bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for a major gene underlying bone size variation in the Chinese
Authors: Liu Peng‐Yuan , Qin Yue‐Juan , Recker Robert R. , Deng Hong‐Wen
Published: December 2003

Osteoporosis is a major public health problem defined as a loss of bone strength, of which bone size is an important determinant. In the present study, familial correlation and segregation analyses for the spine and hip bone sizes were performed for the first time in a Chinese sample composed of 393 nuclear families with a total of 1,193 individuals. The results indicate a major gene of codominant inheritance for spine bone size; however, there is no evidence of a major gene influencing hip bone size. Significant familial residual effects are found for both traits, suggesting their polygenic inheritance. Heritability estimates (±SE) for spine and hip bone size were 0.62 (0.13) and 0.59 (0.12), respectively. Sex and age differences in genotype‐specific average bone size were observed. Compared with our previous study on bone mineral density (BMD) in the same population, this study suggests that genetic determination of bone size may be different from that of BMD, and thus studying bone size as one surrogate phenotype for osteoporotic fractures may be necessary. Am. J. Hum. Biol. 16:68–77, 2004. © 2003 Wiley‐Liss, Inc.
Single‐point plasma or urine dextromethorphan method for determining CYP3A activity
Authors: Kuo Benjamin Pei‐Chung , Hu Oliver Yoa‐Pu , Hsiong Cheng‐Huei , Pao Li‐Heng , Chen Ting‐Shien , Hung Chi‐Feng
Published: December 2003

Dextromethorphan is used widely in vivo to phenotype the polymorphically expressed cytochrome P450 (CYP) 2D6. Also dextromethorphan is N‐demethylated in vivo to 3‐methoxymorphinan by human CYP3A4/5. The metabolic ratio (MR) of dextromethorphan/3‐methoxymorphinan in plasma, saliva and urinary were examined as a possible in vivo probe of CYP3A activity. In limited previous studies, 4 h urinary samples were collected for determining the MR. To evaluate the repeatability and validity of previously reported and other potential phenotyping methods, the MR from urine samples (at various intervals), from plasma and from saliva (at varying time points) were determined after repetitive single doses of immediate‐release or repetitive multiple doses of controlled‐release dextromethorphan preparations. For the single‐dose study, each of 12 subjects received 15 mg of immediate‐release dextromethorphan in periods II and I, respectively, with a 1 week washout period. For the multiple dose study, each of 16 subjects received 60 mg controlled release dextromethorphan twice daily for 5 days in periods I and II, respectively, with a 2 week washout period. Dextromethorphan and 3‐methoxymorphinan are assayed by high‐performance liquid chromatography. In the single‐dose study, all of the urine MR revealed good repeatabilities for the periods (paired t‐test). The urine MR at any time interval of 0–6 h, 0–8 h and 0–12 h correlated significantly with the MR from 0–24 h urine (r>0.8, p<0.05). In the multiple‐dose study, all MR revealed good repeatabilities for the two periods (paired t‐test). The plasma MR at any time between 0.5 h and 12 h, the saliva MR at 12 h and the urine MR at any interval between 0–2 h, 0–4 h, 0–6 h, 0–8 h, 0–12 h and 0–24 h could predict the MR from AUCτss. In conclusion, the urine sample as 0–6 h, 0–8 h or 0–12 h in the single immediate‐release dose (15 mg) or in the multiple controlled‐release dose (60 mg) procedure, the saliva sample at 12 h, the urine sample at 0–2 h, 0–4 h, 0–6 h, 0–8 h, 0–12 h, 0–24 h or all plasma‐sampling points 0.5–12 h could be used as the dextromethorphan MR for determining the CYP3A activity. Copyright © 2003 John Wiley & Sons, Ltd.
Rapid determination of enzyme activities of recombinant human cytochromes P450, human liver microsomes and hepatocytes
Authors: Ghosal Anima , Hapangama Neil , Yuan Yuan , Lu Xiaowen , Horne Debra , Patrick James E. , Zbaida Shmuel
Published: December 2003

