bluuebunny/crossref_metadata_2025 huggingface dataset:
The Dynamics of a Variably Coupled Social System
Authors: Kleymann Birgit , Malloch Hedley , Redman Tom , Angot Jacques
Published: February 2008

This article aims to expand the use of the coupling metaphor in organizational analysis by introducing a conceptual link between coupling and systems closure. The authors present a case study of Les Compagnons du Devoir (CdD), an ancient French Compagnonnage, or workers' brotherhood. This organization has managed to survive for at least 700 years; it is believed to be the oldest extant form of labor organization. The authors analyze the CdD as a highly institutionalized system displaying variable couplings and facing significant changes in its sociocultural environment. These features have been highlighted by recent attempts to internationalize the CdD. The authors distinguish between induced change and change by erosion and discuss how, given certain coupling configurations, an organization has persisted in an almost unchanged state while the world around it evolves.
Commentary on “Recruitment of Women to Public Office: A Discriminant Analysis,” 1978
Authors: Welch Susan
Published: February 2008

Growing out of an interest in why there were not more women in state legislatures, the author's 1978 article tested the explanation that a large part of the problem was the shortage of women in the eligibility pool. The article showed that more than one-third of the discrepancy between the small proportion of women then in the legislature and the 53 percent expected if legislatures reflected the population proportions of women could be accounted for by characteristics of the women's candidate pool, including occupation, education, and membership in groups. Since 1978, we know more about impediments to women's legislative membership, including the effects of incumbency, partisanship, and district characteristics. The article concludes with some suggestions for future research: tracking longitudinal trends in predictors of women's legislative membership, disentangling the factors that facilitate women's election, further examination of partisan factors relating to women's success, and a closer look at minority women.
Linear PID Composite Controller and its Tuning for Flexible Link Robots
Authors: Cheong Joono , Lee Seungjin
Published: February 2008

This article presents both a proposal for a linear PID composite controller, composed of slow and fast sub-controllers, for flexible link robot systems modeled using the singular perturbation approach, and an efficient tuning method for the proposed controller structure. For the slow sub-controller, a PD controller with disturbance observer is used, which eventually takes on PID form. For the fast sub-controller, modal feedback PID control is utilized. The integral action in the controller removes steady state error in the joint caused by step disturbance and imperfect gravity compensation, although it also complicates the analysis. Effects of tuning the parameters of the controller to the closed loop response are investigated, and guidelines on the performance tuning for many flexible systems thus delivered. Through simulation and experiments, the adequacy and performance of the proposed method are verified.
Concentration and Contemplation
Authors: Altobello Robert
Published: February 2008

The author shows in this article how a traditional-Asian contemplative and mediation practice can be used to increase concentration and learning. The author introduces a model of higher learning that captures a traditional linear paradigm of how higher learning unfolds. He then argues that effective use of that paradigm presupposes that students possess well-honed skills in concentration and contemplation, but that they often do not possess them. Thus, educators (at least those of us who use versions of the traditional paradigm) need to broaden curricula to include methods of learning that develop and polish these essential skills. As support, the author develops an argument for the importance of concentration and contemplation as foundational academic competencies. Finally, he introduces a demystified version of a traditional meditation/contemplative practice—the author's lesson in learning to learn—and argues that use of this model can enhance the development of mature academic skills.
Guiding metaphors of nationalism: the Cyprus issue and the construction of Turkish national identity in online discussions
Authors: Baruh Lemi , Popescu Mihaela
Published: February 2008

This article is a study of three major metaphors organizing nationalistic discourse about Cyprus in two online forums for Turkish university students. The analysis suggests that discussants symbolically warranted their constructions of the future of Cyprus and Turkish Cypriots with metaphors of blood and heroism that emphasized their personal and collective memory of sacrifice. Sports metaphors were used predominantly to convey a sense of the strategic importance of Cyprus. In addition, discussants employed gender and sexual metaphors to structure the tension between nationalist feelings associated with motherland Turkey as a pure, virgin female, and the geopolitical demands of the nation-state, portrayed as a father faced with uneasy choices.
Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: an analysis of 10 549 patients from the International Myeloma Working Group
Authors: Ludwig Heinz , Durie Brian G. M. , Bolejack Vanessa , Turesson Ingemar , Kyle Robert A. , Blade Joan , Fonseca Rafael , Dimopoulos Meletios , Shimizu Kazuyuki , San Miguel Jesus , Westin Jan , Harousseau Jean-Luc , Beksac Meral , Boccadoro Mario , Palumbo Antonio , Barlogie Bart , Shustik Chaim , Cavo Michele , Greipp Philip R. , Joshua Douglas , Attal Michel , Sonneveld Pieter , Crowley John
Published: February 2008

