gail K.
Published: August 2006

To determine whether mineralocorticoid receptor (MR) activation plays a role in diabetic renal injury and whether this role differs in types 1 and 2 diabetes mellitus, we examined the effect of a MR antagonist on renal injury in rodent models of type 1 (streptozotocin-treated rat) and type 2 (db/db mouse) diabetes. We studied three groups of 8-wk-old, uninephrectomized Wistar rats for 4 wk: diabetic streptozotocin- (55 mg/kg) treated rats (n = 11), diabetic streptozotocin-treated rats receiving the MR antagonist eplerenone (n = 15), and nondiabetic rats (n = 9). In addition, we studied three groups of 8-wk-old mice for 16 wk: diabetic db/db mice (n = 10), diabetic db/db mice treated with eplerenone (n = 8), and nondiabetic, db/+ littermates (n = 11). Diabetic rats and mice developed albuminuria and histopathological evidence of renal injury, including glomerular hypertrophy, mesangial expansion, and tubulointerstitial injury as well as increased renal cortical levels of MR protein, MR mRNA, TGFβ mRNA, and osteopontin mRNA. All of these changes were significantly reduced by treatment with eplerenone except for the elevated MR levels. The beneficial effects of eplerenone were not attributable to changes in blood pressure or glycemia. In summary, MR expression was increased in kidneys of diabetic rodents, and MR antagonists effectively reduced diabetic renal injury irrespective of the species or specific cause of the diabetes. Thus, these data suggest that MR activation is a critical factor in the early pathogenesis of renal disease in both type 1 and type 2 diabetes mellitus.
Indole-3-Carbinol Selectively Uncouples Expression and Activity of Estrogen Receptor Subtypes in Human Breast Cancer Cells
Authors: Sundar Shyam N. , Kerekatte Vaishali , Equinozio Caterina N. , Doan Victor B. , Bjeldanes Leonard F. , Firestone Gary L.
Published: August 2006

Estrogen-responsive breast cancer cells, such as MCF7 and T47D cells, express both estrogen receptor (ER)-α (ERα) and ERβ. Indole-3-carbinol (I3C) strongly down-regulated ERα protein and transcript levels, without altering the level of ERβ protein, in both cell lines. In cells transfected with the ERα promoter linked to a luciferase gene reporter, I3C ablated ERα promoter activity. Propyl pyrazole triol (PPT) is a highly selective ERα agonist, whereas, 17β-estradiol activates both ERα and ERβ. I3C treatment inhibited the PPT- and 17β-estradiol-induced proliferation of breast cancer cells, disrupted the PPT and 17β-estradiol stimulation of estrogen response element (ERE)-driven reporter plasmid activity as well as of endogenous progesterone receptor transcripts. Using an in vitro ERE binding assay, I3C was shown to inhibit the level of functional ERα and stimulated the level of ERE binding ERβ even though the protein levels of this receptor remained constant. In ERα−/ERβ+ MDA-MB-231 breast cancer cells, I3C treatment stimulated a 6-fold increase in binding of ERβ to the ERE. I3C also induced ERE- and activator protein 1-driven reporter plasmid activities in the absence of an ER agonist, suggesting that ERβ is activated in indole-treated cells. Taken together, our results demonstrate that the expression and function of ERα and ERβ can be uncoupled by I3C with a key cellular consequence being a significantly higher ERβ:ERα ratio that is generally highly associated with antiproliferative status of human breast cancer cells.
Role of Chromatin Accessibility in the Occupancy and Transcription of the Insulin Gene by the Pancreatic and Duodenal Homeobox Factor 1
Authors: Francis Joshua , Babu Daniella A. , Deering Tye G. , Chakrabarti Swarup K. , Garmey James C. , Evans-Molina Carmella , Taylor David G. , Mirmira Raghavendra G.
Published: August 2006

The pancreatic and duodenal homeobox factor 1 (Pdx-1) is a Hox-like transcription factor that is responsible for the activation of the insulin gene. Previous studies have demonstrated the interaction in vitro of Pdx-1 with short (20–40 nucleotide) DNA fragments corresponding to A boxes of the insulin promoter. Precisely how Pdx-1 binds to DNA in the complex milieu of chromatin, however, has never been studied. In this study, we explored how Pdx-1-DNA interactions might be influenced by chromatin accessibility at the insulin gene in β-cells (βTC3) vs. pancreatic ductal cells (mPAC). We demonstrate that Pdx-1 occupies the endogenous insulin promoter in βTC3 cells but not in mPAC cells, a finding that is independent of the intracellular Pdx-1 protein concentration. Based on micrococcal nuclease protection assays, the difference in promoter binding between the two cell types appears to be secondary to chromatin accessibility at predicted Pdx-1 binding sites between bp −126 to −296 (relative to the transcriptional start site) of the insulin promoter. Binding studies using purified Pdx-1 and reconstituted chromatin in vitro suggest that the positioning of a nucleosome(s) within this crucial region of the promoter might account for differences in chromatin accessibility. Consistent with these observations, fluorescence colocalization studies show that Pdx-1 does not occupy regions of compacted, nucleosome-rich chromatin within the nucleus. Our findings suggest a model whereby insulin transcription in the β-cell is at least partially facilitated by enhanced chromatin accessibility within a crucial regulatory region between bp −126 to −296, thereby permitting occupancy by transactivators such as Pdx-1.
Small-Angle X-Ray Scattering Study on the Growth of Metal Silicate Polymers in Solution
Authors: Hayashi Hisashi , Tohji Kazuyuki , Udagawa Yasuo , Ueno Akifumi
Published: August 2006

