bluuebunny/crossref_metadata_2025 huggingface dataset:
Retinoic acid receptor α dominant negative form causes steatohepatitis and liver tumors in transgenic mice
Authors: Yanagitani Atsushi , Yamada Sadako , Yasui Sakiko , Shimomura Takashi , Murai Rie , Murawaki Yoshiyuki , Hashiguchi Koichi , Kanbe Takamasa , Saeki Toshiya , Ichiba Miho , Tanabe Yoshitada , Yoshida Yoko , Morino Shin-ichi , Kurimasa Akihiro , Usuda Nobumitsu , Yamazaki Hidetoshi , Kunisada Takahiro , Ito Hisao , Murawaki Yoshikazu , Shiota Goshi
Published: August 2004

Although attention has focused on the chemopreventive action of retinoic acid (RA) in hepatocarcinogenesis, the functional role of RA in the liver has yet to be clarified. To explore the role of RA in the liver, we developed transgenic mice expressing RA receptor (RAR) α- dominant negative form in hepatocytes using albumin promoter and enhancer. At 4 months of age, the RAR α- dominant negative form transgenic mice developed microvesicular steatosis and spotty focal necrosis. Mitochondrial β-oxidation activity of fatty acids and expression of its related enzymes, including VLCAD, LCAD, and HCD, were down-regulated; on the other hand, peroxisomal β-oxidation and its related enzymes, including AOX and BFE, were up-regulated. Expression of cytochrome p4504a10, cytochrome p4504a12, and cytochrome p4504a14 was increased, suggesting that ω-oxidation of fatty acids in microsomes was accelerated. In addition, formation of H2O2 and 8-hydroxy-2′-deoxyguanosine was increased. After 12 months of age, these mice developed hepatocellular carcinoma and adenoma of the liver. The incidence of tumor formation increased with age. Expression of β-catenin and cyclin D1 was enhanced and the TCF-4/β-catenin complex was increased, whereas the RAR α/ β-catenin complex was decreased. Feeding on a high-RA diet reversed histological and biochemical abnormalities and inhibited the occurrence of liver tumors. These results suggest that hepatic loss of RA function leads to the development of steatohepatitis and liver tumors. In conclusion, RA plays an important role in preventing hepatocarcinogenesis in association with fatty acid metabolism and Wnt signaling. (Hepatology 2004;40:366-375.)
Effects of MgO‐CaO‐P2O5‐Na2O‐based additives on mechanical and biological properties of hydroxyapatite
Authors: Kalita S. J. , Rokusek D. , Bose S. , Hosick H. L. , Bandyopadhyay A.
Published: August 2004

In this research, we improved densification, hardness, and compression strength of synthetic hydroxyapatite (HAp) ceramics by introducing small quantities of MgO‐CaO‐P2O5‐Na2O‐based sintering additives. Biological properties of HAp were not altered by this procedure. Phase analyses were performed by using a Philips Xpert fully automated diffractometer with Co K‐alpha radiation to understand the influence of additives on phase purity in the final products. All compositions were characterized at green and sintered densities to understand the influence of additives on densification. Some of the compositions showed >40% increase in Vickers microhardness compared with pure HAp processed under the same conditions. Improvement in compression strength was also detected in some compositions. In vitro biological testing used a modified human osteoblast cell line to test biocompatibility, cell attachment, and cell proliferation. All these compositions were nontoxic and biocompatible. Our results indicate that MgO‐CaO‐P2O5‐Na2O‐based sintering additives can be used to improve both mechanical and biological properties of HAp ceramics. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 71A: 35–44, 2004
Poly(lactic‐co‐glycolic acid) enhances maturation of human monocyte‐derived dendritic cells
Authors: Yoshida Mutsumi , Babensee Julia E.
Published: August 2004

Immature dendritic cells (iDCs) were derived from human peripheral blood monocytes, and treated with 75:25 poly(lactic‐co‐glycolic acid) (PLGA) microparticles (MPs) or film to assess the resultant dendritic cell (DC) maturation as compared to positive control of lipopolysaccharide (LPS) treatment for DC maturation or negative control of untreated iDCs. The effect of PLGA contact on DC maturation was examined as one possible explanation for the PLGA adjuvant effect we have observed in the enhancement of an immune response to codelivered model antigen, as adjuvants act through the maturation of DCs. Culturing iDCs with PLGA MPs or PLGA film resulted in morphology similar to that of LPS‐matured DCs and the association, or possible internalization, of PLGA MPs. Furthermore, biomaterial‐treated iDCs demonstrated an increase in MHC class II and costimulatory molecule expression compared to iDCs but to a lower level than that of LPS‐matured DCs. Direct iDC contact with PLGA MPs was necessary for maturation. Immature DCs exposed to PLGA MPs were stimulatory of allogeneic T‐cell proliferation, whereas cells exposed to PLGA film were not. Further, PLGA MPs supported a moderate delayed type hypersensitivity reaction in mice indicative of in vivo DC maturation. Taken together, these results suggest that PLGA is a DC maturation stimulus and that the form of the biomaterial may influence the extent of DC maturation. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 71A: 45–54, 2004
Osteoblasts respond to hydroxyapatite surfaces with immediate changes in gene expression
Authors: Xie Jianwei , Baumann Melissa J. , McCabe Laura R.
Published: August 2004