We analyzed the presenting features and survival in 1689 patients with multiple myeloma aged younger than 50 years compared with 8860 patients 50 years of age and older. Of the total 10 549 patients, 7765 received conventional therapy and 2784 received high-dose therapy. Young patients were more frequently male, had more favorable features such as low International Staging System (ISS) and Durie-Salmon stage as well as less frequently adverse prognostic factors including high C-reactive protein (CRP), low hemoglobin, increased serum creatinine, and poor performance status. Survival was significantly longer in young patients (median, 5.2 years vs 3.7 years; P < .001) both after conventional (median, 4.5 years vs 3.3 years; P < .001) or high-dose therapy (median, 7.5 years vs 5.7 years; P = .04). The 10-year survival rate was 19% after conventional therapy and 43% after high-dose therapy in young patients, and 8% and 29%, respectively, in older patients. Multivariate analysis revealed age as an independent risk factor during conventional therapy, but not after autologous transplantation. A total of 5 of the 10 independent risk factors identified for conventional therapy were also relevant for autologous transplantation. After adjusting for normal mortality, lower ISS stage and other favorable prognostic features seem to account for the significantly longer survival of young patients with multiple myeloma with age remaining a risk factor during conventional therapy.
Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound
Authors: Lawrence B. Paige , Denison Michael S. , Novak Hermann , Vorderstrasse Beth A. , Harrer Nathalie , Neruda Wolfgang , Reichel Claudia , Woisetschläger Maximilian
Published: February 2008

VAF347 is a low-molecular-weight compound that inhibits allergic lung inflammation in vivo. This effect is likely the result of a block of dendritic cell (DC) function to generate proinflammatory T-helper (Th) cells because VAF347 inhibits interleukin (IL)–6, CD86, and human leukocyte antigen (HLA)–DR expression by human monocyte-derived DC, 3 relevant molecules for Th-cell generation. Here we demonstrate that VAF347 interacts with the aryl hydrocarbon receptor (AhR) protein, resulting in activation of the AhR signaling pathway. Functional AhR is responsible for the biologic activity of VAF347 because (1) other AhR agonists display an identical activity profile in vitro, (2) gene silencing of wild-type AhR expression or forced overexpression of a trans-dominant negative AhR ablates VAF347 activity to inhibit cytokine induced IL-6 expression in a human monocytic cell line, and (3) AhR-deficient mice are resistant to the compound's ability to block allergic lung inflammation in vivo. These data identify the AhR protein as key molecular target of VAF347 and its essential role for mediating the anti-inflammatory effects of the compound in vitro and in vivo.
In silico analysis of expressed sequence tags from Trichostrongylus vitrinus (Nematoda): comparison of the automated ESTExplorer workflow platform with conventional database searches
Authors: Nagaraj Shivashankar H , Gasser Robin B , Nisbet Alasdair J , Ranganathan Shoba
Published: February 2008

Background

The analysis of expressed sequence tags (EST) offers a rapid and cost effective approach to elucidate the transcriptome of an organism, but requires several computational methods for assembly and annotation. Researchers frequently analyse each step manually, which is laborious and time consuming. We have recently developed ESTExplorer, a semi-automated computational workflow system, in order to achieve the rapid analysis of EST datasets. In this study, we evaluated EST data analysis for the parasitic nematode Trichostrongylus vitrinus (order Strongylida) using ESTExplorer, compared with database matching alone.

Results

We functionally annotated 1776 ESTs obtained via suppressive-subtractive hybridisation from T. vitrinus, an important parasitic trichostrongylid of small ruminants. Cluster and comparative genomic analyses of the transcripts using ESTExplorer indicated that 290 (41%) sequences had homologues in Caenorhabditis elegans, 329 (42%) in parasitic nematodes, 202 (28%) in organisms other than nematodes, and 218 (31%) had no significant match to any sequence in the current databases. Of the C. elegans homologues, 90 were associated with 'non-wildtype' double-stranded RNA interference (RNAi) phenotypes, including embryonic lethality, maternal sterility, sterile progeny, larval arrest and slow growth. We could functionally classify 267 (38%) sequences using the Gene Ontologies (GO) and establish pathway associations for 230 (33%) sequences using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Further examination of this EST dataset revealed a number of signalling molecules, proteases, protease inhibitors, enzymes, ion channels and immune-related genes. In addition, we identified 40 putative secreted proteins that could represent potential candidates for developing novel anthelmintics or vaccines. We further compared the automated EST sequence annotations, using ESTExplorer, with database search results for individual T. vitrinus ESTs. ESTExplorer reliably and rapidly annotated 301 ESTs, with pathway and GO information, eliminating 60 low quality hits from database searches.

Conclusion

We evaluated the efficacy of ESTExplorer in analysing EST data, and demonstrate that computational tools can be used to accelerate the process of gene discovery in EST sequencing projects. The present study has elucidated sets of relatively conserved and potentially novel genes for biological investigation, and the annotated EST set provides further insight into the molecular biology of T. vitrinus, towards the identification of novel drug targets.
Preferential binding of allosteric modulators to active and inactive conformational states of metabotropic glutamate receptors
Authors: Yanamala Naveena , Tirupula Kalyan C , Klein-Seetharaman Judith
Published: February 2008