Cytochrome P450 (CYP) substrates that yield fluorescent metabolites were used for rapid screening of drug metabolism activities of 13 recombinant human cytochromes P450, human liver microsomes and human hepatocytes. Reproducible results were obtained using a fluorescent plate reader (CytoFluor) more expediently than those generated using conventional HPLC methods. Typically, results for 96 samples were obtained with the plate reader in less than 10 min as opposed to 15–35 min/sample required by conventional HPLC. The fluorescent substrates used to measure CYP activities were as follows: 3‐cyano‐7‐ethoxycoumarin (CEC) for CYP1A1, CYP1A2, CYP2C9 and CYP2C19; 7‐ethoxyresorufin (7‐ER) for CYP1A1, CYP1A2 and CYP1B1; 3‐[2‐(N,N‐diethyl‐N‐methylammonium)ethyl]‐7‐methoxy‐4‐methylcoumarin (AMMC) for CYP2D6; dibenzylfluorescein (DBF) for CYP3A4, CYP3A5 and CYP2C8; 7‐methoxy‐4‐trifluoromethylcoumarin (7‐MFC) for CYP2E1, CYP2B6 and CYP2C18; and coumarin for CYP2A6. The chemical inhibition and correlation data indicated that the following substrates can be used as specific functional probes for individual cytochrome P450 present in human liver microsomes: coumarin for CYP2A6 (r=0.82), AMMC for CYP2D6 (r=0.83) and DBF for CYP3A4 (r=0.92). The fluorescent plate reader was found to be useful for the rapid assessment of CYP activities (positive control) in both intact cells and subcellular fractions. Copyright © 2003 John Wiley & Sons, Ltd.
Dose‐dependent pharmacokinetics of 1‐(2‐Deoxy‐β‐D‐ ribofuranosyl)‐2,4‐difluoro‐5‐iodobenzene: A potential mimic of 5‐iodo‐2′‐deoxyuridine
Authors: Khalili Panteha , Naimi Ebrahim , Sun Wei Yan , Knaus Edward E. , Wiebe Leonard I.
Published: December 2003

The dose‐range pharmacokinetics of l‐(2‐deoxy‐β‐D‐ribofuranosyl)‐2,4‐difluoro‐5‐iodobenzene (5‐IDFPdR), a C‐aryl nucleoside mimic of IUdR, were studied in male Sprague‐Dawley rats following single intravenous (i.v.) and oral doses. After i.v. administration, the blood clearance decreased from ∼32 ml/min/kg at a dose of 15 mg/kg, to ∼19 ml/min/kg when dosed at 54 mg/kg, and the elimination half‐life increased from 8.4 min to 21.5 min, for the respective doses. While the dose‐normalized area under the concentration‐time curve (AUCnorm) remained practically unchanged (0.132 kg min ml−1) upon increasing the i.v. dose from 5 to 15 mg/kg, it increased by about 44% (∼0.19 kg min ml−1) when the i.v. dose was increased from 15 to 54 mg/kg. Similarly, there was a dose‐dependent increase in AUCnorm with increasing oral doses: AUCnorm increased by 49% as the oral dose increased from 20 to 40 mg/kg, and further by 55% as the oral dose was increased from 40 mg/kg to 54 mg/kg. For the respective oral doses, the elimination half‐life increased from 24.5 min to 176 min, while blood clearance was reduced from ∼37 ml/min/kg to ∼17 ml/min/kg. The urinary recoveries of unchanged 5‐IDFPdR and its glucuronides (as percent of the dose) were somewhat increased at higher doses. This increase was more pronounced following the highest oral dose. The total biliary recovery of 5‐IDFPdR (as percent of the dose) was, however, decreased with increasing doses.

The overall kinetic profile of 5‐IDFPdR based on these data is suggestive of dose‐dependent pharmacokinetics. Decreased elimination of 5‐IDFPdR with increasing dose, as supported by longer elimination half‐lives at higher doses, is one likely mechanism contributing to the dose‐dependent behaviour of this compound. Saturable non‐renal metabolism might explain the reduced total body clearance of 5‐IDFPdR at higher doses, despite the unchanged or increased urinary clearance.

