bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental Aspects of Bose-Einstein Condensation
Authors: Wilson Andrew C. , McKenzie Callum R.
Published: April 2003

An introductory level review of experimental techniques essential for producing and probing Bose condensates formed with dilute alkali vapours is presented. This discussion includes a summary of evaporative cooling techniques, condensate imaging schemes, and a review of current BEC technology.
MODELING AND ANALYZING MULTI-AGENT BEHAVIORS USING PREDICATE/TRANSITION NETS
Authors: XU DIANXIANG , VOLZ RICHARD A. , IOERGER THOMAS R. , YEN JOHN
Published: April 2003

How agents accomplish a goal task in a multi-agent system is usually specified by multi-agent plans built from basic actions (e.g. operators) of which the agents are capable. The plan specification provides the agents with a shared mental model for how they are supposed to collaborate with each other to achieve the common goal. Making sure that the plans are reliable and fit for the purpose for which they are designed is a critical problem with this approach. To address this problem, this paper presents a formal approach to modeling and analyzing multi-agent behaviors using Predicate/Transition (PrT) nets, a high- level formalism of Petri nets. We model a multi-agent problem by representing agent capabilities as transitions in PrT nets. To analyze a multi-agent PrT model, we adapt the planning graphs as a compact structure for reachability analysis, which is coherent to the concurrent semantics. We also demonstrate that one can analyze whether parallel actions specified in multi-agent plans can be executed in parallel and whether the plans can achieve the goal by analyzing the dependency relations among the transitions in the PrT model.
Tenascin-C Expression Correlates with Prognosis in Gastric Cancer
Authors: Wiksten Jan-Patrik , Lundin Johan , Nordling Stig , Lundin Mikael , Kokkola Arto , von Boguslawski Kristina , Haglund Caj
Published: April 2003

Objectives: Tenascin-C is a hexameric extracellular matrix glycoprotein that is expressed during embryonic development and re-expressed in proliferative processes such as wound healing and tumorigenesis. Stromal tenascin-C may block tumor invasion and thus have a significant influence on tumor spread and prognosis. Methods: In the present study, tissue expression of stromal tenascin-C was studied by immunohistochemistry in a series of 314 patients with gastric cancer. Results: Strong tenascin-C positivity was seen in the stroma of the tumor in 122 (39%) cases. There was a correlation between strong tenascin-C expression and low stage (p = 0.002), superficial tumor penetration (p = 0.02), location of tumor at the distal third of the stomach (p = 0.03), and potentially curative surgery (p = 0.008). No significant correlation was found between tenascin-C positivity and nodal status, distant metastases, age, Laurén classification, gender, tumor size, or Borrmann classification. The cumulative 5-year survival in patients with strong tenascin-C expression was 42% compared to 26% in those with negative-to-moderate expression (p = 0.0053). In multivariate survival analysis stratified for estimated cure of surgery, stage of disease was the only independent prognostic factor. Conclusion: In conclusion, tenascin-C expression seems to correlate with cancer related survival in patients with gastric cancer, but may not add significant prognostic information to that provided by TNM stage.
Beta-Catenin Expression in Intramucosal Neoplastic Lesions of the Stomach
Authors: Tsukashita Shizuki , Kushima Ryoji , Bamba Masamichi , Nakamura Etsuko , Mukaisho Ken-ichi , Sugihara Hiroyuki , Hattori Takanori
Published: April 2003

Objective: To clarify roles of beta-catenin in the early stage of gastric tumorigenesis, we investigate beta-catenin expression in stomach intramucosal neoplasms. Methods: For immunohistochemistry, 84 gland-forming neoplasms and 17 signet-ring cell carcinomas were examined. The gland-forming neoplasms were grouped according to the Vienna classification: group A (low-grade adenoma/dysplasia), group B (high-grade adenoma/dysplasia) and group C (intramucosal carcinoma). Results: Strong nuclear expression was detected not only in group C (21.4%) but in groups A (20.8%) and B (11.2%). Strong cytoplasmic expression was detected in groups A, B and C: 16.7, 11.2 and 16.7%, respectively. Loss of membranous stainings (LOM) were also detected in groups A, B and C: 20.8, 22.2 and 31.0%, respectively. No significant difference was found among groups A, B and C with respect to nuclear, cytoplasmic, and membranous expression. Regarding signet-ring cell carcinomas, all cases were essentially negative for nuclear expression and 11.8% of the cases showed weak cytoplasmic expression as well as LOM. There were obvious differences between gland-forming adenocarcinoma and signet-ring cell carcinoma with respect to nuclear and cytoplasmic expression but not in terms of membranous expression. Conclusion: These findings suggest that beta-catenin expression does not always reflect the malignant transformations in the early stage of gastric tumorigenesis.
Effects of Extracellular Matrices on F9 Teratocarcinoma Stem Cells: A Crucial Role of Type IV Collagen in the Early Stage of Differentiation of F9 Stem Cells
Authors: Watanabe Keiko , Toda Shuji , Yonemitsu Nobuhisa , Sugihara Hajime
Published: April 2003