Metabotropic glutamate receptors (mGluRs) are G protein coupled receptors that play important roles in synaptic plasticity and other neuro-physiological and pathological processes. Allosteric mGluR ligands are particularly promising drug targets because of their modulatory effects – enhancing or suppressing the response of mGluRs to glutamate. The mechanism by which this modulation occurs is not known. Here, we propose the hypothesis that positive and negative modulators will differentially stabilize the active and inactive conformations of the receptors, respectively. To test this hypothesis, we have generated computational models of the transmembrane regions of different mGluR subtypes in two different conformations. The inactive conformation was modeled using the crystal structure of the inactive, dark state of rhodopsin as template and the active conformation was created based on a recent model of the light-activated state of rhodopsin. Ligands for which the nature of their allosteric effects on mGluRs is experimentally known were docked to the modeled mGluR structures using ArgusLab and Autodock softwares. We find that the allosteric ligand binding pockets of mGluRs are overlapping with the retinal binding pocket of rhodopsin, and that ligands have strong preferences for the active and inactive states depending on their modulatory nature. In 8 out of 14 cases (57%), the negative modulators bound the inactive conformations with significant preference using both docking programs, and 6 out of 9 cases (67%), the positive modulators bound the active conformations. Considering results by the individual programs only, even higher correlations were observed: 12/14 (86%) and 8/9 (89%) for ArgusLab and 10/14 (71%) and 7/9 (78%) for AutoDock. These findings strongly support the hypothesis that mGluR allosteric modulation occurs via stabilization of different conformations analogous to those identified in rhodopsin where they are induced by photochemical isomerization of the retinal ligand – despite the extensive differences in sequences between mGluRs and rhodopsin.
Motif-directed network component analysis for regulatory network inference
Authors: Wang Chen , Xuan Jianhua , Chen Li , Zhao Po , Wang Yue , Clarke Robert , Hoffman Eric
Published: February 2008

Background

Network Component Analysis (NCA) has shown its effectiveness in discovering regulators and inferring transcription factor activities (TFAs) when both microarray data and ChIP-on-chip data are available. However, a NCA scheme is not applicable to many biological studies due to limited topology information available, such as lack of ChIP-on-chip data. We propose a new approach, motif-directed NCA (mNCA), to integrate motif information and gene expression data to infer regulatory networks.

Results

We develop motif-directed NCA (mNCA) to incorporate motif information into NCA for regulatory network inference. While motif information is readily available from knowledge databases, it is a "noisy" source of network topology information consisting of many false positives. To overcome this problem, we develop a stability analysis procedure embedded in mNCA to resolve the inconsistency between motif information and gene expression data, and to enable the identification of stable TFAs. The mNCA approach has been applied to a time course microarray data set of muscle regeneration. The experimental results show that the inferred TFAs are not only numerically stable but also biologically relevant to muscle differentiation process. In particular, several inferred TFAs like those of MyoD, myogenin and YY1 are well supported by biological experiments.

Conclusion

A novel computational approach, mNCA, has been developed to integrate motif information and gene expression data for regulatory network reconstruction. Specifically, motif analysis is used to obtain initial network topology, and stability analysis is developed and applied with mNCA to extract stable TFAs. Experimental results on muscle regeneration microarray data have demonstrated that mNCA is a practical and reliable computational method for regulatory network inference and pathway discovery.
Comparative phyloinformatics of virus genes at micro and macro levels in a distributed computing environment
Authors: Singh Dadabhai T , Trehan Rahul , Schmidt Bertil , Bretschneider Timo
Published: February 2008

Background

Preparedness for a possible global pandemic caused by viruses such as the highly pathogenic influenza A subtype H5N1 has become a global priority. In particular, it is critical to monitor the appearance of any new emerging subtypes. Comparative phyloinformatics can be used to monitor, analyze, and possibly predict the evolution of viruses. However, in order to utilize the full functionality of available analysis packages for large-scale phyloinformatics studies, a team of computer scientists, biostatisticians and virologists is needed – a requirement which cannot be fulfilled in many cases. Furthermore, the time complexities of many algorithms involved leads to prohibitive runtimes on sequential computer platforms. This has so far hindered the use of comparative phyloinformatics as a commonly applied tool in this area.

Results

In this paper the graphical-oriented workflow design system calledQuascadeand its efficient usage for comparative phyloinformatics are presented. In particular, we focus on how this task can be effectively performed in a distributed computing environment. As a proof of concept, the designed workflows are used for the phylogenetic analysis of neuraminidase of H5N1 isolates (micro level) and influenza viruses (macro level). The results of this paper are hence twofold. Firstly, this paper demonstrates the usefulness of a graphical user interface system to design and execute complex distributed workflows for large-scale phyloinformatics studies of virus genes. Secondly, the analysis of neuraminidase on different levels of complexity provides valuable insights of this virus's tendency for geographical based clustering in the phylogenetic tree and also shows the importance of glycan sites in its molecular evolution.

Conclusion

The current study demonstrates the efficiency and utility of workflow systems providing a biologist friendly approach to complex biological dataset analysis using high performance computing. In particular, the utility of the platform Quascade for deploying distributed and parallelized versions of a variety of computationally intensive phylogenetic algorithms has been shown. Secondly, the analysis of the utilized H5N1 neuraminidase datasets at macro and micro levels has clearly indicated a pattern of spatial clustering of the H5N1 viral isolates based on geographical distribution rather than temporal or host range based clustering.
GORouter: an RDF model for providing semantic query and inference services for Gene Ontology and its associations
Authors: Xu Qingwei , Shi Yixiang , Lu Qiang , Zhang Guoqing , Luo Qingming , Li Yixue
Published: February 2008

Background

The most renowned biological ontology, Gene Ontology (GO) is widely used for annotations of genes and gene products of different organisms. However, there are shortcomings in the Resource Description Framework (RDF) data file provided by the GO consortium: 1) Lack of sufficient semantic relationships between pairs of terms coming from the three independent GO sub-ontologies, that limit the power to provide complex semantic queries and inference services based on it. 2) The term-centric view of GO annotation data and the fact that all information is stored in a single file. This makes attempts to retrieve GO annotations based on big volume datasets unmanageable. 3) No support of GOSlim.