The development of metal silicate polymers in mixed solutions of nickel and iron 1,2-ethanediolates, water, and tetraethoxysilane was studied using a small-angle X-ray scattering (SAXS) method. The effects of the added metals on the growth of the silicate polymers and the correlation between the structure of the gel and metal particle of the catalyst prepared by calcining and reducing the gel are discussed.
Boiling Point and the Refraction (Polarizability) of Exposed Atoms
Authors: Rich Ronald L
Published: August 2006

Boiling points for an unprecedented variety of substances can herewith be predicted by a method which is both 1, practical even for species with few or no measured properties, and 2, in agreement with this principle form theory: The London forces between molecules, and the refraction of light, both depend on polarizability and thus mainly on the outer electrons of atoms. The London forces on molecular surfaces, however, should not reflect the effects of sufficiently well-shielded internal atoms, and we use an objective geometric criterion to exclude them. Addition of the molar refractions (or atomic polarizabilities) of the other atoms, with an adjustment for electronegativity differences, gives the effective total refraction. We aim for great generality but emphasize inorganic substances at present. Boiling points are calculated for 193 substances from a proportionality to the 3/4 power of the total refractions, with a standard deviation < 4%, up to at least 800 K. Values for 29 others are predicted for possible future experimental checking. Objective criteria for the exclusion of highly polar and other substances are presented, and the boiling temperatures for 19 of these are examined.
A Hydrophobicity Scale of Heteropoly- and Isopolyanions Based on Voltammetric Studies of Their Transfer at the Nitrobenzene/Water Interface
Authors: Osakai Toshiyuki , Katano Hajime , Maeda Kohji , Himeno Sadayuki , Saito Atsuyoshi
Published: August 2006

A hydrophobicity scale of heteropoly- and isopolyanions is proposed on the basis of voltammetric studies concerning their transfer at the nitrobenzene (NB)/water (W) interface. For polyanions of various size and ionic charge (z = −2 to −6), the standard ion-transfer potential (ΔOWφ), which is related to the Gibbs free energy of the transfer as ΔOWφ = −ΔGtrO→W/zF (F, the Faraday constant), depends linearly on the quantity |z|/n2/3 (n, the number of oxygen atoms in the polyanion structure), which should be proportional to the surface charge density of the polyanion. The value of |z|/n2/3 may provide a useful criterion for evaluating the hydrophobic (or hydrophilic) properties of polyanions, including the stability in solutions and extractability into organic solvents.
Syntheses of 6-Deoxyhex-5-enopyranosides from 6-Bromo-6-deoxy- or 6-O-p-Tolylsulfonylhexopyranosides by the Use of DBU in DMSO
Authors: Sato Ken-ichi , Kubo Noriyuki , Takada Ritsuko , Sakuma Shogo
Published: August 2006

Various kinds of nonbranched and methyl-branched 6-deoxyhex-5-enopyranoside derivatives were prepared from 6-bromo-6-deoxy or 6-O-p-tolylsulfonylhexopyranoside in a one-pot procedure by a successive treatment with iodide anion and 1,8-diazabicyclo[5.4.0]undec-7-ene in dimethyl sulfoxide. The scope and limitations of this reaction have become apparent by observing the reactions of 18 substrates. The yields of altropyranoside and 2-deoxyribo-hexopyranoside derivatives were high, except for the 2,3-anhydropyranoside derivative. Methyl-branched 6-deoxyhex-5-enopyranoside derivatives were also obtained in practical yields.
Preparation and Reactions of 6-Aryl-1,5-dihydro-3-phenyl-4H-pyrazolo[4,3-c]pyridin-4-ones
Authors: Marei Mohamed Gaber
Published: August 2006