For drugs exhibiting nonlinear kinetics, the dosage regimens may need to be carefully designed to avoid potential unpredictable toxicity and/or lack of pharmacological response associated with the disproportional changes in steady state drug concentrations on changing dose. Manifestation in the rat of nonlinear kinetics at doses of 5‐IDFPdR, which may be of therapeutic relevance, warrants extended dose‐range evaluations of this compound in future preclinical and clinical studies, to establish safe and efficacious dosage regimens. Copyright © 2003 John Wiley & Sons, Ltd.
Preclinical evaluation of the pharmacokinetics, brain uptake and metabolism of E121, an antiepileptic enaminone ester, in rats
Authors: Khurana Manoj , Salama Noha N. , Scott Kenneth R. , Nemieboka Noble N. , Bauer Kenneth S. , Eddington Natalie D.
Published: December 2003

The present study describes the brain uptake, pharmacokinetics and metabolism of an anticonvulsant enaminone ester E121, which belongs to a new and active series of compounds with potential in vivo anticonvulsant activity in rodent models, in rats. A single dose of E121 was administered i.p. to male Sprague Dawley rats at 10 mg E121/kg body weight. Cohorts of animals (n=3) were killed at varying times over 0–24 h to collect plasma and brain samples. Urinary excretion of E121 was studied in a separate group of five rats at the same dose. A validated HPLC method was used to quantify E121 and its metabolites in plasma, brain and urine. LC‐MS/MS was used to characterize the metabolites. The plasma and brain Cmax of 11.0±3.0 mg/l and 10.4±1.4 mg/kg, respectively, were observed for E121 at 15 min post dose and they declined in a mono‐exponential fashion. The plasma Cl/F and t1/2 were 0.57 l/h/kg and 0.75 h, respectively. The brain uptake ratio of E121 was 0.9. Mass spectral analysis of urine showed two major metabolites (m/z 280) and one minor metabolite (m/z 236) that were consistent with initial hydrolysis of the compound to the acid followed by further decarboxylation and appears to be the major route of elimination of E121. The rapid and moderate brain uptake of E121 correlates well with its potential anticonvulsant activity (ED50 3.0 mg/kg p.o. in rats). The brain uptake, pharmacokinetic and metabolic profile of E121 supports the need to further evaluate this compound for its potential as an antiepileptic. Copyright © 2003 John Wiley & Sons, Ltd.
Subacute toxicities and toxicokinetics of DA‐8159, a new phosphodiesterase type V inhibitor, after single and 4‐Week repeated oral administration in rats
Authors: Shim Hyun J. , Kim Yu C. , Jang Ji M. , Park Kyung J. , Kim Dong H. , Kang Kyung K. , Ahn Byoung O. , Kwon Jong W. , Kim Won B. , Lee Myung G.
Published: December 2003

The subacute toxicities (10 male and 10 female rats at each dose) and the toxicokinetics (5 male rats at each dose) of DA‐8159, a new phosphodiesterase type V (PDE V) inhibitor, were evaluated after single (at day 1) and 4‐week (at day 28) oral administration of the drug at doses of 0 (to serve as a control), 20, 80 and 320 mg/kg/day to rats. DA‐8159 showed a decrease in body weight gain, clinical signs such as chromodacryohaemorrhoea, ptosis and decreased locomotor activity, an increase in WBC number, changes in parameters related to RBCs, an increase in organ weight of the liver, spleen and lung, and finally microscopic lesions such as cholangiofibrosis and inflammatory cell infiltration in the liver, alveolar macrophage accumulation, and inflammatory cell infiltration in the lung, an increase in bone marrow density and extrahaematopoiesis in the spleen. These changes were observed mainly at a dose of 80 mg/kg or above. While some changes were observed at a dose of 20 mg/kg, these changes were non‐specific and transient since this were also observed in control rats. In addition, there was no dose‐dependency in these changes. Based on these results, the NOAEL (No‐Observed‐Adverse‐Effect‐Level) for DA‐8159 in rats was estimated to be 20 mg/kg/day, and the target organs were determined to be liver, bone marrow, spleen, lung and blood cells. After a 4‐week oral administration, accumulation of DA‐8159 was evident at a dose of 20 mg/kg/day, but was not considerable at toxic doses (80 and 320 mg/kg/day). After a single oral administration, the dose‐normalized area under the plasma concentration–time curve from time zero to the last measured time, 24 h, in plasma (AUC0−24 h) was significantly different among the three doses (the AUC0–24 h based on 20 mg/kg/day was 2.33, 7.00 and 4.19 μg h/ml for 20, 80 and 320 mg/kg/day, respectively). Similar results were also obtained from DA‐8164, a metabolite of DA‐8159; the AUC0–24 h of DA‐8164 after dose‐normalized to 20 mg/kg/day of DA‐8159 were 2.74, 5.00 and 1.68 μg h/ml, respectively. Copyright © 2003 John Wiley & Sons, Ltd.
Self‐framing of risky choice
Authors: Wang X. T.
Published: December 2003