Results

We propose a RDF model, GORouter, which encodes heterogeneous original data in a uniform RDF format, creates additional ontology mappings between GO terms, and introduces a set of inference rulebases. Furthermore, we use the Oracle Network Data Model (NDM) as the native RDF data repository and the table function RDF_MATCH to seamlessly combine the result of RDF queries with traditional relational data. As a result, the scale of GORouter is minimized; information not directly involved in semantic inference is put into relational tables.

Conclusion

Our work demonstrates how to use multiple semantic web tools and techniques to provide a mixture of semantic query and inference solutions of GO and its associations. GORouter is licensed under Apache License Version 2.0, and is accessible via the website: http://www.scbit.org/gorouter/.
Effects of GSK3 inhibitors on in vitro expansion and differentiation of human adipose-derived stem cells into adipocytes
Authors: Zaragosi Laure-Emmanuelle , Wdziekonski Brigitte , Fontaine Coralie , Villageois Phi , Peraldi Pascal , Dani Christian
Published: February 2008

Background

Multipotent stem cells exist within adipose tissue throughout life. An abnormal recruitment of these adipose precursor cells could participate to hyperplasia of adipose tissue observed in severe obesity or to hypoplasia of adipose tissue observed in lipodystrophy. Therefore, pharmacological molecules that control the pool of stem cells in adipose tissue are of great interest. Glycogen Synthase Kinase (GSK) 3 has been previously described as involved in differentiation of preadipose cells and might be a potential therapeutic target to modulate proliferation and differentiation of adipocyte precursors. However, the impact of GSK3 inhibition on human adipose-derived stem cells remained to be investigated. The aim of this study was to investigate GSK3 as a possible target for pharmacological inhibition of stem cell adipogenesis. To reach this goal, we studied the effects of pharmacological inhibitors of GSK3, i.e. lithium chloride (LiCl) and BIO on proliferation and adipocyte differentiation of multipotent stem cells derived from human adipose tissue.

Results

Our results showed that GSK3 inhibitors inhibited proliferation and clonogenicity of human stem cells, strongly suggesting that GSK3 inhibitors could be potent regulators of the pool of adipocyte precursors in adipose tissue. The impact of GSK3 inhibition on differentiation of hMADS cells was also investigated. Adipogenic and osteogenic differentiations were inhibited upon hMADS treatment with BIO. Whereas a chronic treatment was required to inhibit osteogenesis, a treatment that was strictly restricted to the early step of differentiation was sufficient to inhibit adipogenesis.

Conclusion

These results demonstrated the feasibility of a pharmacological approach to regulate adipose-derived stem cell function and that GSK3 could represent a potential target for controlling adipocyte precursor pool under conditions where fat tissue formation is impaired.
The nuclear OXPHOS genes in insecta: a common evolutionary origin, a common cis-regulatory motif, a common destiny for gene duplicates
Authors: Porcelli Damiano , Barsanti Paolo , Pesole Graziano , Caggese Corrado
Published: February 2008

Background

When orthologous sequences from species distributed throughout an optimal range of divergence times are available, comparative genomics is a powerful tool to address problems such as the identification of the forces that shape gene structure during evolution, although the functional constraints involved may vary in different genes and lineages.

Results

We identified and annotated in the MitoComp2 dataset the orthologs of 68 nuclear genes controlling oxidative phosphorylation in 11 Drosophilidae species and in five non-Drosophilidae insects, and compared them with each other and with their counterparts in three vertebrates (Fugu rubripes, Danio rerio and Homo sapiens) and in the cnidarian Nematostella vectensis, taking into account conservation of gene structure and regulatory motifs, and preservation of gene paralogs in the genome. Comparative analysis indicates that the ancestral insect OXPHOS genes were intron rich and that extensive intron loss and lineage-specific intron gain occurred during evolution. Comparison with vertebrates and cnidarians also shows that many OXPHOS gene introns predate the cnidarian/Bilateria evolutionary split. The nuclear respiratory gene element (NRG) has played a key role in the evolution of the insect OXPHOS genes; it is constantly conserved in the OXPHOS orthologs of all the insect species examined, while their duplicates either completely lack the element or possess only relics of the motif.

Conclusion

Our observations reinforce the notion that the common ancestor of most animal phyla had intron-rich gene, and suggest that changes in the pattern of expression of the gene facilitate the fixation of duplications in the genome and the development of novel genetic functions.
Mitochondrial DNA structure in the Arabian Peninsula
Authors: Abu-Amero Khaled K , Larruga José M , Cabrera Vicente M , González Ana M
Published: February 2008

Background

Two potential migratory routes followed by modern humans to colonize Eurasia from Africa have been proposed. These are the two natural passageways that connect both continents: the northern route through the Sinai Peninsula and the southern route across the Bab al Mandab strait. Recent archaeological and genetic evidence have favored a unique southern coastal route. Under this scenario, the study of the population genetic structure of the Arabian Peninsula, the first step out of Africa, to search for primary genetic links between Africa and Eurasia, is crucial. The haploid and maternally inherited mitochondrial DNA (mtDNA) molecule has been the most used genetic marker to identify and to relate lineages with clear geographic origins, as the African Ls and the Eurasian M and N that have a common root with the Africans L3.