Bone mineral contains hydroxyapatite (HA). This is the surface that mature osteoblasts and osteocytes interact with. Synthetic HA is widely used in orthopedic surgeries as an implant or implant coating. The bone‐like HA surfaces increase implant union and bone formation; however, the mechanisms accounting for this effect on osteoblasts are not known. In this study, we compared gene expression profiles of osteoblasts responding to HA or plastic surfaces for 24 h. Expression profiles were also compared between HA discs processed with gravity‐sieved compared with combined gravity and air‐jet‐sieved HA powders. The latter, composed of smaller HA particles, exhibits an increase in grain boundary surface area. Discs made with either HA powder similarly up‐regulated osteoblast expression of 10 genes (including proliferin 3, Glvr‐1, DMP‐1, and tenascin C) and down‐regulated 15 genes (such as osteoglycin) by more than 2‐fold compared with plastic surfaces. The overall changes are indicative of an immediate (24‐h) response to the HA surface and a trend toward osteoblast differentiation. In addition, subsets of modulated genes exist that are unique to each HA subtype. Taken together, we identified HA responsive genes evident within 24 h of surface contact, indicating a critical role for extracellular mineral surfaces in the regulation of osteoblast gene expression and phenotype. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 71A: 108–117, 2004
Topiramate therapy for paroxysmal kinesigenic choreoathetosis
Authors: Huang Yuan‐Gui , Chen Yun‐Chun , Du Fang , Li Rui , Xu Ge‐Lin , Jiang Wen , Huang Jing
Published: August 2004

We observed the clinical efficacy of topiramate for paroxysmal kinesigenic choreoathetosis (PKC). Topiramate was administered as a monotherapy with titrated dosages to 8 patients with PKC. Target daily dose of topiramate was 100 to 200 mg; the follow‐up period ranged from 8 months to 2 years. All of the patients became attack‐free, and side effects were mild. The results show that topiramate is effective as a monotherapy for treating patients with PKC. The response to topiramate indicates that the disease may be caused by an ion channel defect. © 2004 Movement Disorder Society
Staging disease severity in movement disorder tauopathies: Brain atrophy separates progressive supranuclear palsy from corticobasal degeneration
Authors: Schofield Emma C. , Caine Diana , Kril Jillian J. , Cordato Nicholas J. , Halliday Glenda M.
Published: August 2004

The movement disorders progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) both deposit tau in degenerating neurons and are considered to be tauopathies. The recently developed scheme for staging tissue degeneration in another tauopathy, frontotemporal dementia [Broe et al., Neurology 2003;60:1005–1011] was applied to pathologically confirmed PSP (n = 24) and CBD (n = 9) cases and correlated with clinical indices. In contrast to frontotemporal dementia, the majority of PSP cases had limited or no visible atrophy, while the pattern of atrophy in CBD cases conformed to the existing staging scheme (all but one case exhibiting substantial visible tissue atrophy). Despite similar clinical severity and disease duration between groups, there was a marked difference between the PSP and CBD cases in pathological disease stage (χ2 = 8.86; P = 0.03). The degree of global atrophy in PSP appears to be distinct from other tauopathies, while CBD fits the same pattern as other pathological forms of frontotemporal dementia. © 2004 Movement Disorder Society
Approximation algorithms for finding low‐degree subgraphs
Authors: Klein Philip N. , Krishnan Radha , Raghavachari Balaji , Ravi R.
Published: August 2004

We give quasipolynomial‐time approximation algorithms for designing networks with a minimum degree. Using our methods, one can design networks whose connectivity is specified by “proper” functions, a class of 0–1 functions indicating the number of edges crossing each cut. We also provide quasipolynomial‐time approximation algorithms for finding two‐edge‐connected spanning subgraphs of approximately minimum degree of a given two‐edge‐connected graph, and a spanning tree (branching) of approximately minimum degree of a directed graph. The degree of the output network in all cases is guaranteed to be at most (1 + ϵ) times the optimal degree, plus an additive O(log1+ϵn) for any ϵ > 0. Our analysis indicates that the degree of an optimal subgraph for each of the problems above is well estimated by certain polynomially solvable linear programs. This suggests that the linear programs we describe could be useful in obtaining optimal solutions via branch and bound. © 2004 Wiley Periodicals, Inc. NETWORKS, Vol. 44(3), 203–215 2004
An exact algorithm for the elementary shortest path problem with resource constraints: Application to some vehicle routing problems
Authors: Feillet Dominique , Dejax Pierre , Gendreau Michel , Gueguen Cyrille
Published: August 2004

In this article, we propose a solution procedure for the Elementary Shortest Path Problem with Resource Constraints (ESPPRC). A relaxed version of this problem in which the path does not have to be elementary has been the backbone of a number of solution procedures based on column generation for several important problems, such as vehicle routing and crew pairing. In many cases relaxing the restriction of an elementary path resulted in optimal solutions in a reasonable computation time. However, for a number of other problems, the elementary path restriction has too much impact on the solution to be relaxed or might even be necessary. We propose an exact solution procedure for the ESPPRC, which extends the classical label correcting algorithm originally developed for the relaxed (nonelementary) path version of this problem. We present computational experiments of this algorithm for our specific problem and embedded in a column generation scheme for the classical Vehicle Routing Problem with Time Windows. © 2004 Wiley Periodicals, Inc. NETWORKS, Vol. 44(3), 216–229 2004
Viscosity, particle size distribution, and structural investigation of tetramethyloxysilane/2‐hydroxyethyl methacrylate sols during the sol–gel process with acid and base catalysts
Authors: Huang Shu‐Ling , Chin Wei‐Kuo , Yang W. P.
Published: August 2004