Previous research on framing effects has largely focused on how choice information framed by external sources influences the response of a decision maker. This research examined how decision makers framed choice options and how the hedonic tone of self‐framing influenced their risk preference. By using pie charts and a complementary sentence‐completion task in Experiment 1, participants were able to interpret and frame the expected choice outcomes themselves before making a choice between a sure option and a gamble in either a life–death or a monetary problem. Each of these self‐frames (phrases) was then rated by a group of independent judges in terms of its hedonic tone. The hedonic tone of self‐frames was mostly positive and was more positive in the life–death than the monetary context, suggesting a motivational function of self‐framing. However, positive outcomes were still more likely to be framed positively than negative outcomes. In Experiment 2, choice outcomes were depicted with a whole‐pie chart instead of a pie slice in order to emphasize positive and negative outcomes equally. The results showed that the hedonic tone of self‐framing was still largely positive and more positive in the life domain than the monetary domain. However, compared to Experiment 1, the risk preference in the life–death domain was reversed, showing an outcome salience effect: when the pie‐slice chart emphasized only survival outcomes, participants were more risk taking under positive hedonic frames whereas when the whole‐pie chart depicted both survival and mortality outcomes, they became risk averse under positive frames. In sum, self‐framing reflected a positive bias in encoding risk information and affected the risk preference of the decision maker. Like the tone of voice used in communication, the hedonic tone of self‐framing, either positive or negative, can affect risk perception of a choice problem. Copyright © 2003 John Wiley & Sons, Ltd.
Revocable commitments to public goods provision under the real‐time protocol of play
Authors: Goren Harel , Rapoport Amnon , Kurzban Robert
Published: December 2003

Using the real‐time protocol of play—a relatively new experimental mechanism in which the order of play and timing of decisions are determinedendogenously—we investigate voluntary contributions to the provision of pure public goods. We consider the case where the good is binary, players are asymmetric, communication is prohibited, and all‐or‐none contributions to the public good can be withdrawn at any time during the round of play. Our results: (1) support an equilibrium in which contributors maximize the sum of their own payoffs; (2) show considerably higher levels of contribution than under the more commonly used simultaneous protocol of play; and (3) exhibit no decrease in level of contribution across multiple iterations of the stage game. On comparing our results to those of Goren et al. (2003), we conclude that modifying the mechanism so that contributions once made cannot be revoked yields significantly higher levels of contribution over the course of the game. Copyright © 2003 John Wiley & Sons, Ltd.
Intuitive evaluation of likelihood judgment producers: evidence for a confidence heuristic
Authors: Price Paul C. , Stone Eric R.
Published: December 2003

This research tests the hypothesis of Yates et al. (1996) that people prefer judgment producers who make extreme confidence judgments. In each of three experiments, college students evaluated two fictional financial advisors who judged the likelihood that each of several stocks would increase in value. One of the advisors (the moderate advisor) was reasonably well calibrated and the other (the extreme advisor) was overconfident. In all three experiments, participants tended to prefer the extreme advisor. Experiments 2 and 3 showed that the advisors' confidence influenced participants' perception of their knowledge, and Experiment 3 showed that it influenced their perception of the number of categorically correct judgments they made. Both of these variables were, in turn, related to participants' preferences. Experiment 3 also suggested that need for cognition and right‐wing authoritarianism are positively related to preference for the extreme advisor. A quantitative model is presented, which captures the basic pattern of results. This model includes the assumption that people use a confidence heuristic; they assume that a more confident advisor makes more categorically correct judgments and is more knowledgeable. Copyright © 2004 John Wiley & Sons, Ltd.
Impact of mood, framing, and need for cognition on decision makers' recall and confidence
Authors: Kuvaas Bård , Kaufmann Geir
Published: December 2003

