bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluoxetine during pregnancy: impact on fetal development
Authors: Morrison Janna L. , Riggs K. Wayne , Rurak Dan W.
Published: July 2005

Women are at greatest risk of suffering from depression during the childbearing years and thus may either become pregnant while taking an antidepressant or may require a prescription for one during pregnancy. The antidepressant fluoxetine (FX) is a selective serotonin reuptake inhibitor (SSRI), which increases serotonin neurotransmission. Serotonin is involved in the regulation of a variety of physiological systems, including the sleep–wake cycle, circadian rhythms and the hypothalamic–pituitary–adrenal axis. Each of these systems also plays an important role in fetal development. Compared with other antidepressant drugs, the SSRIs, such as FX, have fewer side effects. Because of this, they are now frequently prescribed, especially during pregnancy. Clinical studies suggest poor neonatal outcome after exposure to FX in utero. Recent studies in the sheep fetus describe the physiological effects of in utero exposure to FX with an 8 day infusion during late gestation in the sheep. This is a useful model for determining the effects of FX on fetal physiology. The fetus can be studied for weeks in its normal intrauterine environment with serial sampling of blood, thus permitting detailed studies of drug disposition in both mother and fetus combined with monitoring of fetal behavioural state and cardiovascular function. Fluoxetine causes an acute increase in plasma serotonin levels, leading to a transient reduction in uterine blood flow. This, in turn, reduces the delivery of oxygen and nutrients to the fetus, thereby presenting a mechanism for reducing growth and/or eliciting preterm delivery. Moreover, because FX crosses the placenta, the fetus is exposed directly to FX, as well as to the effects of the drug on the mother. Fluoxetine increases high-voltage/non-rapid eye movement behavioural state in the fetus after both acute and chronic exposure and, thus, may interfere with normal fetal neurodevelopment. Fluoxetine also alters hypothalamic function in the adult and increases the magnitude of the prepartum rise in fetal cortisol concentrations in sheep. Fetal FX exposure does not alter fetal circadian rhythms in melatonin or prolactin. Studies of the effects of FX exposure on fetal development in the sheep are important in defining possible physiological mechanisms that explain human clinical studies of birth outcomes after FX exposure. To date, there have been insufficient longer-term follow-up studies in any precocial species of offspring exposed to SSRIs in utero. Thus, further investigation of the long-term consequences of in utero exposure to FX and other SSRIs, as well as the mechanisms involved, are required for a complete understanding of the impact of these agents on development. This should involve studies in both humans and appropriate animal models.
A
Caenorhabditis elegans
model of insulin resistance: Altered macronutrient storage and dauer formation in an OGT-1 knockout
Authors: Hanover John A. , Forsythe Michele E. , Hennessey Patrick T. , Brodigan Thomas M. , Love Dona C. , Ashwell Gilbert , Krause Michael
Published: July 2005

O-linked
N
-acetylglucosamine (O-GlcNAc) is an evolutionarily conserved modification of nuclear pore proteins, signaling kinases, and transcription factors. The O-GlcNAc transferase (OGT) catalyzing O-GlcNAc addition is essential in mammals and mediates the last step in a nutrient-sensing “hexosamine-signaling pathway.” This pathway may be deregulated in diabetes and neurodegenerative disease. To examine the function of O-GlcNAc in a genetically amenable organism, we describe a putative null allele of OGT in
Caenorhabditis elegans
that is viable and fertile. We demonstrate that, whereas nuclear pore proteins of the homozygous deletion strain are devoid of O-GlcNAc, nuclear transport of transcription factors appears normal. However, the OGT mutant exhibits striking metabolic changes manifested in a ≈3-fold elevation in trehalose levels and glycogen stores with a concomitant ≈3-fold decrease in triglycerides levels. In nematodes, a highly conserved insulin-like signaling cascade regulates macronutrient storage, longevity, and dauer formation. The OGT knockout suppresses dauer larvae formation induced by a temperature-sensitive allele of the insulin-like receptor gene
daf-2
. Our findings demonstrate that OGT modulates macronutrient storage and dauer formation in
C. elegans
, providing a unique genetic model for examining the role of O-GlcNAc in cellular signaling and insulin resistance.
Evaluation of bioavailability of nitric oxide in coronary circulation by direct measurement of plasma nitric oxide concentration
Authors: Neishi Yoji , Mochizuki Seiichi , Miyasaka Takehiro , Kawamoto Takahiro , Kume Teruyoshi , Sukmawan Renan , Tsukiji Miwako , Ogasawara Yasuo , Kajiya Fumihiko , Akasaka Takashi , Yoshida Kiyoshi , Goto Masami
Published: July 2005

Although bioavailability of NO in the coronary circulation is commonly evaluated by acetylcholine (ACh)-induced vasodilation, a change in plasma NO concentration and its relation to the flow response after injection of ACh are still unknown. Thus, we directly measured the concentration of NO in the coronary sinus by using a catheter-type NO sensor for coronary sinus. An NO-sensitive sensor was located and fixed in a 4-Fr catheter with a soft tip for protection of vascular wall. After calibration with an NO-saturated pure water, the catheter-type NO sensor was located in the coronary sinus in anesthetized dogs. The coronary flow velocity (CFV) was measured with a Doppler guide wire. Intracoronary injection of ACh (0.4 and 1.0 μg/kg) increased plasma NO concentration in a dose-dependent manner (3–10 nM). Although ACh increased CFV by 95%, there was no significant difference between the two ACh doses. After ACh, the peak value of plasma NO concentration was observed significantly later than CFV.