The tetramethoxysilane (TMOS)/2‐hydroxylethyl methacrylate (HEMA) hybrid gels were synthesized with acid and base catalysts, via the in situ polymerization of HEMA, with and without the cosolvent methanol. With methanol in the TMOS/HEMA sol, the enhanced esterification and depolymerization reactions of the silanols resulted in a slower growth of silica particles. The silica particles that were synthesized with an acid catalyst were less than 40 nm. The thermal resistance of the poly(2‐hydroxyethyl methacrylate) (PHEMA) chains was enhanced by the addition of colloidal silica. The Fourier transform infrared characterizations and the exothermal peaks on the differential scanning calorimetry traces of these hybrid gels indicated chemical hybridization occurring as a result of condensation of the colloid silica and PHEMA at higher temperatures. Hence, the residual weight content of the hybrid gel after its synthesis with the base catalyst was even higher than the content of TMOS in the hybrid sol. © 2004 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 42: 3476–3486, 2004
Structure and properties of the mesophase of syndiotactic polystyrene. VIII. Solvent sorption behavior of syndiotactic polystyrene/p‐chlorotoluene mesophase membranes
Authors: Mahesh K. P. O. , Sivakumar M. , Yamamoto Y. , Tsujita Y. , Yoshimizu H. , Okamoto S.
Published: August 2004

A crystalline δ form of a syndiotactic polystyrene (sPS) membrane was prepared from a solution of sPS (1 wt %) and p‐chlorotoluene (p‐CT) by a solution‐casting method. The mesophase (δ empty form) of sPS was obtained by the extraction of the guest solvent from the δ form of sPS by a stepwise solvent‐extraction method. The sPS/p‐CT mesophase membrane [p‐CT (A‐M)] was used for the sorption of 1 mol % p‐CT for different times and for the sorption of different concentrations of p‐CT, chlorobenzene (CB), p‐xylene (p‐X), toluene, and chloroform for 48 h. The presence of solvents in the sPS membrane was confirmed by IR analysis. A thermal study revealed that the sorption amount of 1 mol % p‐CT increased with increasing immersion time, and the sorption amounts of different solvents increased with increasing solvent concentration. Differential scanning calorimetry results showed that the desorption peak temperature increased as the amount of the solvent increased in the clathrated sPS membrane. Wide‐angle X‐ray diffraction results showed that 2θ at 8.25° was slightly shifted toward 8°, and there was no change in the peak position at 10° for p‐CT (A‐M), which was immersed in different solvents (1 mol %); however, the intensity of 2θ at 10° was not similar for all the samples. Among the solvents used for the sorption studies at 1 mol %, p‐CT (A‐M) could sorb more p‐CT and CB than p‐X, toluene, and chloroform. The solvent sorption isotherm was the Langmuir sorption mechanism. © 2004 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 42: 3439–3446, 2004
Randomized controlled trial of a teacher‐led asthma education program
Authors: Henry Richard L. , Gibson Peter G. , Vimpani Graham V. , Francis J. Lynn , Hazell Juliana
Published: August 2004

Our objective was to determine whether an asthma education program in schools would have 1) a direct impact on student knowledge and attitudes to asthma and quality of life of the students with asthma, 2) an indirect impact on teacher knowledge and attitudes to asthma and on school policies about asthma, and 3) a sustainable program after the resources to implement the research were withdrawn. Seventeen intervention and 15 control schools participated in a controlled trial. Baseline knowledge and attitudes were measured in year 8 students (ages 13–14 years) and their teachers together with quality of life in the students with asthma. A three‐lesson package about asthma was delivered by teachers as part of the Personal Development/Health/Physical Education (PD/H/PE) curriculum. Follow‐up questionnaires were administered to students and staff. Efforts to change school policies were documented. Five years after the intervention, PD/H/PE teachers were contacted to determine whether the program was still operating. Main outcome measures included asthma knowledge, attitudes, and quality of life. Questionnaires were returned by 4,161/4,475 of the year 8 students at baseline and by 3,443 at follow‐up. In intervention schools, compared with control schools, students showed improved asthma knowledge (P < 0.0001), improvement in tolerance to asthma (P = 0.02), internal control (P = 0.03), and less tendency to believe in the role of chance in asthma control (P = 0.04). Students from intervention but not control schools showed significant improvements in overall quality of life (P = 0.003 vs.P = 0.82, respectively). Teachers from intervention schools showed significant increases in knowledge compared to control schools (P < 0.0001). Intervention schools were more likely to seek further health education about asthma (P < 0.01). Five years after the 35 schools involved in the development of the materials or the trial had been offered the Living With Asthma package, 25 (71%) were still teaching the program to most or all of their students. Fifty‐nine of the 61 (97%) high schools in the Hunter Region now have the program. Management and distribution of the Living With Asthma program have been taken over by the Asthma Foundation of New South Wales. The package has been updated and is being offered to all high schools throughout New South Wales as part of the National Asthma‐Friendly Schools Project. In conclusion, a teacher‐led asthma education program in secondary school had direct and indirect beneficial outcomes and was sustained at a high level for 5 years in most schools in the Hunter Region, despite minimal ongoing maintenance and support from health workers. © 2004 Wiley‐Liss, Inc.
Acute hypoxic respiratory failure as the first manifestation of systemic‐onset juvenile rheumatoid arthritis in a child
Authors: Rochat Isabelle , Sayegh Yasmine , Gervaix Alain , Rimensberger Peter C. , Argiroffo Constance Barazzone
Published: August 2004