F9 teratocarcinoma stem cells treated with retinoic acid (RA) differentiate into visceral endoderm, and this process affects the expression of some extracellular matrix (ECM) proteins. As the direct influence of ECM molecules on the differentiation of F9 stem cells has not been studied, we investigated the effects of various ECM proteins on the early differentiation of these cells. Monolayers of F9 stem cells were cultured on dishes coated with various ECM, such as type I or IV collagen, fibronectin, or laminin. They aggregated and formed spheroid bodies in the absence of RA only on type IV collagen. The outer layer cells of the spheroid bodies exhibited numerous microvilli, junctional complexes and mature cell organelles. Alpha-fetoprotein was positive in the outer layer cells. A small amount of laminin was detected in the matrix of the spheroid bodies. These data suggest that type IV collagen promoted the early stage of the differentiation of F9 stem cells without RA. The other ECM molecules failed to induce them to form spheroid bodies. The reversibility of the structure of the spheroid bodies to a monolayer was also examined. When the spheroid bodies were reseeded only on fibronectin- or laminin-coated culture dishes, they broke down and the cells spread to the surface in the absence of RA. The differentiation of F9 stem cells induced by type IV collagen seemed to be reversible and to take place at an early stage of their morphogenesis. These findings suggest that type IV collagen plays an important role in early embryogenesis.
Unresponsiveness to Surface Antigen 1 Modifies Cytokine Profiles in Acute Toxoplasma gondii Infection
Authors: Seng S. , Makala L.H.C. , Maki Y. , Choi Y. , Yokoyama M. , Suzuki N. , Toyoda Y. , Nagasawa H.
Published: April 2003

Resistance to Toxoplasma gondii involves the development of a highly polarized Th1-type cytokine expression. SAG1 transgenic mice are highly susceptible to T. gondii infection due to their non-reactivity to SAG1 of the protozoan parasite. Here we describe cytokine profiles during the acute phase of T. gondii infection, which are associated with the susceptibility of SAG1 transgenic mice. SAG1 transgenic mice showed a 4.5-fold increase in susceptibility upon inoculation with a sublethal dose of the Beverley strain of T. gondii compared to their wild-type counterparts (mortality: 81 vs. 18%, respectively). When analysis of the most important cytokines involved in the mediation of resistance to infection was carried out, SAG1 transgenic mice exhibited low production levels of IL-12, IFN-γ and TNF-α in sera during the acute phase of T. gondii infection. Antibody and T cells specific for SAG1 were not mounted upon SAG1 stimulation in SAG1 transgenic mice. Moreover, in vitro studies indicated that in SAG1 transgenic mice IFN-γ and IL-12 production was lower than in their wild-type counterparts, although levels of TNF-α increased in SAG1 transgenic mice on day 9 after infection. Low IgG2a levels were detected in SAG1 transgenic mouse sera. Unresponsiveness to SAG1 of T. gondii renders SAG1 transgenic mice unable to develop a strong Th1-based protection against T. gondii infection. These results provide evidence that SAG1 is a pivotal antigen involved in the induction of immune responses towards the development of Th1-protective immunity during T. gondii infection.
Long-Term Outcome after Ischaemic Stroke/Transient Ischaemic Attack
Authors: Hankey Graeme J.
Published: April 2003

During the first 30 days after a stroke, the case fatality is about 25% and the major cause of death is the index stroke and its sequelae. The most consistent predictor of 30-day mortality after stroke is stroke severity. Other predictors include increasing age, a history of previous stroke, cardiac failure, and a high blood glucose concentration and white blood cell count. Other less common, but important, causes of early mortality are recurrent ischaemic stroke and a coronary event. The risk of a recurrent cerebrovascular event is highest in the first month (4%) and year (12%) after a stroke and transient ischaemic attack (TIA), probably reflecting the presence of active, unstable atherosclerotic plaque. Thereafter, the risk of a recurrent cerebrovascular event falls to about 5% per year, similar to the risk of a coronary event. During years 1–5 after a TIA and ischaemic stroke, cardiovascular disease increasingly becomes the major cause of death, reflecting the generalized nature of atherothrombosis, the most common cause of the index stroke. The most robust predictor of death within 1–5 years after stroke is increasing age, closely followed by cardiac failure. Additional baseline predictors of longer-term mortality include a history of previous symptomatic atherothrombosis (TIA, ischaemic stroke, peripheral arterial disease, and early-onset ischaemic heart disease), risk factors for atherothrombosis (smoking), other heart diseases (cardiac failure, atrial fibrillation) and increasing stroke severity. Lacunar syndromes can be predictive of relative longevity. At 5 years after stroke, survival is about 40%, and about half of survivors are disabled and dependent. The most robust predictors of disability at 5 years after stroke are increasing age, stroke severity, and recurrent stroke. The most powerful predictor of early recurrent stroke (within 30 days after stroke) is an atherosclerotic ischaemic stroke caused by large-artery atherosclerosis with >50% stenosis, whereas the strongest predictor of stroke recurrence over 5 years is diabetes. Other predictors of recurrent stroke include increasing age, previous TIA, atrial fibrillation, high alcohol consumption, haemorrhagic index stroke, and hypertension at discharge. The clinical implication of these findings is that strategies for optimizing long-term outcome after TIA and stroke should be directed toward reducing the high risk of recurrent stroke and coronary events by removing/recanalizing the symptomatic atherosclerotic plaque, controlling the underlying causal vascular risk factors, and administering long-term, effective antiplatelet therapy.
Increased Frequency of HLA A2/DR4 and A2/DR8 Haplotypes in Young Saskatchewan Aboriginal People with Diabetic End-Stage Renal Disease
Authors: Dyck Roland , Bohm Clara , Klomp Helena
Published: April 2003