The title compounds have been prepared in excellent yields by the reaction of 5-aryl-2-phenylpyrazolo[1,5-c]pyrimidine-7(6H)-thiones with potassium hydroxide. The reactions of these pyrazolopyridones have been investigated. The ring system readily undergoes electrophilic substitution at the 7-position. They are converted to the corresponding pyrazolopyridinethiones on reaction with phosphorus pentasulfide. The structures of the above compounds were elucidated by their spectral characteristics.
Nucleophilic Reaction upon Electron-Deficient Pyridone Derivatives. XII. Novel Additions of 3,5-Dinitro-2-pyridone with Ethyl Vinyl Ether: Formation and Reactions of a Six-membered Cyclic Nitronate
Authors: Tohda Yasuo , Tani Keita , Yamawaki Norihiko , Ariga Masahiro , Nishiwaki Nagatoshi , Kotani Katsuroh , Matsumura Eizo
Published: August 2006

Successive additions of 3,5-dinitro-2-pyridone (1) with three molecules of ethyl vinyl ether (EVE) were investigated. The first addition is the first example of reverse electron-demand Diels–Alder (REDA) cyclization of 2-pyridone which acts as a diene to give an unstable bicyclic intermediate 9. Meisenheimer complexes 2a and 2b are isolated as a quenched intermediate of 9. The second addition is a REDA cyclization between the nitroalkene moiety of 9 and EVE to afford a six-membered nitronate 4, which are characterized by some chemical reactions. The third step is 1,3-dipolar addition of the nitronate with EVE to give a 1 : 3 adduct 3.
Structure and Thermal E–Z Isomerization of Substituted 4-Phenylimino-5-pyrazolones and Hexafluoroacetone Anils
Authors: Hofmann Hans-Jörg , Asano Tsutomu , Cimiraglia Renzo , Bonaccorsi Rosanna
Published: August 2006

The structure of the title compounds was examined by means of ab initio MO theory employing the STO-3G basis set. The optimized geometries represent a good basis for the discussion of conformation and configuration of these molecules. A quantum-chemical solvation model was applied for the estimation of the solvent influence. Dependent on the extent of push-pull conjugation in the investigated systems, the conformation of the linear inversion state, which has to be passed during the isomerization process, changes between a planar and perpendicular orientation of the N-phenyl ring. These conformation differences could be responsible for deviations of Hammett plots of the isomerization rate from linearity for special groups of aromatic azomethines.
Synthesis and Reaction of Triphenylvinylphosphonium Salts from Epoxides
Authors: Okuma Kentaro , Ono Masaaki , Ohta Hiroshi
Published: August 2006

Triphenylvinylphosphonium salts were prepared by the reaction of 2-hydroxyalkyltriphenylphosphonium salts with acetyl chloride or oxalyl chloride. These salts were also synthesized by a one-pot operation of treating epoxides with triphenylphosphonium tetrafluoroborate, followed by the addition of acetyl chloride or oxalyl chloride successively. The reaction of these salts with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and aromatic aldehydes afforded the corresponding dienes in moderate yields via α,β-unsaturated ylide intermediates.
Synthesis of d-Biotin Chiral Intermediates via a Biochemical Method
Authors: Yamano Toru , Tokuyama Shinji , Aoki Isao , Nishiguchi Yumiko , Nakahama Kazuo , Takanohashi Kunio
Published: August 2006

The enzyme-catalyzed kinetic resolution of (±)-(3aα,4α,6aα)-4-acetoxy-1,3-dibenzyl-3a,4,6,6a-tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-one [(RS)-(3a)] was examined. Lipase B from Pseudomonas fragi and rabbit liver esterase gave (−)-[3aR-(3aα,4α,6aα)]-1,3-dibenzyl-3a,4,6,6a-tetrahydro-4-hydroxy-1H-thieno[3,4-d]imidazol-2(3H)-one [(R)-(2)], while Streptomyces rochei var. volubilis gave the alcohol (S)-(2), which is a key intermediate in the synthesis of d-biotin, with high enantioselectivity.
Effect of Cation Binding on the Conformation of Gramicidin A′ and Valinomycin in Monolayers
Authors: Mita Tomoyoshi
Published: August 2006

In order to obtain information concerning the conformational features of cation-complexed ionophores on biological membranes, surface-pressure studies of the monolayers of ionophores, such as gramicidin A′ and valinomycin formed at an air/water interface, were carried out. The effect on the films when various salts were present in the subphase was also studied. At a concentration of 4 × 10−1 mol dm−3 the π–A isotherms for gramicidin A′ on all of the salts studied exhibited a maximal expansion in the condensed state. Based on the concentration dependence on the expansion of the gramicidin A′ monolayer, the efficiency of monovalent cations was found to be in the order NH4+ > K+ > Na+ > Li+. At a concentration of 4 × 10−1 mol dm−1, although the π–A isotherms for a valinomycin monolayer on KCl were indistinguishable from that on water at the liquid-expanded state, the π–A isotherms on LiCl, NaCl, and NH4Cl showed incremental shifts. On the other hand, by additional compression of a valinomycin monolayer on KCl over the plateau zone, an increase in the surface pressure appeared. However, the valinomycin monolayer on the other salts did not show such a behavior. This result indicates that valinomycin is specific for K+ in a membrane.
Synthesis of Annulated γ-Lactams via Intramolecular 1,3-Dipolar Cycloadditions of Functionalized N-Allyl α-Diazo Amides
Authors: Minami Toru , Kamitamari Masashi , Utsunomiya Tomohisa , Tanaka Tetsuya , Ichikawa Junji
Published: August 2006