Systemic onset juvenile rheumatoid arthritis is the most common rheumatologic disorder of childhood. Pleuropulmonary manifestations are rare in children in this multiorgan disease, and are usually not severe. The diagnosis of systemic onset juvenile rheumatoid arthritis is made by exclusion, in the presence of clinical findings constellation. We present the case of an 8‐year‐old girl who developed acute hypoxic respiratory failure as the first manifestation of systemic onset juvenile rheumatoid arthritis, then severe respiratory relapse 16 months later. Clinical and radiological improvement were achieved at both times after high dose pulse methylprednisolone therapy. © 2004 Wiley‐Liss, Inc.
Impact of adolescence and gender on asthma hospitalization: A population‐based birth cohort study
Authors: Debley Jason S. , Redding Gregory J. , Critchlow Cathy W.
Published: August 2004

Our objective was to determine the impact of gender and age on asthma hospitalization rates among children. We used a population‐based retrospective birth cohort study to determine yearly age‐ and gender‐specific asthma hospitalization rates between ages 2–18 years in a cohort of all children born in Washington State between 1980–1985. In addition, we assessed factors associated with the hospitalization of a given child for asthma both before and during adolescence, and factors associated with an initial asthma hospitalization during adolescence. Outcome measures included age‐ and gender‐specific rates of hospitalization for asthma, diabetes, seizures/epilepsy, and nonasthma respiratory diagnoses. Asthma hospitalization rates for boys were significantly higher than for girls between ages 2–12 years, the gender gap in asthma hospitalizations reversed between ages 13–14 years, and rates for girls were significantly higher than boys between 16–18 years of age. The male peak asthma hospitalization rate per 100,000 cohort members occurred at age 4 years (12.7; 95% confidence interval (CI), 11.1–14.3), and the male trough rate occurred at age 18 years (4.1; 95% CI, 2.8–5.4), whereas the female peak asthma hospitalization rate occurred at age 17 years (9.4; 95% CI, 7.8–11) and the female trough rate at age 2 years (5.2; 95% CI, 4.2–6.2). Age‐specific hospitalization rates for diabetes mellitus and epilepsy were similar for boys and girls throughout childhood. Female gender was strongly associated with asthma hospitalization occurring in an individual child both prior to and during adolescence (rate ratio (RR), 2.0; 95% CI, 1.4–2.9), and was modestly associated with initial hospitalization in adolescence (RR, 1.15; 95% CI, 1.0–1.3). In conclusion, asthma hospitalization rates for boys and girls exhibit strikingly different patterns during adolescence. Potential explanations for these gender differences include hormonal changes during puberty, or gender‐specific differences in environmental exposures such as diet, obesity, allergen exposure, or cigarette smoking. © 2004 Wiley‐Liss, Inc.
Separable pseudopotentials: Effective core potential and the embedding potential
Authors: Abarenkov I. V. , Antonova I. M.
Published: August 2004

In the present paper the separable potentials are considered. The main attention is paid to the embedding separable potential. The method of generating the exact (in the Hartree–Fock approximation) embedding potential is proposed for covalently bonded systems, the most difficult case for embedding. Approximations to the exact embedding potential are introduced that enable one to incorporate the obtained embedding potential into existing molecule calculations packets. The test calculations on (CH3)2O molecule are performed and discussed. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2004
Foundation of quantum similarity measures and their relationship to QSPR: Density function structure, approximations, and application examples
Authors: Carbó‐Dorca Ramon , Gironés Xavier
Published: August 2004

This work presents a schematic description of the theoretical foundations of quantum similarity measures and the varied usefulness of the enveloping mathematical structure. The study starts with the definition of tagged sets, continuing with inward matrix products, matrix signatures, and vector semispaces. From there, the construction and structure of quantum density functions become clear and facilitate entry into the description of quantum object sets, as well as into the construction of atomic shell approximations (ASA). An application of the ASA is presented, consisting of the density surfaces of a protein structure. Based on this previous background, quantum similarity measures are naturally constructed, and similarity matrices, composed of all the quantum similarity measures on a quantum object set, along with the quantum mechanical concept of expectation value of an operator, allow the setup of a fundamental quantitative structure–activity relationship (QSPR) equation based on quantum descriptors. An application example is presented based on the inhibition of photosynthesis produced by some naphthyridinone derivatives, which makes them good herbicide candidates. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2005
Effect of matrix and solvent on the analysis of novel poly(phenylenevinylene) derivatives by matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry
Authors: Zhang Zhenying , Deng Huimin , Deng Qinying , Zhao Shankai
Published: August 2004

Six novel poly(phenylenevinylene) (PPV) derivatives carrying butoxy or myrtanyl groups, including poly(2‐butoxy‐m‐phenylenevinylene) (Bu‐MPV), poly(2,5‐dibutoxy‐p‐phenylenevinylene‐alter‐p‐phenylenevinylene) (Bu‐PPPV), poly(2,5‐dibutoxy‐p‐phenylenevinylene‐alter‐m‐phenylenevinylene) (Bu‐PMPV), poly(2‐myrtanyl‐m‐phenylenevinylene) (Myr‐MPV), poly(2,5‐dimyrtanyl‐p‐phenylenevinylene‐alter‐p‐phenylenevinylene) (Myr‐PPPV), and poly(2,5‐dimyrtanyl‐p‐phenylenevinylene‐alter‐m‐phenylenevinylene) (Myr‐PMPV), were characterized by matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOFMS). The repeat unit mass and the end‐group structures of each sample were obtained. Distinctly different spectra with different ion series and/or different ion signal intensities were observed for the analytes Bu‐MPV, Myr‐MPV, Bu‐PPPV, Myr‐PPPV and Myr‐PMPV when different matrices were used, and different ion series were acquired when different solvents were used for Myr‐PPPV and Myr‐PMPV. The results show that the PPV oligomers with different shapes and/or with different end groups can be selectively desorbed and ionized in MALDI by using different matrices. Copyright © 2004 John Wiley & Sons, Ltd.
Improving opioid effectiveness: from ideas to evidence
Authors: Kalso Eija
Published: August 2004