N
G

-methyl-
l
-arginine (NO synthase inhibitor) decreased basal NO concentration by 3 nM and suppressed the ACh-induced NO synthesis with no significant change in average peak velocity. We conclude that production of NO in the coronary circulation can be evaluated in the coronary sinus. Although ACh increases both CFV and NO concentration, CFV dose not reflect NO concentration in terms of magnitude and time course. Direct measurement of plasma NO concentration by the catheter-type NO sensor is useful to evaluate bioavailability of NO in the coronary circulation.
Crystal structure and DNA binding functions of ERCC1, a subunit of the DNA structure-specific endonuclease XPF–ERCC1
Authors: Tsodikov Oleg V. , Enzlin Jacquelin H. , Schärer Orlando D. , Ellenberger Tom
Published: August 2005

Human XPF–ERCC1 is a DNA endonuclease that incises a damaged DNA strand on the 5′ side of a lesion during nucleotide excision repair and has additional role(s) in homologous recombination and DNA interstrand crosslink repair. We show that a truncated form of XPF lacking the N-terminal helicase-like domain in complex with ERCC1 exhibits a structure-specific endonuclease activity with similar specificity to that of full-length XPF–ERCC1. Two domains of ERCC1, a central domain and a C-terminal tandem helix–hairpin–helix (HhH
2
) dimerization domain, bind to ssDNA. The central domain of ERCC1 binds ssDNA/dsDNA junctions with a defined polarity, preferring a 5′ single-stranded overhang. The XPF–ERCC1 HhH
2
domain heterodimer contains two independent ssDNA-binding surfaces, which are revealed by a crystal structure of the protein complex. A crystal structure of the central domain of ERCC1 shows its fold is strikingly similar to that of the nuclease domains of the archaeal Mus81/XPF homologs, despite very low sequence homology. A groove lined with basic and aromatic residues on the surface of ERCC1 has apparently been adapted to interact with ssDNA. On the basis of these crystallographic and biochemical studies, we propose a model in which XPF–ERCC1 recognizes a branched DNA substrate by binding the two ssDNA arms with the two HhH
2
domains of XPF and ERCC1 and by binding the 5′-ssDNA arm with the central domain of ERCC1.
In their very own words: authors and scholarly journal publishing
Authors: Nicholas David , Jamali M. Hamid R. , Huntington Paul , Rowlands Ian
Published: August 2005

This paper presents the results of a major investigation by questionnaire of author attitudes towards scholarly publishing, which was funded by the Publisher's Association. Altogether, the views of nearly 4,000 authors were obtained and this paper concerns just those thousand or so authors who accepted the invitation to write freely about their own personal feelings and experiences. Using QSR N6 textual analysis software, their comments were processed and themes extracted. While the rest of the questionnaire, which was formed of closed‐question, tick‐box type questions, clearly must have had some impact on their thinking, the authors had considerable latitude in regard to what they could say. The paper provides a unique opportunity to hear their views directly. The pressing topics turned out to be (in rough order of concern): the peer‐review system, copyright, journal prices, alternative business models for journal publishing, big deals, Elsevier, electronic publishing and digital journals.
The high-affinity phosphate-binding protein PstS is accumulated under high fructose concentrations and mutation of the corresponding gene affects differentiation in Streptomyces lividans
Authors: Díaz Margarita , Esteban Ana , Fernández-Abalos José Manuel , Santamaría Ramón I.
Published: August 2005

The secreted protein pattern ofStreptomyces lividansdepends on the carbon source present in the culture media. One protein that shows the most dramatic change is the high-affinity phosphate-binding protein PstS, which is strongly accumulated in the supernatant of liquid cultures containing high concentrations (>3 %) of certain sugars, such as fructose, galactose and mannose. The promoter region of this gene and that of itsStreptomyces coelicolorhomologue were used to drive the expression of a xylanase inS. lividansthat was accumulated in the culture supernatant when grown in the presence of fructose. PstS accumulation was dramatically increased in aS. lividanspolyphosphate kinase null mutant (Δppk) and was impaired in a deletion mutant lackingphoP, the transcriptional regulator gene of the two-componentphoR-phoPsystem that controls the Pho regulon. Deletion of thepstSgenes inS. lividansandS. coelicolorimpaired phosphate transport and accelerated differentiation and sporulation on solid media. Complementation with a single copy in aS. lividans pstSnull mutant returned phosphate transport and sporulation to levels similar to those of the wild-type strain. The present work demonstrates that carbon and phosphate metabolism are linked in the regulation of genes and that this can trigger the genetic switch towards morphogenesis.
Experience of systems migration at the University of Botswana Library: a case study
Authors: Baathuli Nfila Reason , Nini Dintwe Motumi , Rao K.N.
Published: August 2005

Purpose

To share experiences of the University of Botswana Library (UBL) in migrating from the TINLIB to Innopac library automation systems.

Design/methodology/approach

Discusses various steps involved in system migration at UBL. Provides a historical background of UBL, the reasons for migration, selection of the system and implementation. Details training on the new system, with emphasis on cataloguing and acquisitions.