Results

To assess the role of the Arabian Peninsula in the southern route, we genetically analyzed 553 Saudi Arabs using partial (546) and complete mtDNA (7) sequencing, and compared the lineages obtained with those present in Africa, the Near East, central, east and southeast Asia and Australasia. The results showed that the Arabian Peninsula has received substantial gene flow from Africa (20%), detected by the presence of L, M1 and U6 lineages; that an 18% of the Arabian Peninsula lineages have a clear eastern provenance, mainly represented by U lineages; but also by Indian M lineages and rare M links with Central Asia, Indonesia and even Australia. However, the bulk (62%) of the Arabian lineages has a Northern source.

Conclusion

Although there is evidence of Neolithic and more recent expansions in the Arabian Peninsula, mainly detected by (preHV)1 and J1b lineages, the lack of primitive autochthonous M and N sequences, suggests that this area has been more a receptor of human migrations, including historic ones, from Africa, India, Indonesia and even Australia, than a demographic expansion center along the proposed southern coastal route.
Identification of a contemporary human parechovirus type 1 by VIDISCA and characterisation of its full genome
Authors: de Souza Luna Luciano Kleber , Baumgarte Sigrid , Grywna Klaus , Panning Marcus , Drexler Jan Felix , Drosten Christian
Published: February 2008

Background

Enteritis is caused by a spectrum of viruses that is most likely not fully characterised. When testing stool samples by cell culture, virus isolates are sometimes obtained which cannot be typed by current methods. In this study we used VIDISCA, a virus identification method which has not yet been widely applied, on such an untyped virus isolate.

Results

We found a human parechovirus (HPeV) type 1 (strain designation: BNI-788st). Because genomes of contemporary HPeV1 were not available, we determined its complete genome sequence. We found that the novel strain was likely the result of recombination between structural protein genes of an ancestor of contemporary HPeV1 strains and nonstructural protein genes from an unknown ancestor, most closely related to HPeV3. In contrast to the non-structural protein genes of other HPeV prototype strains, the non-structural protein genes of BNI-788st and HPeV3 prototype strains did not co-segregate in bootscan analysis with that of other prototype strains.

Conclusion

HPeV3 nonstructural protein genes may form a distinct element in a pool of circulating HPeV non-structural protein genes. More research into the complex HPeV evolution is required to connect virus ecology with disease patterns in humans.
Gene expression analyses in breast cancer epidemiology: the Norwegian Women and Cancer postgenome cohort study
Authors: Dumeaux Vanessa , Børresen-Dale Anne-Lise , Frantzen Jan-Ole , Kumle Merethe , Kristensen Vessela N , Lund Eiliv
Published: February 2008

Introduction

The introduction of high-throughput technologies, also called -omics technologies, into epidemiology has raised the need for high-quality observational studies to reduce several sources of error and bias.

Methods

The Norwegian Women and Cancer (NOWAC) postgenome cohort study consists of approximately 50,000 women born between 1943 and 1957 who gave blood samples between 2003 and 2006 and filled out a two-page questionnaire. Blood was collected in such a way that RNA is preserved and can be used for gene expression analyses. The women are part of the NOWAC study consisting of 172,471 women 30 to 70 years of age at recruitment from 1991 to 2006 who answered one to three questionnaires on diet, medication use, and lifestyle. In collaboration with the Norwegian Breast Cancer Group, every NOWAC participant born between 1943 and 1957 who is admitted to a collaborating hospital for a diagnostic biopsy or for surgery of breast cancer will be asked to donate a tumor biopsy and two blood samples. In parallel, at least three controls are approached for each breast cancer case in order to obtain blood samples from at least two controls per case. The controls are drawn at random from NOWAC matched by time of follow-up and age. In addition, 400 normal breast tissues as well as blood samples will be collected among healthy women participating at the Norwegian Mammography Screening program at the Breast Imaging Center at the University Hospital of North-Norway, Tromsø.

Results

The NOWAC postgenome cohort offers a unique opportunity (a) to study blood-derived gene expression profiles as a diagnostic test for breast cancer in a nested case-control design with adjustment for confounding factors related to different exposures, (b) to improve the reliability and accuracy of this approach by adjusting for an individual's genotype (for example, variants in genes coding for hormone and drug-metabolizing and detoxifying enzymes), (c) to study gene expression profiles from peripheral blood as surrogate tissue to biomonitor defined exposure (for example, hormone) and its association with disease risk (that is, breast cancer), and (d) to study gene variants (single nucleotide polymorphisms and copy number variations) and environmental exposure (endogenous and exogenous hormones) and their influence on the incidence of different molecular subtypes of breast cancer.

Conclusion

The NOWAC postgenome cohort combining a valid epidemiological approach with richness of biological samples should make an important contribution to the study of the etiology and system biology of breast cancer.
Craniotabes in Normal Newborns: The Earliest Sign of Subclinical Vitamin D Deficiency
Authors: Yorifuji Junko , Yorifuji Tohru , Tachibana Kenji , Nagai Shizuyo , Kawai Masahiko , Momoi Toru , Nagasaka Hironori , Hatayama Hiroshi , Nakahata Tatsutoshi
Published: February 2008

Context: Craniotabes in otherwise normal neonates has been regarded as physiological and left untreated.