Aims: To determine the association of HLA with diabetic end-stage renal disease (DESRD) in Saskatchewan aboriginal people. Methods: This was a retrospective study of HLA profiles in four groups of Saskatchewan residents with ESRD diagnosed from 1980 to 1998: aboriginal people with and without DESRD, and non-aboriginal people with and without DESRD. The aboriginal DESRD group was also subdivided into those ≤50 and >50 years of age. Frequencies of individual and combinations of HLA antigens were compared between groups and subgroups. Results: HLA data were available for 634 subjects. Young aboriginal people with DESRD had a higher frequency of HLA-A2 than older AB DESRD subjects (69 vs. 36%; p = 0.03), and of HLA-DR4 and/or DR8 compared to older AB DESRD subjects (91 vs. 68%; p = 0.07) and AB non-DESRD subjects (91 vs. 67%; p = 0.03). Over 65% of young AB DESRD subjects had either an A2/DR4 or A2/DR8 haplotype (odds ratio 5.09 [confidence intervals 1.35, 20.15] versus older AB DESRD subjects; odds ratio 3.32 [confidence intervals 1.20, 9.3] versus AB non-DESRD subjects). Forty percent of young AB DESRD subjects were homozygous for at least one of A2, DR4 or DR8. Conclusions: Our findings suggest that DESRD in young AB subjects with T2DM has a genetic basis related to HLA.
Application of Nanoparticle Technology for the Prevention of Restenosis After Balloon Injury in Rats
Authors: Uwatoku Toyokazu , Shimokawa Hiroaki , Abe Kohtaro , Matsumoto Yasuharu , Hattori Tsuyoshi , Oi Keiji , Matsuda Takehisa , Kataoka Kazunori , Takeshita Akira
Published: April 2003

Restenosis after percutaneous coronary intervention continues to be a serious problem in clinical cardiology. Recent advances in nanoparticle technology have enabled us to deliver an antiproliferative drug selectively to the balloon-injured artery for a longer time. NK911, which is a core-shell nanoparticle of polyethyleneglycol-based block copolymer encapsulating doxorubicin, accumulates in vascular lesions with increased permeability. We first confirmed that balloon injury caused a marked and sustained increase in vascular permeability (as evaluated by Evans blue staining) for a week in the rat carotid artery. We then observed that intravenous administration of just 3 times of NK911, but not doxorubicin alone, significantly inhibited the neointimal formation of the rat carotid artery at 4 weeks after the injury in both a single- and double-injury model. Immunostaining demonstrated that the effect of NK911 was due to inhibition of vascular smooth muscle proliferation but not to enhancement of apoptosis or inhibition of inflammatory cell recruitment. Measurement of vascular concentrations of doxorubicin confirmed the effective delivery of the agent to the balloon-injured artery by NK911 in both a single- and double-injury model. RNA protection assay demonstrated that NK911 inhibited expression of several cytokines but not that of apoptosis-related molecules. NK911 was well tolerated without any adverse systemic effects. These results suggest that nanoparticle technology to target vascular lesions with increased permeability is a promising and safe approach for the prevention of restenosis after balloon injury. The full text of this article is available at http://www.circresaha.org.
A FRESH LOOK AT MALACHI II 13-16
Authors: Zehnder Markus
Published: April 2003

In this study it is argued that the main thrust of Mal. ii 13-16 is against those men within the YHWH-congregation in Yehud, who expel their first, "Israelite", wives in order to marry women of foreign faiths. In the context of a fresh exegesis of the passage, a reinterpretation of the textually difficult verse 15a is offered. As it stands, the MT is most adequately rendered by: "And no one who has acted that way, has a remnant of spirit". With slight emendations, however, the text can be reconstructed as referring to God's creation of man and woman in Gen. i-ii. This reconstruction makes good sense in the context of the dispute in which Malachi is engaged, providing an additional argument against the dissolution of marriage. Though verse 16a does not contain a general prohibition of divorce, the reconstructed text of verse 15a should be understood as a general argument for the indissolubility of marriage.
The zebrafishnodal-related genesouthpawis required for visceral and diencephalic left-right asymmetry
Authors: Long Sarah , Ahmad Nadira , Rebagliati Michael
Published: April 2003

We have identified and characterized a new zebrafish gene, southpaw, that is required for visceral and diencephalic left-right asymmetry. southpaw encodes a new member of the nodal-related class of proteins, a subfamily within the transforming growth factorβsuperfamily of secreted factors. southpaw is expressed bilaterally in paraxial mesoderm precursors and then within the left lateral plate mesoderm. At late somite stages, left-sided southpaw expression transiently overlaps the left-sided expression domains of other genes that mark the developing heart, such as lefty2. We have injected morpholinos to block the translation of the southpaw mRNA or to block splicing of the southpaw pre-mRNA. These morpholinos cause a severe disruption of early (cardiac jogging) and late (cardiac looping) aspects of cardiac left-right asymmetry. As the left-right asymmetry of the pancreas is also affected, southpaw appears to regulate left-right asymmetry throughout a large part of the embryo. Consistent with the morphological changes, the left-sided expression domains of downstream genes (cyclops,pitx2, lefty1 and lefty2) are severely downregulated or abolished within the lateral plate mesoderm of Southpaw-deficient embryos. Surprisingly, despite the absence of southpaw expression in the brain, we find that early diencephalic left-right asymmetry also requires Southpaw activity. These observations lead to a model of how visceral organ and brain left-right asymmetry are coordinated during embryogenesis.
Erbb2 regulates neuromuscular synapse formation and is essential for muscle spindle development
Authors: Leu Marco , Bellmunt Elena , Schwander Martin , Fariñas Isabel , Brenner Hans Rudolf , Müller Ulrich
Published: April 2003