Findings

Emphasises the need to prepare ahead and plan well before the implementation of the system. Indicates data conversion steps used for both TINLIB and CDS/ISIS data and various problems encountered in translating non‐MARC data into USMARC.

Research limitations/implications

The emphasis is on Technical Services leaving out circulation and periodicals modules.

Practical implications

Provides a case study for libraries to consider during the library automated system migration and training.

Originality/value

The paper is a case study of the UBL system migration, intended to help other libraries in planning the change.
Disability, workplace characteristics and job satisfaction
Authors: Uppal Sharanjit
Published: August 2005

Purpose

Previous research has shown that individuals with disabilities are likely to be less satisfied with their jobs as compared to the able‐bodied. None of them explain the reasons for this difference. The purpose of this paper is to contend that this might be due to certain factors such as discrimination, harassment, or other conditions at the workplace. It might also be due to lower relative incomes.

Design/methodology/approach

The paper uses nationally representative Canadian data and attempts to account for the low levels of job satisfaction among Canadians with disabilities.

Findings

The results show that when certain workplace characteristics are introduced into the model, individuals with a mobility disability are no longer likely to be less satisfied as compared to individuals without disabilities. However, the negative effect for certain other types of disabilities remains, though the magnitude decreases. It is concluded that absence of assistive technology or employer accommodations might be the reason for the remaining satisfaction difference between those with disabilities and the able‐bodied.

Originality/value

This paper adds to the existing literature on job satisfaction by studying the relationship between disability, workplace characteristics and job satisfaction.
Closing the gap? Building surveyors in Oceania
Authors: Wilkinson Sara J. , Russell Gillian
Published: August 2005

Purpose

The Royal Institution of Chartered Surveyors (RICS) has implemented a policy to expand its influence around the world. Quantity or construction surveyors had an established presence and history of working overseas, offering their services particularly in the Middle‐ and Far‐East. Property surveyors found the transition to working in European Union (EU) countries relatively straightforward and numerous UK property consultancies have European, Asian, North American and Oceanic offices. Furthermore UK‐based firms establishing partnerships with overseas real estate firms expanded significantly over the past decade. Building surveying (BS) is a different case. Small numbers work in commonwealth countries but it is limited and in many countries professional and academic qualifications are not recognised. This paper aims to consider the extent of the barriers and opportunities facing RICS chartered building surveyors (CBS) in Oceania (taken as Australia, New Zealand, Papua New Guinea and Fiji) and whether the gap is closing.

Design/methodology/approach

A desktop study reviewed the political, economic and sociological issues that affect the employment opportunities and professional services CBS offer throughout the world. Six opportunities and ten barriers were put to the RICS Oceania Building Surveying Faculty to ascertain their perceptions of these barriers and opportunities. No previous study had identified barriers and opportunities in Oceania for the BS and this research adopted a census survey of RICS practitioners currently employed in the region and the results form the most comprehensive picture of the current position.

Findings

Many respondents felt that stronger links and/or mergers with the different Oceania professional property and surveying bodies would open a large field of opportunities to the CBS. Some provided comments on future business opportunities, for example “leaky buildings”, “dilapidations/‘make good’ work”, and seemed to be in general agreement that, as businesses came to know the benefits of protecting themselves from rogue tenants (and landlords) by using the services of a CBS, then opportunities would continue to rise. The principal barrier is communicating those skills and the value they add.

Research limitations/implications

The limitations that affected this research were time constraints and communicating with surveyors in Oceania, to whom the authors were not permitted direct access. The research methodology methods were, with hindsight, not ideal for the type and range of data that the researchers sought.

Originality/value

The research will be of use to building surveyors and providers of building‐surveying education in Oceania.
The international strategies of Europe's incumbent telecommunications operators: towards a strategic typology
Authors: Turner Colin
Published: August 2005

Purpose

The paper seeks to examine the evolving international strategies of Europe's incumbent telecommunications operators. The aim is to develop a typology of how these different operators have sought to position themselves within an internationalising marketplace.

Design/methodology/approach

The objectives of the paper were addressed through a multiple case study analysis of 15 incumbent telecommunication operators within Western Europe. The approach was essentially strategic, seeking to develop an awareness of how each of these operators' corporate strategy has adapted to the challenges of internationalisation. The nature of this response will be defined by a broad typology.

Findings

Four types of strategy were found to exist, most of which were defined by the scale of the business. The research found that most operators were developing international strategies based on developing an effective competitive presence in the European region. There was only limited evidence of operators developing a global strategy. Some operators have attempted such a strategy but have since retreated from such offensive strategies.

Originality/value

The work highlights how businesses that have a dominant core domestic market are affected by internationalisation in both a proactive and a reactive manner.
The Czech women in the labour market: a European comparison
Authors: Valentova Marie
Published: August 2005

Purpose

The aim of the paper is to analyse the position of the Czech women in the labour market in a comparison to the EU‐15 countries. The paper critically reviews three domains of female labour market participation: general characteristics of the female employment, work‐life balance indicators, and disadvantages of the female labour force related to motherhood.

Design/methodology/approach

The data draw on harmonized data from international/supranational institutions (EUROSTAT, OECD, ILO) in order to compile comparative statistics on gender and labour market characteristics. A cluster analysis is performed in order to group countries with similar gender and labour market characteristics together.