Objective: Our objective was to investigate the role of vitamin D deficiency in the development of craniotabes in normal neonates.

Design and Setting: Newborn screening of craniotabes was conducted at the single largest obstetrical facility in Kyoto, Japan. Follow-up study at 1 month was conducted at Kyoto University Hospital.

Subjects: A total of 1120 consecutive normal Japanese neonates born in May, 2006, through April, 2007, were included in the study.

Main Outcome Measures: The incidence of craniotabes was scored each month. Neonates with craniotabes were followed up at 1 month with measurements of serum calcium, phosphorus, alkaline phosphatase (ALP), intact PTH, 25-OH vitamin D (25-OHD), urinary calcium, phosphorus, creatinine, and hand x-rays.

Results: Craniotabes was present in 246 (22.0%) neonates, and the incidence had obvious seasonal variations, highest in April-May and lowest in November. At 1 month, infants with craniotabes had significantly higher serum ALP compared with normal neonates; 6.9% of them had elevated intact PTH over 60 pg/ml, and 37.3% had 25-OHD less than 10 ng/ml. When separately analyzed according to the method of feeding, 56.9% of breast-fed infants showed 25-OHD less than 10 ng/ml, whereas none of formula/mixed-fed infants did, and breast-fed infants had significantly higher serum PTH and ALP compared with formula/mixed-fed infants.

Summary: These results suggest that craniotabes in normal neonates is associated with vitamin D deficiency in utero, and the deficiency persists at 1 month in many of them, especially when breast-fed.
Use of a toxicity factor to explain differences in nephrotoxicity and myelosuppression among the platinum antitumour derivatives cisplatin, carboplatin and nedaplatin in rats
Authors: Hanada Kazuhiko , Asano Kunihito , Nishimura Takako , Chimata Tomomi , Matsuo Yusuke , Tsuchiya Maki , Ogata Hiroyasu
Published: February 2008

The platinum antitumour drugs cisplatin, carboplatin and nedaplatin differ in their toxicity. The relationships between the pharmacokinetics of these drugs and developed parameters for predicting their nephrotoxicity and myelosuppression were investigated. The drugs were administered to male Wistar rats by intravenous bolus or infusion, and linearity of pharmacokinetics, total clearance and the apparent ratio of tissue concentrations of unchanged drug to plasma concentration (Kpapp) at steady state were determined. Apparent hydrolysis rates of each drug were determined in-vitro. Nephrotoxicity and myelosuppression were estimated by blood urea nitrogen (BUN) and platelet count, respectively. Tissue exposure to platinum was estimated as the product of the area under the plasma concentration-time curve for unchanged drug (AUCp), Kpapp and the apparent hydrolysis rate constant (khydrolysis), and toxicity factor was defined as the product of Kpapp × khydrolysis as an intrinsic drug parameter. The relationship between AUCp × toxicity factor and BUN fitted well to an Emax model. In bone marrow, this function was also correlated with platelet count. In summary, the product of AUCp × toxicity factor is a factor determining the pharmacokinetics of platinum drug-induced nephrotoxicity and myelosuppression in rats, and this toxicity factor may be a useful parameter for predicting the degree of toxicity of platinum antitumour compounds.
Antidiabetic activity of Croton klozchianus in rats and direct stimulation of insulin secretion in-vitro
Authors: Govindarajan R , Vijayakumar M , Rao Ch V , Pushpangadan P , Asare-Anane Henry , Persaud Shanta , Jones Peter , Houghton Peter J
Published: February 2008

Croton klozchianus is a relatively uninvestigated species with no pharmacological or phytochemical reports available, although it has been used clinically by Ayurvedic physicians to treat diabetes. We have investigated this use by studying the insulin secretion and antidiabetic activity of C. klozchianus. Treatment of diabetic rats with aerial parts of C. klozchianus extract (CK, 100 and 300 mg kg−1 body weight) for three weeks showed significant reduction in blood glucose (45.8% after 14 days for 300 mg kg−1). C. klozchianus extract caused a significant concentration-dependent increase in insulin secretion (8-fold at 2 mg mL−1 for cells challenged with 20 mm glucose) from MIN6 cells grown as monolayers and as pseudoislets, indicating that the antidiabetic activity may have been as a result of increased insulin secretion. It also had a role on the lipid profile of the rats by causing reduction in cholesterol and triglycerides and increasing high density lipoprotein significantly. The results obtained gave some scientific support to the traditional use of the plant as a treatment for diabetes.
Gastroprotective effect of a flavone from Lonchocarpus araripensis Benth. (Leguminosae) and the possible mechanism
Authors: Campos Deive A , de Lima Almi F , Ribeiro Saulo Rodrigo L , Silveira Edilberto R , Pessoa Otilia Deusdênia L , Rao Vietla S , Santos Flávia A
Published: February 2008