Neuregulins and their Erbb receptors have been implicated in neuromuscular synapse formation by regulating gene expression in subsynaptic nuclei. To analyze the function of Erbb2 in this process, we have inactivated the Erbb2 gene in developing muscle fibers by Cre/Lox-mediated gene ablation. Neuromuscular synapses form in the mutant mice, but the synapses are less efficient and contain reduced levels of acetylcholine receptors. Surprisingly, the mutant mice also show proprioceptive defects caused by abnormal muscle spindle development. Sensory Ia afferent neurons establish initial contact with Erbb2-deficient myotubes. However, functional spindles never develop. Taken together, our data suggest that Erbb2 signaling regulates the formation of both neuromuscular synapses and muscle spindles.
Wnt signaling mediates reorientation of outer hair cell stereociliary bundles in the mammalian cochlea
Authors: Dabdoub Alain , Donohue Maura J. , Brennan Angela , Wolf Vladimir , Montcouquiol Mireille , Sassoon David A. , Hseih Jen-Chih , Rubin Jeffrey S. , Salinas Patricia C. , Kelley Matthew W.
Published: April 2003

In the mammalian cochlea, stereociliary bundles located on mechanosensory hair cells within the sensory epithelium are unidirectionally oriented. Development of this planar polarity is necessary for normal hearing as stereociliary bundles are only sensitive to vibrations in a single plane;however, the mechanisms governing their orientation are unknown. We report that Wnt signaling regulates the development of unidirectional stereociliary bundle orientation. In vitro application of Wnt7a protein or inhibitors of Wnt signaling, secreted Frizzled-related protein 1 or Wnt inhibitory factor 1,disrupts bundle orientation. Moreover, Wnt7a is expressed in a pattern consistent with a role in the polarization of the developing stereociliary bundles. We propose that Wnt signaling across the region of developing outer hair cells gives rise to planar polarity in the mammalian cochlea.
fear of intimacy encodes a novel transmembrane protein required for gonad morphogenesis in Drosophila
Authors: Van Doren Mark , Mathews Wendy R. , Samuels Monique , Moore Lisa A. , Broihier Heather Tarczy , Lehmann Ruth
Published: April 2003

Gonad formation requires specific interactions between germ cells and specialized somatic cells, along with the elaborate morphogenetic movements of these cells to create an ovary or testis. We have identified mutations in the fear of intimacy (foi) gene that cause defects in the formation of the embryonic gonad in Drosophila. foi is of particular interest because it affects gonad formation without affecting gonad cell identity, and is therefore specifically required for the morphogenesis of this organ. foi is also required for tracheal branch fusion during tracheal development. E-cadherin/shotgun is similarly required for both gonad coalescence and tracheal branch fusion, suggesting that E-cadherin and FOI cooperate to mediate these processes. foi encodes a member of a novel family of transmembrane proteins that includes the closely related human protein LIV1. Our findings that FOI is a cell-surface protein required in the mesoderm for gonad morphogenesis shed light on the function of this new family of proteins and on the molecular mechanisms of organogenesis.
Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells
Authors: Suzuki Atsushi , Iwama Atsushi , Miyashita Hitoshi , Nakauchi Hiromitsu , Taniguchi Hideki
Published: April 2003

In liver development, a number of growth factors (GFs) and components of the extracellular matrix (ECMs) lead to differentiation of liver parenchymal cells. As the liver contains many cell types, specifically investigating their functional effects on hepatic stem cell populations is difficult. Prospective isolation and clonal assays for hepatic stem cells enable the examination of direct effects of GFs and ECMs on this rare cell fraction. Using previously purified cells that fulfill the criteria for hepatic stem cells, we examined how GFs and ECMs regulate differentiation in the developing liver. We show here that hepatocyte growth factor (HGF) induced early transition of albumin(ALB)-negative stem cells to ALB-positive hepatic precursors resembling hepatoblasts and then oncostatin M (OSM) promoted their differentiation to tryptophan-2, 3-dioxygenase (TO)-positive mature hepatocytes. During this transition, ECMs were necessary for the differentiation of stem cells and precursors, but their effects were only supportive. In the first step of stem cell differentiation induced by HGF, the expression of CCAAT/enhancer binding protein (C/EBP), a basic leucine zipper transcription factor, changed dramatically. When C/EBP function was inhibited in stem cells, they stopped differentiating to hepatocyte-lineage cells and proliferated actively. These are the first findings to illustrate the mechanism of hepatic stem cell differentiation in liver development.
The retinoic-like juvenile hormone controls the looping of left-right asymmetric organs in Drosophila
Authors: Ádám Géza , Perrimon Norbert , Noselli Stéphane
Published: April 2003

In vertebrate development, the establishment of left-right asymmetry is essential for sidedness and the directional looping of organs like the heart. Both the nodal pathway and retinoic acid play major and conserved regulatory roles in these processes. We carried out a novel screen in Drosophila to identify mutants that specifically affect the looping of left-right asymmetric organs. We report the isolation of spin, a novel mutant in which the looping of the genitalia and spermiduct are incomplete; under-rotation of the genitalia indicates that spincontrols looping morphogenesis but not direction, thus uncoupling left-right asymmetry and looping morphogenesis. spin is a novel,rotation-specific allele of the fasciclin2 (Fas2) gene,which encodes a cell-adhesion protein involved in several aspects of neurogenesis. In spin mutants, the synapses connecting specific neurosecretory cells to the corpora allata are affected. The corpus allatum is part of the ring gland and is involved in the control of juvenile hormone titers during development. Our genetic and pharmacological results indicate that Fas2spin rotation defects are linked to an abnormal endocrine function and an elevated level of juvenile hormone. As juvenile hormone is an insect sesquiterpenoid related to retinoic acid, these results establish a new genetic model for studying organ looping and demonstrate an evolutionarily conserved role for terpenoids in this process.
N-cadherin mediates retinal lamination, maintenance of forebrain compartments and patterning of retinal neurites
Authors: Masai Ichiro , Lele Zsolt , Yamaguchi Masahiro , Komori Atsuko , Nakata Asuka , Nishiwaki Yuko , Wada Hironori , Tanaka Hideomi , Nojima Yasuhiro , Hammerschmidt Matthias , Wilson Stephen W. , Okamoto Hitoshi
Published: April 2003