Findings

The results identify three clusters with respect to the position of women in the labour market: southern model, Scandinavian model, and mixed model. The southern model includes Spain, Italy and Greece. These countries are characterised by women's low participation in the labour market, shorter working careers and a low incidence of part‐time working. The Scandinavian model (Denmark, Sweden, Finland) represents countries, which have high levels of female labour market participation, and a work culture that fosters high numbers of part‐time and flexible work systems. The mixed model (UK, France, Germany) falls in between these two extremes and includes the Czechoslovakia. The mixed model has relatively high female employment rates both full‐ and part‐time but tends to have less support structures for combining work‐life balance.

Originality/value

The data provide an insight into the gendered labour market systems in the Czech Republic and highlight how state and private employer organisations can develop gender sensitive policies to assist women's career and professional development. It is suggested that the Czech Republic needs to develop policies that will foster part‐time and flexible working arrangements.
Combining ontologies and peer‐to‐peer technologies for inter‐organizational knowledge management
Authors: Stuckenschmidt Heiner , Siberski Wolf , Nejdl Wolfgang
Published: August 2005

Purpose

The purpose of the paper is to review the characteristics of systems that combine P2P technology with explicit ontologies and assess the benefits of these technologies for inter‐organizational knowledge management.

Design/methodology/approach

We characterize existing technologies with respect to a number of aspects that are relevant to knowledge management on a technical level. We further provide an example of an existing system and categorize it according to the aspects.

Findings

We conclude that ontology‐based P2P systems are in general beneficial for distributed knowledge management systems and that the design of such systems can be guided using the aspects we distinguish.

Originality/value

The paper presents the first attempt to rigorously identify and discuss the design space of ontology‐based P2P systems.
Estimating the cost of capital: considerations for small business
Authors: Palliam Ralph
Published: August 2005

Purpose

For publicly traded firms, calculating the cost of capital is predicated typically on information from the financial markets. Small businesses do not have the necessary market‐based information. As an alternative to traditional proxy approaches, this paper argues for a multi‐criteria model to determine an appropriate equity risk premium, and thereby, a cost of capital.

Design/methodology/approach

The study proposes a multi‐criteria model – an analytical hierarchy process (AHP) – to determine the cost of capital for small businesses.

Findings

Since the three proxy methods are shown to have numerous shortcomings, the use of the AHP model is clearly a method to determine the equity risk premium and the cost of capital for small businesses.

Research limitations/implications

The model requires small business managers to identify all information sources for the required input data.

Originality/value

The article offers practical help to lenders and small businesses wishing to invest in new capital projects.
Microeconomic analysis of the balanced scorecard: a case of Nokia Corporation
Authors: Laitinen Erkki K.
Published: August 2005

Purpose

The purpose of the research is to analyse the theoretical foundations of the balanced scorecard (BSC) with the aid of a microeconomic model and to illustrate the results in an empirical case.

Design/methodology/approach

The model includes demand, production, and objective functions. Demand is presented as a function of price and customer relationship management (CRM) costs. Production depends on labour, capital, and development and learning (D&L) costs. The strategy is depicted by objective function based on profit and net sales. The output variables are classified as four perspectives of BSC. Shadow prices and performance measures are analysed. The theoretical model is applied to the annual financial statement data from Nokia Corporation. Simulation is used to find appropriate estimates for the parameters of the model.

Findings

It is shown that a shift in the objective function (strategy) towards revenue maximization may alter the importance order of the BSC perspectives. Non‐financial and financial performance ratios may change into opposite directions, when the strategy is shifted. The figures extracted from the data of Nokia Corporation give support to these interpretations.

Research limitations/implications

The theoretical model is based on the traditional assumptions of microeconomic analysis. Empirical analysis is only based on a naive estimation methods. The sensitivity of the results with respect to the assumptions should be analysed in further studies. The parameters should be estimated with more advanced statistical methods.

Practical implications

The focus of the BSC should be elastic and react to changes in the strategy. When evaluating the causal relationships between non‐financial and financial performance measures, attention should be paid to potential shifts in the strategy. The present model for example in a worksheet version would be useful in analysing the optimal behaviour of a firm and the causal relationships within the firm. It would be useful also in teaching the BSC and in general the behaviour of the firm to university students and managers. The model offers a platform for teaching and learning how the market (demand) and production (technology) environments affect the performance measures in the BSC.

Originality/value

There is a lack of theoretical modelling and analysis of the BSC. The present mathematical model is discussed earlier in Managerial Finance. However, this paper throws light to modelling the approach in a real‐life case of the Nokia Corporation and shows the value of the approach in interpreting the BSC in practice.
Marketing research performance and strategy
Authors: Bednall David H.B. , Valos Michael J.
Published: August 2005

Purpose

To investigate whether strategic orientation affects the evaluation of specific market research projects in for‐profit firms.

Design/methodology/approach

A small‐scale follow‐up survey was conducted, building on qualitative and quantitative research among a sample of the top‐1,000 marketing managers in Australia. The study used an existing market research evaluation tool, the USER scale and items generated from the qualitative research, to investigate the firm's most recent market research project.

Findings

Four market research performance factors were identified – market research as a knowledge enhancing (KE) function, the internal political use of market research, the misuse of market research and the generation of market understanding. The Miles and Snow strategy types were related to these factors, with Prospector types more likely to use market research rationally and less likely to use it for internal political purposes. Tactical projects were more likely to be misused than were those with a strategic orientation. Prospectors were far less likely and Analyzers far more likely to misuse tactical research projects. Prospectors were more often satisfied with the performance of their most recent market research. The Porter typology was less successful in predicting market research performance.