Opioid effectiveness can be improved by individualizing dosing, route of administration and the drug. Particularly in the treatment of chronic non‐cancer pain, careful patient selection is essential. The current review concentrates on new ideas about improving opioid effectiveness by increasing efficacy or reducing adverse effects by combining other drugs that modulate opioid receptor mediated effects. These pharmacological “oipoid adjuvants” include e.g. α2‐adrenergic agonists, non‐steroidal anti‐flammatory analgesics, NMDA‐receptor antagonists, CCK‐antagonists, gabapentinoids and NK‐1 receptor antagonists. The theoritical background and the clinical evidence of these combinations will be discussed.
Imaging of acute versus pathological pain in humans
Authors: Lorenz J. , Casey K.L.
Published: August 2004

Pain subserves different functions. Acute pain from the intact body alerts the victim to immediately react and withdraw from the bodily threat, ideally before an injury happens. However, during manifest injury and tissue inflammation, withdrawal and flight are no longer adaptive. Instead, sparing the affected body part to promote healing requires heightened awareness and avoidance behaviour over longer periods of time. Quality and time scales of behavioural adaptations are therefore substantially different between pain during normal compared to abnormal tissue states. Given these functional differences we postulated that the two phenomena also recruit different forebrain systems. We used positron emission tomography (PET) and subtracted scans obtained during painful heating of normal skin from scans during equally intense but normally non‐painful heating of capsaicin‐treated skin. This comparison reveals the specific activation of a medial thalamic pathway to limbic forebrain structures such as anterior insula, perigenual anterior cingulate, ventral striatum, and prefrontal cortex during pain originating in the chemically sensitised skin. It is possible that the unique forebrain recruitment by pain under a patho‐physiological tissue status is caused by a significantly greater facilitation of the multi‐synaptic projections from the spino‐parabrachial tract of the superficial dorsal horn to the medial thalamus compared to deeper and direct lateral thalamic projections from the spino‐thalamic tract.
Rank products: a simple, yet powerful, new method to detect differentially regulated genes in replicated microarray experiments
Authors: Breitling Rainer , Armengaud Patrick , Amtmann Anna , Herzyk Pawel
Published: August 2004

One of the main objectives in the analysis of microarray experiments is the identification of genes that are differentially expressed under two experimental conditions. This task is complicated by the noisiness of the data and the large number of genes that are examined simultaneously. Here, we present a novel technique for identifying differentially expressed genes that does not originate from a sophisticated statistical model but rather from an analysis of biological reasoning. The new technique, which is based on calculating rank products (RP) from replicate experiments, is fast and simple. At the same time, it provides a straightforward and statistically stringent way to determine the significance level for each gene and allows for the flexible control of the false‐detection rate and familywise error rate in the multiple testing situation of a microarray experiment. We use the RP technique on three biological data sets and show that in each case it performs more reliably and consistently than the non‐parametric t‐test variant implemented in Tusher et al.'s significance analysis of microarrays (SAM). We also show that the RP results are reliable in highly noisy data. An analysis of the physiological function of the identified genes indicates that the RP approach is powerful for identifying biologically relevant expression changes. In addition, using RP can lead to a sharp reduction in the number of replicate experiments needed to obtain reproducible results.
Identification of region‐specific transcription factor genes in the adult mouse brain by medium‐scale real‐time RT‐PCR
Authors: Suzuki Harukazu , Okunishi Rie , Hashizume Wataru , Katayama Shintaro , Ninomiya Noriko , Osato Naoki , Sato Kenjiro , Nakamura Mari , Iida Juri , Kanamori Mutsumi , Hayashizaki Yoshihide
Published: August 2004

We established a medium‐scale real‐time RT‐PCR system focusing on transcription factors and applied it to their expression profiles in the adult mouse 11 brain regions (http://genome.gsc.riken.jp/qRT‐PCR/). Almost 90% of the examined genes showed significant expression in at least one region. We successfully extracted 179 region‐specific genes by clustering analysis. Interestingly, the transcription factors involved in the development of the pituitary were still expressed in the adult pituitary, suggesting that they also play important roles in maintenance of the pituitary. These results provide unique molecular markers that may account for the molecular basis of the unique functions of specific brain regions.
Oligomerization activity of a double‐stranded RNA‐binding domain
Authors: Hitti Edward G. , Sallacz Nina B. , Schoft Vera K. , Jantsch Michael F.
Published: August 2004