The complex, yet highly ordered and predictable, structure of the neural retina is one of the most conserved features of the vertebrate central nervous system. In all vertebrate classes, retinal neurons are organized into laminae with each neuronal class adopting specific morphologies and patterns of connectivity. Using genetic analyses in zebrafish, we demonstrate that N-cadherin (Ncad) has several distinct and crucial functions during the establishment of retinal organization. Although the location of cell division is disorganized in embryos with reduced or no Ncad function, different classes of retinal neurons are generated. However, these neurons fail to organize into correct laminae, most probably owing to compromised adhesion between retinal cells. In addition, amacrine cells exhibit exuberant and misdirected outgrowth of neurites that contributes to severe disorganization of the inner plexiform layer. Retinal ganglion cells also exhibit defects in process outgrowth, with axons exhibiting fasciculation defects and adopting incorrect ipsilateral trajectories. At least some of these defects are likely to be due to a failure to maintain compartment boundaries between eye, optic nerve and brain. Although in vitro studies have implicated Fgf receptors in modulating the axon outgrowth promoting properties of Ncad, most aspects of the Ncad mutant phenotype are not phenocopied by treatments that block Fgf receptor function.
Multiple roles foru-turn/ventral veinlessin the development ofDrosophilaPNS
Authors: Inbal Adi , Levanon Daniel , Salzberg Adi
Published: April 2003

Most of the cells in the embryonic peripheral nervous system (PNS) of Drosophila are born in their final location. One known exception is the group of lateral chordotonal organs (lch5) whose precursors form in a dorsal position, yet the mature organs are located in the lateral PNS cluster. Mutations in the u-turn (ut) locus perturb the localization of lch5 neurons and result in a `dorsal chordotonals' phenotype. We show that ut is allelic to ventral veinless (vvl), also known as drifter. VVL, a POU-domain transcription factor, has been shown to participate in the development of tracheae and CNS in the embryo, and in wing development in the adult; however, its role in PNS development has not been described. Characterization of the `dorsal chordotonals' phenotype of vvl mutant embryos revealed that in the absence of VVL, cell fates within the lch5 lineage are determined properly and the entire organ is misplaced. Based on the positions of lch5 cells relative to each other in mutant embryos, and in normal embryos at different developmental stages, we propose a two-step model for lch5 localization. lch5 organs must first rotate to assume a correct polarity and are then stretched ventrally to their final position. In this process, VVL function is required in the ectoderm and possibly in the lch5 organs too.

VVL is also expressed in developing external sensory organs in the embryo and in the adult. In the embryo, loss of VVL function results in increased apoptosis in specific es organs. Analysis of vvl mutant clones in adults revealed a requirement for VVL in the control of cell number within the bristle lineage.
Identification of the yeast gene encoding the tRNA m1G methyltransferase responsible for modification at position 9
Authors: JACKMAN JANE E. , MONTANGE REBECCA K. , MALIK HARMIT S. , PHIZICKY ERIC M.
Published: April 2003

Methylation of tRNA at the N-1 position of guanosine to form m1G occurs widely in nature. It occurs at position 37 in tRNAs from all three kingdoms, and the methyltransferase that catalyzes this reaction is known from previous work of others to be critically important for cell growth in Escherichia coli and the yeast Saccharomyces cerevisiae. m1G is also widely found at position 9 in eukaryotic tRNAs, but the corresponding methyltransferase was unknown. We have used a biochemical genomics approach with a collection of purified yeast GST-ORF fusion proteins to show that m1G9 formation of yeast tRNAGly is associated with ORF YOL093w, named TRM10. Extracts lacking Trm10p have undetectable levels of m1G9 methyltransferase activity but retain normal m1G37 methyltransferase activity. Yeast Trm10p purified from E. coli quantitatively modifies the G9 position of tRNAGly in an S-adenosylmethionine-dependent fashion. Trm10p is responsible in vivo for most if not all m1G9 modification of tRNAs, based on two results: tRNAGly purified from a trm10-Δ/trm10-Δ strain is lacking detectable m1G; and a primer extension block occurring at m1G9 is removed in trm10-Δ/trm10-Δ-derived tRNAs for all 9 m1G9-containing species that were testable by this method. There is no obvious growth defect of trm10-Δ/trm10-Δ strains. Trm10p bears no detectable resemblance to the yeast m1G37 methyltransferase, Trm5p, or its orthologs. Trm10p homologs are found widely in eukaryotes and many archaea, with multiple homologs in several metazoans, including at least three in humans.
Methylenetetrahydrofolate reductase (MTHFR): incidence of mutations C677T and A1298C in Brazilian population and its correlation with plasma homocysteine levels in spina bifida
Authors: Perez Ana Beatriz Alvarez , D'Almeida Vânia , Vergani Naja , de Oliveira Allan C. , de Lima Fernanda Teresa , Brunoni Decio
Published: April 2003