Research limitations/implications

The study was based on a small sample of market research projects in Australian for‐profit firms. Future studies need to study these phenomena more intensively using ethnographic methods and more extensively using larger multi‐country samples.

Practical implications

Market research suppliers should learn the nature of their client's strategic intent to improve their effectiveness. Defender firms should carefully monitor the use of market research, especially that of a tactical nature, which may be wasted or misused.

Originality/value

The paper contributes to an understanding of how strategic orientation relates to the ways market research information is used within the firm.
Regulation of cancer cell motility through actin reorganization
Authors: Yamazaki Daisuke , Kurisu Shusaku , Takenawa Tadaomi
Published: July 2005

Cell migration is a critical step in tumor invasion and metastasis, and regulation of this process will lead to appropriate therapies for treating cancer. Cancer cells migrate in various ways, according to cell type and degree of differentiation. The different types of cell migration are regulated by different mechanisms. Reorganization of the actin cytoskeleton is the primary mechanism of cell motility and is essential for most types of cell migration. Actin reorganization is regulated by Rho family small GTPases such as Rho, Rac, and Cdc42. These small GTPases transmit extracellular chemotactic signals to downstream effectors. Of these downstream effectors, Wiskott–Aldrich syndrome protein (WASP) family proteins are key regulators of cell migration. Activated WASP family proteins induce the formation of protrusive membrane structures involved in cell migration and degradation of the extracellular matrix. Inhibition of Rho family small GTPase signaling suppresses the migration and invasion of cancer cells. Thus, control of cell migration via the actin cytoskeleton provides the possibility of regulating cancer cell invasion and metastasis. (Cancer Sci 2005; 96: 379 – 386)
Whole‐genome analyses of loss of heterozygosity and methylation analysis of four tumor‐suppressor genes in N‐methyl‐N′‐nitro‐N‐nitrosoguanidine‐induced rat stomach carcinomas
Authors: Niwa Tohru , Yamashita Satoshi , Tsukamoto Tetsuya , Kuramoto Takashi , Nomoto Tomoko , Wakazono Kuniko , Fujita Hirofumi , Matsushima Taijiro , Tatematsu Masae , Sugimura Takashi , Ushijima Toshikazu
Published: July 2005

N‐Methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG)‐induced rat stomach carcinomas are considered to be a good model for differentiated‐type human stomach carcinomas. However, as for their molecular basis, only infrequent mutations of Catnb (β‐catenin) and Trp53 (p53) have been observed. Here, we carried out a whole‐genome analysis of loss of heterozygosity (LOH) using 21 stomach carcinomas induced by MNNG in F1 hybrids of ACI and BUF rats, and also analyzed promoter methylation of four tumor‐suppressor genes. LOH analysis was performed using 130 polymorphic markers covering rat chromosomes 1–20 with an average interval of 20 Mbp. Despite adapting conditions so that LOH could be detected with up to a 50% contamination of stromal cells, no LOH was detected at any loci. CpG islands in putative promoter regions of four tumor‐suppressor genes, Cdh1 (E‐cadherin), Cdkn2a (p16), Mlh1, and Rassf1a, were analyzed by methylation‐specific polymerase chain reaction (PCR). However, no methylation was detected. In contrast, the promoter region of Pgc (pepsinogen C), which lacks a CpG island, was methylated in all 21‐cancer samples. These results indicated that LOH spanning a chromosomal region larger than 30–40 Mbp or silencing of Cdh1, Cdkn2a, Mlh1, and Rassf1a, was not involved in MNNG‐induced rat stomach carcinomas. The search for other genes involved in these carcinomas needs to be continued. (Cancer Sci 2005; 96: 409  – 413)
Increased DNA methyltransferase 1 (DNMT1) protein expression in precancerous conditions and ductal carcinomas of the pancreas
Authors: Peng Dun‐Fa , Kanai Yae , Sawada Morio , Ushijima Saori , Hiraoka Nobuyoshi , Kosuge Tomoo , Hirohashi Setsuo
Published: July 2005

Aberrant DNA methylation has been shown to play an important role during multistage carcinogenesis in various human organs. The aim of the present study was to evaluate the significance of DNA methyltransferase 1 (DNMT1) protein expression during pancreatic carcinogenesis. Immunohistochemical analysis of DNMT1 in 48 peripheral pancreatic duct epithelia showing no remarkable histological findings without an inflammatory background (DE), 54 peripheral pancreatic duct epithelia with an inflammatory background (DEI), 188 pancreatic intraepithelial neoplasias (PanIN), and 220 areas of invasive ductal carcinoma from surgical specimens resected from 100 patients, was carried out. The average incidence of DNMT1 immunoreactivity increased progressively from DE to DEI (P = 0.003), from DE and DEI to PanIN (P < 0.0001), among PanIN with different grades of dysplasia (from PanIN I to PanIN II, P = 0.0012), from PanIN to invasive ductal carcinomas (P < 0.0001) and among invasive ductal carcinomas with different grades of histological differentiation (from well or moderately to poorly differentiated adenocarcinomas, P < 0.0001). High‐level DNMT1 protein expression in invasive ductal carcinomas was correlated significantly with an advanced t category (P = 0.0224) and an advanced stage (P = 0.0294). Moreover, patients with invasive ductal carcinomas showing high‐level DNMT1 protein expression had a poorer outcome (P = 0.0469). These data suggest that increased DNMT1 protein expression participates in multistage pancreatic carcinogenesis from the precancerous stage to malignant progression of ductal carcinomas and may be a biological predictor of poor prognosis. (Cancer Sci 2005; 96: 403–408)
Trends in the prevalence of peptic ulcer disease and Helicobacter pylori infection in family physician‐referred uninvestigated dyspeptic patients in Hong Kong
Authors: XIA B. , XIA H. H. X. , MA C. W. , WONG K. W. , FUNG F. M. Y. , HUI C. K. , CHAN C. K. , CHAN A. O. O. , LAI K. C. , YUEN M. F. , WONG B. C. Y.
Published: July 2005