The gastroprotective effect of DDF (3,6-dimethoxy-6“, 6”-dimethyl-[2“, 3”: 7,8]-chromeneflavone) from Lonchocarpus araripensis Benth. (Leguminosae) on gastric damage induced by absolute ethanol (96%, 0.2 mL/mouse) and indometacin (30 mg kg−1, p.o.) in mice was investigated. Intraperitoneally administered DDF at dose levels of 50, 100 and 200 mg kg−1 markedly reduced the gastric lesions in the ethanol model by 62, 72 and 96%, and in the indometacin model by 34, 70 and 75%, respectively, as compared with misoprostol (50 μg kg−1, p.o.), the reference compound that caused lesion suppression by 67% in ethanol model and by 72% against indometacin-induced ulceration. The ED50 of DDF in reducing gastric lesions induced by ethanol and indometacin (dose of the DDF that reduced the gastric lesion area by 50% in relation to the control value) was 50.87 and 61.56 mg kg−1, respectively. Mechanistic studies were carried out at 100 mg kg−1 DDF using the ethanol model. Compared with N-acetylcysteine (750 mg kg−1, p.o.), a donor of sulfhydryls, DDF only partially replenished the ethanol-induced depletion of gastric mucosal NP-SH. Pretreatment with TRPV1 antagonist capsazepine (5 mg kg−1, i.p.) or the non-selective cyclooxygenase inhibitor indometacin (10 mg kg−1, p.o.) effectively blocked the gastroprotective effect of DDF (100 mg kg−1) against ethanol damage. Furthermore, the effect of DDF was significantly reduced in mice pretreated with L-NAME, or glibenclamide, the respective inhibitors of nitric oxide synthase and K+ATP channel activation. These data provide evidence to show that DDF affords gastroprotection against gastric damage induced by ethanol and indometacin by different and complementary mechanisms, which include involvement of endogenous prostaglandins, nitric oxide release, the activation of TRPV1 receptor or K+ATP channels, besides a sparing effect on NP-SH reserve.
The Fiction of Marcel Proust's Autobiography
Authors: Balsamo Gian
Published: February 2008

This essay discusses the literary genre of Proust's In Search of Lost Time as analogous with the genre peculiar to Dante's Commedia and Augustine's Confessions. Both Dante and Augustine narrate their autobiography in terms of a writerly vocation pursued by means of a love quest; both authors' success in the affirmation of their respective identity depends on the success of the love quest. Dante's case is especially relevant to this essay insofar as his poem instantiates his authorial identity as coincident with that of his fictional character. Augustine's confessions, however driven by a love quest, belong to the more conventionally autobiographic genre of the personal memoir. The fiction of the Commedia is that the biography of its fictional protagonist is the author's autobiography. The same principle, which challenges the narratological distinction among real author, implied author, and narrator, may be applied to Proust's novel. Marcel, the protagonist, crowns his literary vocation only at the end of a protracted love quest. His success in the love quest coincides with the end of the novel, and it is at this point that the distinction between fictional character and historical author loses its force. After Erich Auerbach on the Commedia, one can argue that Marcel and Marcel Proust come to coincide at the point of intersection of allegory and history; the fictional character is the allegory of the author's historical authenticity. Toward the end, Marcel-the-character, finally equipped with the means and determination to write the novel we have just read, metamorphoses into Proust-the-author: he is Proust's deliberate choice for his own autobiography.
The Impossibly Many Loves of Charles Swann: The Myth of Proustian Love and the Reader's “Impression” inUn amour de Swann
Authors: Picherit Hervé G.
Published: February 2008

Much in Marcel Proust's Un amour de Swann—notably its position in the Recherche and the title itself—suggests that we might derive from the tale of Swann's love for Odette a general “law” about love, applicable throughout the Recherche. Yet far from conveying a clear account of Swann's passion, the story presents nine different falling-in-love scenes, which, it seems, contradict the prevailing view that Swann's tale is a relatively “easy” section of Proust's novel. Indeed, I argue here that the illusive transparency of Un amour de Swann is at the heart of a textual mechanism that elicits from us spontaneous and lasting reactions to the text. Proust in fact withholds a clear characterization of love and, instead, imparts to our subjective impressions about this emotion an illusion of objectivity. When the reader applies what he or she has “discovered” about love in Un amour de Swann to the rest of the Recherche, then, the reader unknowingly becomes inscribed into the novel, making it a reflection of the deepest, most essential parts of his or her being.
The R-Ras interaction partner ORP3 regulates cell adhesion
Authors: Lehto Markku , Mäyränpää Mikko I. , Pellinen Teijo , Ihalmo Pekka , Lehtonen Sanna , Kovanen Petri T. , Groop Per-Henrik , Ivaska Johanna , Olkkonen Vesa M.
Published: February 2008

Oxysterol-binding protein (OSBP)-related protein 3 (ORP3) is highly expressed in epithelial, neuronal and hematopoietic cells, as well as in certain forms of cancer. We assessed the function of ORP3 in HEK293 cells and in human macrophages. We show that ORP3 interacts with R-Ras, a small GTPase regulating cell adhesion, spreading and migration. Gene silencing of ORP3 in HEK293 cells results in altered organization of the actin cytoskeleton, impaired cell-cell adhesion, enhanced cell spreading and an increase of β1 integrin activity–effects similar to those of constitutively active R-Ras(38V). Overexpression of ORP3 leads to formation of polarized cell-surface protrusions, impaired cell spreading and decreased β1 integrin activity. In primary macrophages, overexpression of ORP3 leads to the disappearance of podosomal structures and decreased phagocytotic uptake of latex beads, consistent with a role in actin regulation. ORP3 is phosphorylated when cells lose adhesive contacts, suggesting that it is subject to regulation by outside-in signals mediated by adhesion receptors. The present findings demonstrate a new function of ORP3 as part of the machinery that controls the actin cytoskeleton, cell polarity and cell adhesion.
The tumour-associated antigen L6 (L6-Ag) is recruited to the tetraspanin-enriched microdomains: implication for tumour cell motility
Authors: Lekishvili Tamara , Fromm Elisa , Mujoomdar Michelle , Berditchevski Fedor
Published: February 2008