Homocysteine (Hcy) is converted to cysteine or is remethylated to methionine by methylenetetrahydrofolate reductase (MTHFR). MTHFR plays a central role in the metabolism of folate. Two common polymorphisms in the MTHFR gene (C677T and A1298C) have been described and studies suggest that these polymorphisms are positively associated with the occurrence of spina bifida (SB). Among Brazilians, the incidence of 677T allele homozygosity is 4%. We compared Hcy levels with the genotypes obtained for the mutations C677T and A1298C in the gene MTHFR. Levels of plasma Hcy were higher in children with SB than in controls (average 7.95 vs. 5.55 (μmol/L); P < 0.001). There was no significant difference in the levels of Hcy for these childrens's mothers and controls (average 7.76 vs. 8.36 (μmol/L); P = 0.27). Eighty one (61.8%) of the affected children were white and 50 (38.2%) were non‐white. A similar ratio was observed in the mothers. In the control group, 51 children (40.5%) were white and 75 (59.5%) were non‐white, and 52 mothers (41.3%) were white and 74 (58.7%) were non‐white. There was no significant difference in the homozygous frequency for the mutated allele 677T among different racial groups. We obtained a prevalence of TT homozygosity of 10/131 (7.64%) in affected children and 13/126 (10.32%) in controls. With respect to the mutation A1298C, the homozygous prevalence for the wild allele was greater among non‐white individuals than in white individuals both in case and control groups. Hyperhomocysteinemia is a risk factor for SB. However, in our population, the increase in plasma levels of Hcy is not explained by the presence of the homozygous TT. It is possible that low folic acid intake combined with other genetic factors plays a more important role in the cause of this disease. © 2003 Wiley‐Liss, Inc.
Twin brothers with MIDAS syndrome and XX karyotype
Authors: Anguiano A. , Yang X. , Felix J.K. , Hoo J.J.
Published: April 2003

Twin brothers with microphthalmia, facial dermal hypoplasia, sclerocornea, and supraventricular tachycardia, are reported. Their clinical features are compatible with MIDAS syndrome, a known X‐linked and hemizygous male lethal condition. Their karyotypes showed an XX sex chromosome modality with a subtle Xp/Yp translocation proven by the presence of SRY gene. The pregnancy was complicated with fetal supraventricular tachycardia, which was treated with digoxin prenatally. Postnatally, both twins required treatment with adenosine, digoxin, and propanolol to remain in normal sinus rhythm. The possible involvement of the heart, only in the form of cardiomyopathy with arrhythmia is emphasized. Both twins had a selective X‐inactivation of the derivative chromosome X with Xp/Yp translocation. © 2003 Wiley‐Liss, Inc.
Macrodystrophia lipomatosa of the feet and subcutaneous lipomas
Authors: Aydos S.E. , Fitoz S. , Bökesoy I.
Published: April 2003

We report on a girl aged 16 months with localized gigantism of the lower limb and widespread subcutaneous lipomas. This is the first case of macrodystrophia lipomatosa with lipomatous involvement in areas other than the involved limb. © 2003 Wiley‐Liss, Inc.
X‐inactivation pattern in multiple tissues from two leber's hereditary optic neuropathy (LHON) patients
Authors: Pegoraro Elena , Vettori Andrea , Valentino Maria L. , Molon Annamaria , Mostacciuolo Maria L. , Howell Neil , Carelli Valerio
Published: April 2003

The more frequent manifestation of ophthalmological abnormalities in males, relative to females, is an unexplained feature of Leber's hereditary optic neuropathy (LHON) that suggests an X‐linked modifying gene acting in concert with the pathogenic LHON mitochondrial DNA (mtDNA) mutation. In addition, segregation analysis of the optic neuropathy in LHON pedigrees was compatible with the presence of a recessive‐modifying gene on chromosome X. According to this two‐locus model, females would be affected only if homozygous or if they were susceptible to skewed X‐inactivation. Attempts both to localize the putative LHON‐modifying gene by linkage analysis and to find an excess of skewed X‐inactivation in affected females were unsuccessful, although the inactivation pattern was only studied in DNA isolated from blood cells. We had the opportunity to analyze a wide range of tissues at autopsy, including the optic nerves and the retina, from two LHON female patients. We found no evidence of skewed X‐inactivation in the affected tissues, thus weakening further the hypothesized involvement of a specific X chromosome locus in the pathophysiological expression of LHON. © 2003 Wiley‐Liss, Inc.
Lambert–Eaton Myasthenic syndrome in a child with an autoimmune phenotype
Authors: Hoffman William H. , Helman Sandra W. , Sekul Elizabeth , Carroll James E. , Vega Roger A.
Published: April 2003

We report on a child with a family history of autoimmune defects, who presented at the age of 3½ years with alopecia and Graves disease. He subsequently developed vitiligo and psoriasis. At 9½ years, he developed an autoimmune form of Lambert–Eaton Myasthenic syndrome (LEMS) with a significant elevation of glutamic acid decarboxylase (GAD) autoantibodies. Shortly thereafter he developed chronic urticaria. HLA associations were present for Graves disease, vitiligo, psoriasis, and IgA deficiency. There was also evidence of autoimmunity involving the pancreatic islet cells and gastric parietal cells. © 2003 Wiley‐Liss, Inc.
A distinctive type of metaphyseal chondrodysplasia with characteristic thickening of the distal ulna and radius: Possible metaphyseal chondrodysplasia‐rosenberg
Authors: Lee Yung‐Seng , Elliott Alison M. , Loke Kah‐Yin , Lachman Ralph S.
Published: April 2003

We report an 8‐year‐old boy with a distinctive form of metaphyseal chondrodysplasia (MCD). He presented with moderate disproportionate short stature and bony swelling of his wrists, knees, and ankles. There were severe metaphyseal abnormalities with a honeycomb appearance affecting the distal tibiae and fibulae, proximal tibiae, distal femurs, distal ulnae and radii, and both hands. His thoracolumbar spine was normal. Radiological examination of the mother's forearms revealed widening of the distal radii and short ulnae with hypoplastic distal ends. Rosenberg and Löhr [1986: Eur J Pediatr 145:40–45] reported a four‐generational kindred in which affected members had thickening of the wrist proximal to the styloid process of the ulna and thickening of the dorsum sellae. Although many of the radiographic features of this patient are those of MCD‐Rosenberg, the skeletal features of our patient do not appear to represent any known classified forms of MCD. © 2003 Wiley‐Liss, Inc.
Genetic approaches to polydipsia in schizophrenia: A preliminary report of a family study and an association study of an angiotensin‐converting enzyme gene polymorphism
Authors: Shinkai Takahiro , Ohmori Osamu , Hori Hiroko , Nakamura Jun
Published: April 2003