Background:  Peptic ulcer disease is mainly caused by Helicobacter pylori infection and the use of non‐steroidal anti‐inflammatory drugs.

Aim:  To investigate the trends in the prevalence of peptic ulcer disease, H. pylori infection and non‐steroidal anti‐inflammatory drug use in uninvestigated dyspeptic patients over recent years in Hong Kong.

Methods:  Data from consecutive patients with uninvestigated dyspeptic symptoms referred by family physicians for open access upper endoscopy during 1997 and 2003 were analysed in relation to peptic ulcer disease, H. pylori infection and non‐steroidal anti‐inflammatory drug use.

Results:  Among 2700 patients included, 405 (15%) had peptic ulcer disease and 14 (0.5%) had gastric cancer. There was a reduced trend from 1997 to 2003 in the prevalence of peptic ulcer disease (17, 20, 14, 16, 13, 14 and 14%, respectively, χ2 = 5.80, P = 0.016) (mainly because of decrease in duodenal ulcers), H. pylori infection (44, 50, 49, 44, 40, 40, 36 and 43%, respectively, χ2 = 13.55, P < 0.001) and non‐steroidal anti‐inflammatory drug use (13, 5, 5, 6, 3, 4, 4 and 5% respectively, χ2 = 13.61, P < 0.001). The prevalence of peptic ulcer disease, H. pylori infection and non‐steroidal anti‐inflammatory drug use between 2001 and 2003 were significantly lower than that between 1997 and 2000 (17% vs. 13%, OR = 0.78, 95% CI: 0.63–0.96, P = 0.020 for peptic ulcer disease; 47% vs. 39%, OR =0.72, 95% CI: 0.60–0.86, P < 0.001 for H. pylori infection; and 6% vs. 4%, OR = 0.56, 95% CI: 0.39–0.82, P = 0.002 for non‐steroidal anti‐inflammatory drug use). H. pylori infection was associated with both duodenal ulcer (OR = 15.87, 95% CI: 10.60–23.76, P < 0.001) and gastric ulcer (OR = 3.12, 95% CI: 2.15–4.53, P < 0.001) whereas non‐steroidal anti‐inflammatory drug use was only associated with gastric ulcer (OR = 2.97, 95% CI: 1.70–5.20, P < 0.001).

Conclusions:  The prevalence of peptic ulcer disease, mainly duodenal ulcers, was reduced in association with a decreasing trend in the prevalence of H. pylori infection and non‐steroidal anti‐inflammatory drug use from 1997 to 2003.
Inhibition of infectious haematopoietic necrosis virus in cell cultures with peptide‐conjugated morpholino oligomers
Authors: Alonso M , Stein D A , Thomann E , Moulton H M , Leong J C , Iversen P , Mourich D V
Published: July 2005

Delivery of phosphorodiamidate morpholino oligomers (PMO) into fish cells in vitro and tissues in vivo was examined. Uptake was evaluated by fluorescence microscopy and flow cytometry after treating cultured cells or live rainbow trout with 3′ fluorescein‐tagged PMO. Arginine‐rich peptide conjugated to the 5′ end of the PMO markedly enhanced cellular uptake in culture by 8‐ to 20‐fold compared with non‐peptide‐conjugated PMO as determined by flow cytometry. Enhanced uptake of PMO conjugated to peptide was also observed in tissues of fish treated by immersion. The efficacy of PMO as inhibitors of infectious haematopoietic necrosis virus (IHNV) replication was determined in vitro. Peptide‐conjugated PMOs targeting sequences within the IHNV genomic RNA (negative polarity) or antigenomic RNA (positive polarity) significantly inhibited replication in a dose‐dependent and sequence‐specific manner. A PMO complementary to sequence near the 5′ end of IHNV genomic RNA was the most effective, diminishing titre by 97%, as measured by plaque assay and Western blot. These data demonstrate that replication of a negative‐stranded non‐segmented RNA virus can be inhibited by antisense compounds that target positive polarity viral RNA, or by a compound that targets negative polarity viral RNA.
Facilitated diffusion in chromatin lattices: mechanistic diversity and regulatory potential
Authors: Kampmann Martin
Published: July 2005