Xenopus laevis RNA‐binding protein A (Xlrbpa) is a highly conserved, ubiquitously expressed hnRNP‐ and ribosome‐associated RNA‐binding protein that contains three double stranded RNA‐binding domains (dsRBDs) in tandem arrangement. A two‐hybrid screen with Xlrbpa as a bait recovered Xlrbpa itself as the strongest interaction partner, indicating multimerization of this protein. To search for regions responsible for the observed interaction, we conducted two‐hybrid assays with Xlrbpa deletion constructs and identified the third dsRBD of Xlrbpa as the exclusive interacting domain. Additionally, these results were confirmed by coimmunoprecipitation experiments with truncated proteins expressed both in yeast and Xenopus oocytes. In PACT, the human homologue of Xlrbpa, we could demonstrate that the third dsRBD displays the same multimerization activity. Interestingly, this domain is essential for the activation of the dsRNA‐activated protein kinase PKR. Addition of RNAses to coimmunoprecipitation experiments did not affect the dimerization, suggesting that the interaction is independent of RNA‐binding. We report here a homomultimerization activity of a type B dsRBD and suggest possible implications that include a model for PKR activation by PACT.
Tumour necrosis factor alpha regulates iron transport and transporter expression in human intestinal epithelial cells
Authors: Johnson Deborah , Bayele Henry , Johnston Kelly , Tennant Jason , Srai Surjit Kaila , Sharp Paul
Published: August 2004

TNFα has dramatic effects on iron metabolism contributing to the generation of hypoferraemia in the anaemia of chronic disease. Interestingly, TNFα is also synthesised and released within the intestinal mucosa, suggesting that this pro‐inflammatory cytokine may play a role in regulating dietary iron absorption. To investigate this possibility, we stimulated intestinal Caco‐2 cells with TNFα (10 ng/ml). In TNFα‐treated cells, apical iron uptake was significantly decreased and this was accompanied by a reduction in divalent metal transporter protein and mRNA expression. Our data suggest that TNFα could regulate dietary iron absorption and that the apical transport machinery is the target for these actions.
Modulation of smooth muscle contractility by CHASM, a novel member of the smoothelin family of proteins
Authors: Borman Meredith A. , MacDonald Justin A. , Haystead Timothy A.J.
Published: August 2004

Cyclic nucleotides acting through their associated protein kinases, the cGMP‐ and cAMP‐dependent protein kinases, can relax smooth muscles without a change in free intracellular calcium concentration ([Ca2+]
i
), a phenomenon referred to as Ca2+ desensitization. The molecular mechanisms by which these kinases bring about Ca2+ desensitization are unknown and an understanding of this phenomenon may lead to better therapies for treating diseases involving defects in the contractile response of smooth muscles such as hypertension, bronchospasm, sexual dysfunction, gastrointestinal disorders and glaucoma. Utilizing a combination of real‐time proteomics and smooth muscle physiology, we characterized a distinct subset of protein targets for cGMP‐dependent protein kinase in smooth muscle. Among those phosphoproteins identified was calponin homology‐associated smooth muscle (CHASM), a novel protein that contains a calponin homology domain and shares sequence similarity with the smoothelin family of smooth muscle specific proteins. Recombinant CHASM was found to evoke relaxation in a concentration dependent manner when added to permeabilized smooth muscle. A co‐sedimentation assay with actin demonstrated that CHASM does not possess actin binding activity. Our findings indicate that CHASM is a novel member of the smoothelin protein family that elicits Ca2+ desensitization in smooth muscle.
Auto‐inhibition of Arabidopsis thaliana plasma membrane Ca2+‐ATPase involves an interaction of the N‐terminus with the small cytoplasmic loop
Authors: Luoni Laura , Meneghelli Silvia , Bonza Maria Cristina , DeMichelis Maria Ida
Published: August 2004

Type IIB Ca2+‐ATPases have a terminal auto‐inhibitory, domain the action of which is suppressed by calmodulin (CaM) binding. Here, we show that a peptide (6His‐1M‐I116) corresponding to the first 116 aminoacids (aa) of At‐ACA8, the first cloned isoform of Arabidopsis thaliana plasma membrane Ca2+‐ATPase, inhibits the activity of the enzyme deprived of the N‐terminus by controlled trypsin treatment 10‐fold more efficiently than a peptide (41I‐T63) corresponding only to the CaM‐binding site. A peptide (268E‐W348) corresponding to 81 aa of the small cytoplasmic loop of At‐ACA8 binds peptide 6His‐1M‐I116 immobilized on Ni–NTA agarose. Peptide 268E‐W348 stimulates Ca2+‐ATPase activity. Its effect is not additive with that of CaM and is suppressed by tryptic cleavage of the N‐terminus. These results provide the first functional identification of a site of intramolecular interaction with the terminal auto‐inhibitory domain of type IIB Ca2+‐ATPases.
Pyrenean orogeny and plate kinematics
Authors: Sibuet Jean‐Claude , Srivastava Shiri P. , Spakman Wim
Published: August 2004

The evolution of the Pyrenees, a mountain range between Iberia and Eurasia, has remained the subject of many debates between geologists and geophysicists for a long time. By combining the identification of seafloor spreading anomalies A33o to M0 in the Bay of Biscay with those in the North Atlantic, we have derived a position of a mean pole of rotation for the entire opening of the Bay of Biscay. Four hundred kilometers of shortening took place between the Iberian and Eurasian plates in the Pyrenean domain during the opening of the Bay of Biscay, from chrons M0 to A33o time (118 to 80 Ma). The deep seismic Etude Continentale et Océanique par Réflexion et réfraction Sismique (ECORS) profile shot across the Pyrenees and teleseismic data show the presence of two distinct slabs, which dip to the north. The southern slab is linked to the subduction of the neo‐Tethys Ocean, which was created from late Jurassic to early Aptian. Simultaneously, elongated back arc basins formed along the future Pyrenean domain. This slab was active from at least 118 Ma (early Aptian) to 100 Ma (late Albian). The northern slab, active since 85 Ma, is linked to the subduction of the lower continental crust located south of the Pyrenean domain. In the upper crust, normal faults as well as the north Pyrenean fault became reverse faults, and former back arc basins were inverted, giving rise to the uplift of the Pyrenees as a double asymmetrical wedge.
Wave period and flow asymmetry effects on the transition to turbulence in relation to sediment dynamics
Authors: Lambkin D. O. , Collins M. B. , Paphitis D.
Published: August 2004