The pathophysiology of polydipsia in patients with schizophrenia is inadequately understood. This study aims to investigate the genetic influence on polydipsia in schizophrenia, and is comprised of a family study and an association study. First, we screened in‐patients in 14 psychiatric hospitals and found a total of 36 pairs of a proband and his/her first‐degree relative, both of whom were diagnosed with schizophrenia. Among these pairs, a significant familial concordance of polydipsia was found (Fisher's exact test, two‐sided, P = 0.0014; odds ratio, 88.20; 95% confidence interval, 7.31–1064.34). These results indicate that genetic factors may underlie the pathophysiology of polydipsia in patients with schizophrenia. Subsequently, we examined the genetic association between polydipsia/water intoxication and the angiotensin‐converting enzyme (ACE) insertion (I)/deletion (D) polymorphism in patients with chronic schizophrenia (polydipsics: n = 65; non‐polydipsics: n = 97) because several lines of evidence suggested that ACE might be involved in the development of polydipsia in schizophrenia. The D allele of ACE was found to be associated with a non‐significant trend toward an increased risk of polydipsia (P = 0.086). Furthermore, a significant allelic association was found between the D allele of ACE and water intoxication (P = 0.0392). This significance remained after the data were adjusted for confounding variables by regression analysis. These results suggest that the ACE D allele may be a risk factor for polydipsia/water intoxication in patients with schizophrenia. © 2003 Wiley‐Liss, Inc.
Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer's disease and correlation with APOE
Authors: Pulliam Joseph F. , Jennings C. Darrell , Kryscio Richard J. , Davis Daron G. , Wilson Dianne , Montine Thomas J. , Schmitt Frederick A. , Markesbery William R.
Published: April 2003

Oxidative stress enhanced by transition metals such as iron forms an attractive hypothesis for neurodegeneration in Alzheimer's Disease (AD). Iron is increased in the brain in AD, but whether this is a primary abnormality or the result of secondary accumulation is unclear. Among several genetic loci associated with AD, the locus at chromosome 6p21 contains the hereditary hemochromatosis gene HFE. To determine whether a genetic predisposition to iron accumulation is associated with AD, we evaluated three hemochromatosis‐associated HFE mutations and APOE in cognitively and histopathologically evaluated subjects with AD, mild cognitive impairment (MCI), non‐demented controls with AD‐like pathologic changes defined by Braak stage ≥ 3 (high pathology controls (HPC)), and non‐demented controls without significant histologic changes (low‐pathology controls (LPC)). In a subset, we examined ventricular (CSF) fluid F2‐isoprostane (F2‐IsoP) levels, a marker of lipid peroxidation. Seventeen subjects demonstrated homozygous or compound heterozygous HFE mutations, 13 (9.4%) in the AD/MCI group (P = 0.019 vs. LPC) and four (20%) in the HPC group (P = 0.006, P < 0.05 with Bonferroni correction vs. LPC). In contrast, the APOE4 allele frequency was increased only in the AD/MCI patients (P < 10−3 vs. HPC, P < 10−6 vs. LPC). F2‐IsoP levels were increased in AD subjects with any HFE mutation versus wild type HFE (P = 0.027). Although confirmation is required, these findings suggest that HFE mutations are associated with increased oxidative stress and Braak stage, and that HFE and APOE genotypes are different between AD patients, high pathology and low pathology controls. © 2003 Wiley‐Liss, Inc.
CHIP: Defining a dimension of the vulnerability to attention deficit hyperactivity disorder (ADHD) using sibling and individual data of children in a community‐based sample
Authors: Curran Sarah , Rijsdijk Fruhling , Martin Neilson , Marusic Katja , Asherson Philip , Taylor Eric , Sham Pak
Published: April 2003

We are taking a quantitative trait approach to the molecular genetic study of attention deficit hyperactivity disorder (ADHD) using a truncated case‐control association design. An epidemiological sample of children aged 5 to 15 years was evaluated for symptoms of ADHD using a parent rating scale. Individuals scoring high or low on this scale were selected for further investigation with additional questionnaires and DNA analysis. Data in studies like this are typically complicated. In the study reported on here, individuals have from 1 to 4 questionnaires completed on them and the sample is composed of a mixture of singletons and siblings. In this paper, we describe how we used a genetic hierarchical model to fit our data, together with a twin dataset, in order to estimate genetic factor loadings. Correlation matrices were estimated for our data using a maximum likelihood approach to account for missing data. We describe how we used these results to create a composite score, the heritability of which was estimated to be acceptably high using the twin dataset. This score measures a quantitative dimension onto which molecular genetic data will be mapped. © 2003 Wiley‐Liss, Inc.
HLA‐DRB genotyping in Gilles de la Tourette patients and their parents
Authors: Schoenian Sarah , König Inke , Oertel Wolfgang , Remschmidt Helmut , Ziegler Andreas , Hebebrand Johannes , Bandmann Oliver
Published: April 2003