Tumour-associated antigen L6 (L6-Ag, also known as TM4SF1) regulates tumour cell motility and invasiveness. We found that L6-Ag is abundant on the plasma membrane and on intracellular vesicles, on which it is co-localised with the markers for late endosomal/lysosomal compartments, including Lamp1/Lamp2 proteins and LBPA. Antibody internalisation and live-imaging experiments suggested that L6-Ag is targeted to late endocytic organelles (LEO) predominantly via a biosynthetic pathway. Mapping experiments showed that the presence of transmembrane regions is sufficient for directing L6-Ag to LEO. On the plasma membrane, L6-Ag is associated with tetraspanin-enriched microdomains (TERM). All three predicted cytoplasmic regions of L6-Ag are crucial for the effective recruitment of the protein to TERM. Recruitment to TERM correlated with the pro-migratory activity of L6-Ag. Depletion of L6-Ag with siRNA has a selective effect on the surface expression of tetraspanins CD63 and CD82. By contrast, the expression levels of other tetraspanins and β1 integrins was not affected. We found that L6-Ag is ubiquitylated and that ubiquitylation is essential for its function in cell migration. These data suggest that L6-Ag influences cell motility via TERM by regulating the surface presentation and endocytosis of some of their components.
Nuclear organisation in totipotent human nuclei and its relationship to chromosomal abnormality
Authors: Finch Katie A. , Fonseka Gothami , Ioannou Dimitris , Hickson Nicholas , Barclay Zoe , Chatzimeletiou Katerina , Mantzouratou Anna , Handyside Alan , Delhanty Joy , Griffin Darren K.
Published: February 2008

Studies of nuclear organisation, most commonly determining the nuclear location of chromosome territories and individual loci, have furthered our understanding of nuclear function, differentiation and disease. In this study, by examining eight loci on different chromosomes, we tested hypotheses that: (1) totipotent human blastomeres adopt a nuclear organisation akin to that of committed cells; (2) nuclear organisation is different in chromosomally abnormal blastomeres; and (3) human blastomeres adopt a `chromocentre' pattern. Analysis of in vitro fertilisation (IVF) conceptuses permits valuable insight into the cell biology of totipotent human nuclei. Here, extrapolations from images of preimplantation genetic screening (PGS) cases were used to make comparisons between totipotent blastomeres and several committed cells, showing some differences and similarities. Comparisons between chromosomally abnormal nuclei and those with no detected abnormality (NDA) suggest that the former display a significant non-random pattern for all autosomal loci, but there is a less distinct, possibly random, pattern in `NDA' nuclei. No evidence was found that the presence of an extra chromosome is accompanied by an altered nuclear location for that chromosome. Centromeric loci on chromosomes 15 and 16 normally seen at the nuclear periphery were mostly centrally located in aneuploid cells, providing some evidence of a `chromocentre'; however, the chromosome-18 centromere was more peripheral, similar to committed cells. Our results provide clues to the nature of totipotency in human cells and might have future applications for preimplantation diagnosis and nuclear transfer.
Numbers of Achiral and Chiral Monosubstituted Alkanes Having a Given Carbon Content and Given Numbers of Asymmetric and Pseudoasymmetric Centers
Authors: Fujita Shinsaku
Published: February 2008

Monosubstituted alkanes as stereoisomers have been counted combinatorially by regarding them as nested planted promolecules, where the resulting numbers have been itemized with respect to carbon content (k), to the number of asymmetric carbons (l), as well as to the number of pseudoasymmetric carbons (m). To accomplish such itemization, the definitions of RS-stereogenic centers, asymmetric centers, and pseudoasymmetric centers have been discussed in detail. Each itemized number has been obtained as the coefficient of the term xkylzm appearing in a respective generating function, which has been derived by following Fujita’s proligand method (S. Fujita, Theor. Chem. Acc.2005, 113, 73; 2005, 113, 80; S. Fujita, Theor. Chem. Acc.2006, 115, 37). The itemized values up to carbon content 30 have been listed in tabular forms, which are distinctively concerned with achiral stereoisomers, chiral stereoisomers, and constitutional isomers (graphs).
Rhodium-catalyzed Addition of Organo[2-(hydroxymethyl)phenyl]dimethylsilanes to Arenesulfonylimines
Authors: Nakao Yoshiaki , Takeda Masahide , Chen Jinshui , Hiyama Tamejiro , Ichikawa Yoshitaka , Shintani Ryo , Hayashi Tamio
Published: February 2008

The title reaction is found to proceed in the presence of a rhodium/diene catalyst. Variously substituted diarylmethylamines and allylamines having an N-arenesulfonyl protection are obtained in good yields, which are important building blocks in organic synthesis.