N-Allyldiazoacetamides containing a phosphinyl group at the α-position underwent the intramolecular 1,3-cycloaddition, followed by 1,3-hydrogen shift to afford 6a-diethoxyphosphinyl-3a,4,5,6a-tetrahydropyrrolo[3,4-c]pyrazol-6(1H)-ones in 74—78% yields, while the corresponding α-phenylthio amide produced 1-phenylthio-3-azabicyclo[3.1.0]hexan-2-one in 74% yield via extrusion of N2 from the intramolecular 1,3-cycloadduct. In the application of these compounds to the conversion of functionality, the former gave a fused tricyclic heterocycle and the latter gave deallylated compounds.
Silicon Effects. V. β-Silicon Effect in the Solvolysis of 2-Phenylethyl Compounds
Authors: Hayakawa Fumie , Watanabe Sin-ichiro , Shimizu Nobujiro , Tsuno Yuho
Published: August 2006

The rates of the solvolysis of 2-aryl-2-(trimethylsilyl)ethyl compounds, ArCH(SiMe3)CH2X (4: X = Cl and OCOCF3; Ar = C6H5 and p-MeOC6H4), have been measured in various solvents at 25°C. The solvolysis of the chloride, 4 (X = Cl; Ar = C6H5), exhibited an m value of 0.90 in aqueous dioxane consistent with rate-determining ionization; it gave (2-ethoxy-2-phenylethyl) trimethylsilane together with styrene in ethanol indicating a 1, 2-SiMe3 migration during the solvolysis. The p-MeO-substitution effect, kp–MeO/kH, was measured with the trifluoroacetates to be 2.1, in contrast to a factor of 269 observed in solvolysis of 1-aryl-2-(trimethylsilyl)ethyl compounds (1), indicating that distinct intermediates are involved in ionization of the two regioisomeric systems, 1 and 4.
Characterization of Peptides Isolated from Trimeresurus flavoviridis and Trimeresurus okinavensis Venoms
Authors: Maeda Iori , Kato Tamaki , Tani Ayako , Aoyagi Haruhiko , Kihara Hiroshi , Ohno Motonori
Published: August 2006

Three peptides were isolated from both Trimeresurus flavoviridis (Habu snake) and T. okinavensis (Himehabu snake) venoms. Their structures were determined to be pGlu–Lys–Trp, pGlu–Asn–Trp, and pGlu–Gln–Trp. Only pGlu–Lys–Trp showed weak inhibitory activities against angiotensin converting enzyme and H2-protease.
Effect of Serum Albumins from Several Mammals on the Photoisomerization of Bilirubin
Authors: Kanna Yoko , Arai Tatsuo , Tokumaru Katsumi
Published: August 2006

ZZ-Bilirubin undergoes photoisomerization to configurational (ZE and EZ isomers) and structural (LR) isomers in buffered aqueous solution containing serum albumins. The efficiency and the course of the isomerization are very much dependent on the mammals from which serum albumins are taken.
Time-Resolved Observation of Vibrationally Excited 1,3-Butadiene in Laser Induced Photolysis of Bromocyclobutane and Cyclohexene
Authors: Kumar Awadhesh , Vatsa Rajesh Kumar , Chowdhury Pradyot Kumar , Rama Rao Kuchimanchi Venkata Subba , Mittal Jai Pal
Published: August 2006

The pulsed CO2 laser induced SF6 sensitized photodissociation of bromocyclobutane (BCB) and cyclohexene (CHN) is investigated. BCB has two dissociation channels from its ground electronic state, HBr elimination yielding 1,3-butadiene is the major channel (>90%) whereas, the ring cleavage producing vinyl bromide and ethylene is the minor one. The time-resolved formation of 1,3-butadiene is monitored by UV absorption from which unimolecular rate constants for BCB and CHN dissociation are found to be 8 × 105 s−1 and 1 × 106 s−1, respectively. A red-shift of 38 nm and 50 nm observed in the UV spectra of butadiene produced respectively from BCB and CHN, suggests that vibrationally hot butadiene molecules are formed. The effects of laser fluence, pressure of SF6 and the no. of laser pulses on dissociation yield and the branching ratio in BCB are also investigated.