Gilles de la Tourette syndrome (GTS) is a common neuropsychiatric disorder of unknown cause. There is, however, growing evidence that both autoimmune and genetic factors are involved in the pathogenesis of GTS. In classical autoimmune disorders such as diabetes mellitus or multiple sclerosis, genetic susceptibility is at least in part conferred by human leucocyte antigen (HLA‐) subtypes, in particular by distinct HLA‐DRB alleles. We undertook modern, PCR‐based HLA‐DRB typing in 83 trios (affected index child and both parents) to investigate whether GTS may be associated with a particular HLA‐DRB allele. The extended transmission/disequilibrium test (ETDT) was applied to analyze transmission disequilibrium for any of the 13 alleles detected. The ETDT failed to detect transmission disequilibrium for any allele at the DRB1 locus (overall allele‐wise χ2 (12) = 12.741, Monte Carlo P = 0.4998). Our results imply that the HLA‐DRB locus does not confer genetic susceptibility to GTS. © 2003 Wiley‐Liss, Inc.
Genetics of recurrent early‐onset depression (GenRED): Design and preliminary clinical characteristics of a repository sample for genetic linkage studies
Authors: Levinson Douglas F. , Zubenko George S. , Crowe Raymond R. , DePaulo Raymond J. , Scheftner William S. , Weissman Myrna M. , Holmans Peter , Zubenko Wendy N. , Boutelle Sandra , Murphy‐Eberenz Kathleen , MacKinnon Dean , McInnis Melvin G. , Marta Diana H. , Adams Philip , Sassoon Stephanie , Knowles James A. , Thomas Jo , Chellis Jennifer
Published: April 2003

This is an initial report on a six‐site collaborative project, Genetics of Recurrent Early‐Onset Depression (GenRED). This is a study of a large sample of families with recurrent major depressive disorder (DSM‐IV) beginning by the age 30 in probands or 40 in relatives. Evidence suggests that early onset and recurrence of depressive episodes predict substantially increased risk of depression in first‐degree relatives compared with the general population, suggesting that susceptibility genes might be mapped with this phenotype. The projected sample of 800–1,000 affected sibling pairs (ASPs) and other relatives will be studied using genome scan methods. Biological materials and blinded clinical data will be made available through the NIMH cell repository program. The sample should have good‐to‐excellent power to detect a locus associated with a 24% or greater population‐wide increase in risk to siblings. We describe 838 affected individuals from the first 305 families containing 434 independent ASPs, or 613 ASPs counting all possible pairs. The mean age at the onset was 18.5 years, with a mean of 7.3 episodes and longest episode of 655 days. Almost all subjects had experienced at least 4 weeks of depression with five or more additional symptom criteria. Frequencies of symptoms and psychiatric and medical comorbid are provided. Substance use was more common in males, and panic disorder in females. Within pairs of affected siblings, correlations were significant for age at onset, substance abuse/dependence, panic disorder, obsessive‐compulsive disorder and nicotine initiation and persistence. We replicated previously reported associations among comorbid panic disorder and social phobia, chronicity of depression and suicidal behavior. This suggests comparability of our cases to those in earlier large family studies. This dataset should prove useful for genetic studies of a highly familial form of major depressive disorder. © 2003 Wiley‐Liss, Inc.
N‐methyl‐d‐aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia: TDT and case‐control analyses
Authors: Martucci Livia , Wong Albert H.C. , Trakalo Joseph , Cate‐Carter Tasha , Wong Gregory W.H. , Macciardi Fabio M. , Kennedy James L.
Published: April 2003

The N‐methyl‐d‐aspartate glutamate receptors (NMDAR) act in the CNS as regulators of the release of neurotransmitters such as dopamine, noradrenaline, acetylcholine, and GABA. It has been suggested that a weakened glutamatergic tone increases the risk of sensory overload and of exaggerated responses in the monoaminergic system, which is consistent with the symptomatology of schizophrenia. We studied two silent polymorphisms in GRIN1. GRIN1/1 is a G/C substitution localized on the 5′ untranslated region; GRIN1/10 is an A/G substitution localized in exon 6 of GRIN1. Minor allele frequencies in our sample were calculated to be 0.05 and 0.2 respectively. We genotyped 86 nuclear families and 91 ethnically matched case‐control pairs. Both samples were collected from the Toronto area. We tested the hypothesis that GRIN1 polymorphisms were associated with schizophrenia using the transmission disequilibrium test (TDT) and comparing allele frequencies between cases and controls. The results are as follows: GRIN1/1: χ2 = 2.19, P = 0.14; GRIN1/10: χ2 = 1.5, P = 0.22. For the case‐control sample: GRIN1/1: χ2 = 0.013, P = 0.908; GRIN1/10: χ2 = 0.544, P = 0.461. No significant results were obtained. Haplotype analyses showed a borderline significant result for the 2,1 haplotype (χ2 = 3.86, P‐value = 0.049). An analysis of variance (ANOVA) to evaluate the association between genetic makeup and age at onset was performed, with no significant results: GRIN1/1, F[df = 2] = 0.42, P‐value = 0.659; GRIN1/10, F[df = 2] = 0.16, P‐value = 0.853. We are currently collecting additional samples to increase the power of the analyses. © 2003 Wiley‐Liss, Inc.
Titelbild: Diastereoselective Temporary Silicon‐Tethered Ring‐Closing‐Metathesis Reactions with Prochiral Alcohols: A New Approach to Long‐Range Asymmetric Induction (Angew. Chem. 15/2003)
Authors: Evans P. Andrew , Cui Jian , Buffone Gerald P.
Published: April 2003

Eine steuerbare Stereochemie könnte der Schlüssel zu einem verbesserten Verständnis der konformationellen Aspekte sein, die die Diastereoselektivität bei mittleren Ringen beeinflussen. P. A. Evans et al. präsentieren auf S. 1776 ff. eine Ringschlussmetathese unter temporärer Beteiligung einer Siloxaneinheit als neuartige Strategie für die asymmetrische 1,4‐, 1,5‐ und 1,6‐Induktion.