The presence or absence of turbulence in near‐bed flows is known to affect patterns of sediment transport. Therefore the accurate prediction of turbulence is important when considering the initiation of motion of medium to coarse sands as such grains may be eroded by conditions similar to those causing turbulence. An experimental study is described to investigate boundary layer stability under nonlinear (asymmetric) oscillatory flows. In addition, the results are combined with data collected elsewhere to better explain the dependence of initial transition to turbulence on bed roughness and oscillatory period. An oscillating trolley system simulating such oscillatory flows at prototype scale is described. The transition to turbulence under asymmetric (nonlinear) oscillatory flow is investigated utilizing visual techniques and the high‐resolution measurement of near‐bed velocity. These data are used in conjunction with the extensive data sets of Li [1954] and Manohar [1955] for linear oscillatory flows, collected using similar equipment and methods. Relationships are presented to describe the transition over smooth and fixed (granular) roughness beds under linear and nonlinear flows. The transition to turbulence is shown to have a strong positive linear correlation with both oscillatory period and grain roughness up to a maximum Reynolds number for linear flows. An additional positive nonlinear relationship with asymmetry is observed; this was proportionately greater with increasing bed roughness (from smooth beds to a uniform bed roughness of 550 μm). These relationships suggest that transition is regulated by a balance between stabilizing and destabilizing forces or conditions, namely, rates of fluid acceleration, the time frame for development of turbulence, and sources of the initial flow perturbation. It is argued that (wave) period dependence observed in threshold of motion data may be explained by a combination of (a) period dependency in the transition to turbulence or of (b) translation of the proposed regulatory mechanisms for the transition to turbulence.
Early breakthrough of colloids and bacteriophage MS2 in a water‐saturated sand column
Authors: Keller Arturo A. , Sirivithayapakorn Sanya , Chrysikopoulos Constantinos V.
Published: August 2004

We conducted column‐scale experiments to observe the effect of transport velocity and colloid size on early breakthrough of free moving colloids, to relate previous observations at the pore scale to a larger scale. The colloids used in these experiments were bacteriophage MS2 (0.025 μm), and 0.05‐ and 3‐μm spherical polystyrene beads, and were compared with a conservative nonsorbing tracer (KCl). The results show that early breakthrough of colloids increases with colloid size and water velocity, compared with the tracer. These results are in line with our previous observations at the pore scale that indicated that larger colloids are restricted by the size exclusion effect from sampling all paths, and therefore they tend to disperse less and move in the faster streamlines, if they are not filtered out. The measured macroscopic dispersion coefficient decreases with colloid size due to the preferential flow paths, as observed at the pore scale. Dispersivity, typically considered only a property of the medium, is in this case also a function of colloid size, in particular at low Peclet numbers due to the size exclusion effect. Other parameters for colloid transport, such as collector efficiency and colloid filtration rates, were also estimated from the experimental breakthrough curve using a numerical fitting routine. In general, we found that the estimated filtration parameters follow the clean bed filtration model, although with a lower filtration efficiency overall.
Ion distributions of 14 amu pickup ions associated with Titan's plasma interaction
Authors: Ledvina Stephen A. , Brecht Stephen H. , Luhmann Janet G.
Published: August 2004

Titan has an extensive ionosphere consisting of ions of nitrogen and a variety of hydrocarbons that can be picked up by Titan's interaction with the surrounding plasma. Usually Titan is within Saturn's magnetosphere, however, there may be times when Titan exits the magnetosphere and interacts directly with the solar wind. We compare and contrast ion kinetic energy and spatial distributions of 14 amu pickup ions from hybrid simulations of Titan's plasma interaction with both Saturn's magnetosphere and the solar wind. These results can be compared with ion spectrometer measurements to be made during the upcoming Cassini mission.
Velocity field of the “La Clapière” landslide measured by the correlation of aerial and QuickBird satellite images
Authors: Delacourt C. , Allemand P. , Casson B. , Vadon H.
Published: August 2004

Two displacement maps of the “La Clapière” landslide (France) have been derived over two periods of 4 years (1995–1999 and 1999–2003) by correlation of aerial photographs and a QuickBird satellite image. The movement of the landslide ranges from 2.5 m to 20 m per year. Those values have been validated over 13 points monitored by conventional tacheometric measurements. Three areas with significant differences in velocity field have been mapped. Limits of those areas are in good agreement with in situ observations. Velocity maps show the low long term temporal variability of the landslide movement and its spatial variability. The optical correlation method using images derived from various sensors (airborne and spatial) is a promising technique for improving the spatial resolution of velocity field observation of landslides over several years.
Vertical resolution and information content of CO profiles retrieved by MOPITT
Authors: Deeter M. N. , Emmons L. K. , Edwards D. P. , Gille J. C. , Drummond James R.
Published: August 2004