The interaction between a protein and a specific DNA site is the molecular basis for vital processes in all organisms. Location of the DNA target site by the protein commonly involves facilitated diffusion. Mechanisms of facilitated diffusion vary among proteins; they include one‐ and two‐dimensional sliding along DNA, direct transfer between uncorrelated sites, as well as combinations of these mechanisms. Facilitated diffusion has almost exclusively been studied in vitro. This review discusses facilitated diffusion in the context of the living cell and proposes a theoretical model for facilitated diffusion in chromatin lattices. Chromatin structure differentially affects proteins in different modes of diffusion. The interplay of facilitated diffusion and chromatin structure can determine the rate of protein association with the target site, the frequency of association–dissociation events at the target site, and, under particular conditions, the occupancy of the target site. Facilitated diffusion is required in vivo for efficient DNA repair and bacteriophage restriction and has potential roles in fine‐tuning gene regulatory networks and kinetically compartmentalizing the eukaryotic nucleus.
Mutagenesis of PepA suggests a new model for the Xer/cer synaptic complex
Authors: Reijns Martin , Lu Yangjie , Leach Stephen , Colloms Sean D.
Published: July 2005

PepA is an aminopeptidase and also functions as a DNA‐binding protein in two unrelated systems in Escherichia coli: Xer site‐specific recombination and transcriptional regulation of carAB. In these systems, PepA binds to and brings together distant segments of DNA to form interwrapped, nucleosome‐like structures. Here we report the selection of PepA mutants that were unable to support efficient Xer recombination. These mutants were defective in DNA‐binding and in transcriptional regulation of carAB, but had normal peptidase activity. The mutations define extended patches of basic residues on the surface of the N‐terminal domain of PepA that flank a previously proposed DNA‐binding groove in the C‐terminal domain of PepA. Our results suggest that DNA passes through this C‐terminal groove in the PepA hexamer, and is bound by N‐terminal DNA‐binding determinants at each end of the groove. Based on our data, we propose a new model for the Xer synaptic complex, in which two recombination sites are wrapped around a single hexamer of PepA, bringing the cross‐over sites together for strand exchange by the Xer recombinases. In this model, PepA stabilizes negative plectonemic interwrapping between two segments of DNA by passing one segment through the C‐terminal groove while the other is held in place in a loop over the groove.
Selection and characterization of Yersinia pestis YopN mutants that constitutively block Yop secretion
Authors: Ferracci Franco , Schubot Florian D. , Waugh David S. , Plano Gregory V.
Published: July 2005

Secretion of Yop effector proteins by the Yersinia pestis plasmid pCD1‐encoded type III secretion system (T3SS) is regulated in response to specific environmental signals. Yop secretion is activated by contact with a eukaryotic cell or by growth at 37°C in the absence of calcium. The secreted YopN protein, the SycN/YscB chaperone and TyeA form a cytosolic YopN/SycN/YscB/TyeA complex that is required to prevent Yop secretion in the presence of calcium and prior to contact with a eukaryotic cell. The mechanism by which these proteins prevent secretion and the subcellular location where the block in secretion occurs are not known. To further investigate both the mechanism and location of the YopN‐dependent block, we isolated and characterized several YopN mutants that constitutively block Yop secretion. All the identified amino‐acid substitutions that resulted in a constitutive block in Yop secretion mapped to a central domain of YopN that is not directly involved in the interaction with the SycN/YscB chaperone or TyeA. The YopN mutants required an intact TyeA‐binding domain and TyeA to block secretion, but did not require an N‐terminal secretion signal, an intact chaperone‐binding domain or the SycN/YscB chaperone. These results suggest that a C‐terminal domain of YopN complexed with TyeA blocks Yop secretion from a cytosolic, not an extracellular, location. A hypothetical model for how the YopN/SycN/YscB/TyeA complex regulates Yop secretion is presented.
Involvement of SRD2‐mediated activation of snRNA transcription in the control of cell proliferation competence in Arabidopsis
Authors: Ohtani Misato , Sugiyama Munetaka
Published: July 2005

The transcription machinery of small nuclear RNA (snRNA) genes has been investigated extensively in human cell‐free systems, but its physiological function in vivo has not been addressed. This paper demonstrates the physiological role of an activator of snRNA transcription using a temperature‐sensitive mutant of Arabidopsis thaliana, srd2. Phenotypic characteristics of the srd2 mutant suggest that the SRD2 gene participates in the control of competence in cell proliferation. The SRD2 gene encodes a nuclear protein that shares sequence similarity with the human SNAP50 protein, which is a subunit of SNAPc and is required for snRNA transcription in vitro. Our results, obtained from analysis of snRNA expression in the srd2 mutant, indicate that the SRD2 protein functions in the upregulation of transcription of snRNA genes, the promoters of which contain the upstream sequence element, to elevate cell proliferation competence.
Light and plastid signals regulate the expression of the pea plastocyanin gene through a common region at the 5′ end of the coding region
Authors: Brown Naomi J. , Sullivan James A. , Gray John C.
Published: July 2005