The MOPITT (Measurements of Pollution in the Troposphere) remote sensing instrument monitors the global distribution of carbon monoxide from a polar‐orbiting platform. Calculated averaging kernels for operational MOPITT CO profiles indicate the capability of independently retrieving mid‐ and upper‐tropospheric CO. The information content in MOPITT retrievals is objectively quantified through calculation of the Degrees of Freedom for Signal (DFS), which indicates the number of independent pieces of information in the retrieved profile. DFS values larger than 1 (indicating some amount of profile shape information) are common in tropical and midlatitude scenes. The existence of shape information in actual MOPITT retrieved profiles is also verified through (1) a quantitative comparison with in‐situ data acquired as part of MOPITT validation and (2) a qualitative comparison with monthly mean rain rate (as an index for convection) in the Tropical Eastern Pacific Ocean.
Simulated and observed decadal variability in ocean heat content
Authors: Gregory J. M. , Banks H. T. , Stott P. A. , Lowe J. A. , Palmer M. D.
Published: August 2004

Previous analyses by Levitus et al. [2000] (“Levitus”) of ocean temperature data have shown that ocean heat content has increased over the last fifty years with substantial temporal variability superimposed. The HadCM3 coupled atmosphere–ocean general circulation model (AOGCM) simulates the Levitus trend if both natural and anthropogenic forcings are included. In the relatively well‐observed northern hemisphere upper ocean, HadCM3 has similar temporal variability to Levitus but, like other AOGCMs, it has generally less variability than Levitus for the world ocean. We analyse the causes of this discrepancy, which could result from deficiencies in either the model or the observational dataset. A substantial contribution to the Levitus variability comes from a strong maximum around 500 m depth, absent in HadCM3. We demonstrate a possibly large sensitivity to the method of filling in the observational dataset outside the well‐observed region, and advocate caution in using it to assess AOGCM heat content changes.
Geomagnetic conjugate observations of medium‐scale traveling ionospheric disturbances at midlatitude using all‐sky airglow imagers
Authors: Otsuka Y. , Shiokawa K. , Ogawa T. , Wilkinson P.
Published: August 2004

We report for the first time simultaneous observations of medium‐scale traveling ionospheric disturbances (MSTIDs) at geomagnetic conjugate points in both hemispheres, using two all‐sky airglow imagers at midlatitudes. A 630‐nm all‐sky CCD imager at Sata, Japan, detected MSTIDs with a wavefront elongated from NW to SE on the night of August 9, 2002. During this event, MSTIDs with a wavefront elongated from SW to NE were observed at the geomagnetic conjugate point, Darwin, Australia. To investigate geomagnetic conjugacy of the MSTID structures, the Darwin images were mapped The MSTID structures mapped from Darwin to its magnetic conjugate points along the geomagnetic field lines (B) coincide closely with those in the Sata images. This result suggests that polarization electric field (Ep) plays an important role in the generation of MSTIDs. Ep maps along B and moves the F region plasma upward or downward by E × B drifts, causing plasma density perturbations with structures mirrored in the northern and southern hemispheres.
An extraordinary upwelling event in a deep thermally stratified lake
Authors: Schladow S. Geoffrey , Pálmarsson Sveinn Ó. , Steissberg Todd E. , Hook Simon J. , Prata Fred E.
Published: August 2004

A unique combination of temporal and spatial measurements provides a description of an extraordinarily large upwelling event in Lake Tahoe, CA‐NV. The 4 d event, which engulfed half of the lake's surface and had an amplitude of 500 m, was recorded with in situ and space‐borne instruments. The vertical mixing that ensued, was characterized by a large transfer of heat across the thermocline, resulting in the replacement of the distinct two‐layer thermal structure by a diffuse, temperature gradient. Prior to the event, mixing energy due to the cooling flux at the surface was two orders of magnitude larger than the mixing energy associated with the wind. This dominance by cooling yielded the two‐layer structure. During the event, wind energy was of similar magnitude to the cooling energy. The large bottom velocities that were produced at the end of the event were sufficient to re‐suspend sediment into the water column.
Electrokinetic mechanism for the “W”‐shaped self‐potential profile on volcanoes
Authors: Ishido T.
Published: August 2004

Numerical simulations of electrokinetic potentials were performed to investigate the mechanisms responsible for the generation of the “W”‐shaped self‐potential (SP) profiles observed on volcanoes. The primary cause of the SP pattern is shown to be the drag current associated with downward liquid flows in the unsaturated and underlying saturated fresh‐water layers within the volcanic body, which make the shallow and deep regions low and high in electric potential respectively. If a conductive structure extending to deep levels is present below the summit area, SP around the summit is substantially increased, resulting in the characteristic “W”‐shaped SP profile.
Conditional statistics of the Reynolds stress in the under‐ice boundary layer
Authors: Fer Ilker , McPhee Miles G. , Sirevaag Anders
Published: August 2004

Velocity fluctuations at 1 m and 5 m below pack‐ice drifting at an average speed of 15 cm s−1 are analyzed to describe the conditional statistics of Reynolds stress in the under‐ice boundary layer, under melting conditions. The fractional contributions to the Reynolds stress show that ejection and sweep events dominate over interaction events. The sweeps are found to be more intense close to the boundary where the third and higher order moments are most pronounced. Third order cumulant expansions are found to describe the conditional Reynolds stress statistics reasonably well. Existing models for the turbulent kinetic energy transport term using cumulant expansion methods capture the effect of observed increase in the friction velocity with depth.