Expression of the pea plastocyanin gene (PetE) is regulated by light and plastid signals. Previous work indicated that light and plastid regulation of pea PetE operates post‐transcriptionally in transgenic tobacco, and requires the correct 5′ terminus of the PetE transcript and the PetE‐coding region. The post‐transcriptional light and plastid regulation of pea PetE has now been demonstrated to operate in transgenic Arabidopsis, where in contrast the endogenous PETE gene is regulated transcriptionally. Transgenic tobacco seedlings containing constructs with progressive 3′ deletions of the PetE‐coding region fused to the luciferase (Luc) reporter gene demonstrate that the first 60 nucleotides of the coding region are sufficient for regulated accumulation of Luc transcripts by light and plastid signalling pathways affected by treatment with norflurazon and lincomycin. PetE constructs containing premature stop codons were generated to investigate whether translation has a role in light or plastid regulation. Insertion of a stop codon in place of the second codon of the PetE‐coding region diminished both light and plastid regulation of PetE transcripts, whereas stop codons inserted later in the transcript had no effect on light or plastid regulation. These experiments indicate that the 5′ end of the plastocyanin‐coding region contains sequences important for regulation by light and plastid signals.
Validation of basophil histamine release against the autologous serum skin test and outcome of serum‐induced basophil histamine release studies in a large population of chronic urticaria patients
Authors: Platzer M. H. , Grattan C. E. H. , Poulsen L. K. , Skov P. S.
Published: August 2005

Background:  Endogenous histamine‐releasing factors (HRFs) are involved in 30–60% of patients with chronic urticaria (CU). Evidence for their existence comes from in vivo studies of autoreactivity with the autologous serum skin test (ASST), in vitro immunoassays demonstrating autoantibodies against the immunoglobulin E (IgE) or the high affinity IgE receptor (FcɛRI) and serum‐induced histamine release (HR) from basophils and mast cells. We have examined the correlation between the ASST and a new basophil histamine‐releasing assay (the HR‐Urtikaria test) in a group of well‐characterized CU patients and subsequently determined the frequency of HR‐Urticaria‐positive sera from a larger population of CU patients.

Subjects:  Group 1 consisted of 28 patients with CU (16 were ASST‐positive) 20 patients with atopic dermatitis, 24 patients with allergy to birch and nine healthy controls. Group 2 consisted of 873 unselected CU patients.

Methods:  White blood cells containing 1–2% basophils from a healthy nonatopic donor were incubated with patients sera in the presence of interleukin (IL)‐3. Histamine was measured by the glass fibre method.

Results:  Using the ASST as the true outcome, the HR‐Urticaria test showed a sensitivity and specificity of 75% in group 1 using a cut‐off value for HR of >16.5%. None of the controls was positive in the HR‐Urticaria test. In group 2, we found no difference in the frequency of positives between male (34.6%, n = 254) and female adults (35.1%, n = 576) but twice as many females as males were tested.

Conclusions:  Our studies have shown that the HR‐Urticaria test has a good sensitivity and specificity for endogenous HRFs demonstrated by the ASST in patients with CU and that about one‐third of unselected patients with CU have a positive result.
Prevalence of food allergy and its relationship to asthma and allergic rhinitis in schoolchildren
Authors: Pénard‐Morand C. , Raherison C. , Kopferschmitt C. , Caillaud D. , Lavaud F. , Charpin D. , Bousquet J. , Annesi‐Maesano I.
Published: August 2005

Background:  Food allergy (FA) is an important health problem. However, epidemiological studies at the population level are scarce. We assessed the prevalence of FA and its associations with respiratory manifestations among schoolchildren.

Methods:  A total of 6672 schoolchildren aged 9–11 years recruited from 108 randomly chosen schools in six French cities underwent a clinical examination including skin prick test (SPT) to common food and aeroallergens and the standardized protocol of the run test to assess exercise‐induced bronchial hyper‐responsiveness (EIB). Asthma, allergic rhinitis (AR) and clinical symptoms of FA were determined using a standardized questionnaire completed by parents.

Results:  About 2.1% of the children reported symptoms of FA, 1.9% were sensitized to food allergens, and 0.1% had SP‐tested FA. The AR was more prevalent than asthma (20.0% lifetime, 11.9% past year vs 9.8%, 8.7% respectively). Reported FA, food sensitization and SP‐tested FA were all positively associated with asthma and AR (P < 0.001). These associations persisted also for FA not manifesting as respiratory symptoms (P < 0.001). Asthma and AR remained significantly associated with reported symptoms of FA and allergic sensitization to food allergens after adjustment for confounders as well as for sensitization to aeroallergens. No relationship existed between EIB (9.0%) and FA.

Conclusion:  The relationships between FA and asthma and AR could be totally explained neither by the existence of respiratory manifestations of FA nor by sensitization to aeroallergens. The FA might intervene differently in asthma and AR.
Identification and characterization of quantitative trait loci related to lodging resistance and associated traits in bread wheat
Authors: Verma V. , Worland A. J. , Savers E. J. , Fish L. , Caligari P. D. S. , Snape J. W.
Published: July 2005

Lodging is a major constraint to increasing yield in many crops, but is of particular importance in the small‐grained cereals. This study investigated the genetic control of lodging and component traits in wheat through the detection of underlying quantitative trait loci (QTL), The analysis was based on the identification of genomic regions which affect various traits related to lodging resistance in a population of 96‐doubled haploid lines of the cross ‘Milan’×‘Catbird’, mapped using 126‐microsatellite markers. Although major genes related to plant height (Rht genes) were responsible for increasing lodging resistance in this cross, several other traits independent of plant height were shown to be important such as fool and shoot traits, and various components of plant yield. Yield components such as grain number and weight were shown to be an indicator of plant susceptibility to lodging. QTL for lodging and associated traits were found on chromosomes IB, ID. 2B. 2D. 4B, 4D. 6D and 7D. QTL for yield and associated traits were identified on chromosomes IB, ID. 2A. 2B. 2D. 4D and 6A,