This study examined the impact of mood, information framing, and need for cognition on participants' amount of recall and level of confidence in a simulated business‐decision‐making setting. No main effect was obtained for either positive or negative mood. However, in support of the congruity–incongruity hypothesis, participants who received mood‐congruent framing information (positive mood/positive framing and negative mood/negative framing) showed significantly better recall and were significantly less overconfident than those who received mood‐incongruent framing information (positive mood/negative framing and negative mood/positive framing). Yet, congruity–incongruity effects were moderated by decision makers' need for cognition and were obtained only among participants' with a lower cognitive processing requirement. Copyright © 2004 John Wiley & Sons, Ltd.
Biology of insulin‐like growth factors in development
Authors: Dupont Joëlle , Holzenberger Martin
Published: December 2003

Insulin‐like growth factors (IGFs) provide essential signals for the control of embryonic and postnatal development in vertebrate species. In mammals, IGFs act through and are regulated by a system of receptors, binding proteins, and related proteases. In each of the many tissues dependent on this family of growth factors, this system generates a complex interaction specific to the tissue concerned. Studies carried out over the last decade, mostly with transgenic and gene knockout mouse models, have demonstrated considerable variety in the cell type–specific and developmental stage–specific functions of IGF signals. Brain, muscle, bone, cartilage, pancreas, ovary, skin, and fat tissue have been identified as major in vivo targets for IGFs. Concentrating on several of these organ systems, we review here phenotypic analyses of mice with genetically modified IGF systems. Much progress has also been made in understanding the specific intracellular signaling cascades initiated by the binding of circulating IGFs to their cognate receptor. We also summarize the most relevant aspects of this research. Considerable efforts are currently focused on deciphering the functional specificities of intracellular pathways, particularly the molecular mechanisms by which cells distinguish growth‐stimulating insulin‐like signals from metabolic insulin signals. Finally, there is a growing body of evidence implicating IGF signaling in lifespan control, and it has recently been shown that this function has been conserved throughout evolution. Very rapid progress in this domain seems to indicate that longevity may be subject to IGF‐dependent neuroendocrine regulation and that certain periods of the life cycle may be particularly important in the determination of individual lifespan. Birth Defects Research (Part C) 69:257–271, 2003. © 2003 Wiley‐Liss, Inc.
TGF‐β signaling in human skeletal and patterning disorders
Authors: Serra Rosa , Chang Chenbei
Published: December 2003

Members of the transforming growth factor beta (TGF‐β) family of multifunctional peptides are involved in almost every aspect of development. Model systems, ranging from genetically tractable invertebrates to genetically engineered mice, have been used to determine the mechanisms of TGF‐β signaling in normal development and in pathological situations. Furthermore, mutations in genes for the ligands, receptors, extracellular modulators, and intracellular signaling molecules have been associated with several human disorders. The most common are those associated with the development and maintenance of the skeletal system and axial patterning. This review focuses on the mechanisms of TGF‐β signaling with special emphasis on the molecules involved in human disorders of patterning and skeletal development. Birth Defects Research (Part C) 69:333–351, 2003. © 2003 Wiley‐Liss, Inc.
From the cradle to the clinic: VEGF in developmental, physiological, and pathological angiogenesis
Authors: Harry Lorraine E. , Paleolog Ewa M.
Published: December 2003

Formation of new blood vessels, which is fundamental in embryonic development, occurs through a combination of angiogenesis and vasculogenesis. Angiogenesis also plays a vital role postnatally, especially in reparative processes such as wound and fracture healing. Some of these events, especially in fracture healing, recapitulate processes observed in developmental angiogenesis. However, dysregulated angiogenesis is well documented to underlie a number of pathological disorders, including rheumatoid arthritis (RA). The vascular endothelial growth factor (VEGF)/VEGF receptor system is the best characterized regulator of angiogenesis. VEGF is expressed in a range of cells in response to soluble mediators (such as cytokines and growth factors), cell‐bound stimuli (such as CD40 ligand), and environmental factors (such as hypoxia). As a consequence, this molecule is vital in the modulation of physiological and pathological angiogenesis. This review will focus in particular on the role played by VEGF in embryogenesis and skeletal growth, in fracture healing (in which increased angiogenesis is likely to be beneficial in promoting union), and in RA (in which excessive angiogenesis is thought to play a significant role in disease pathogenesis). In the not‐too‐distant future, targeting VEGF may prove to be of benefit in the treatment of diseases associated with excessive or aberrant angiogenesis, such as malignancies and RA. Birth Defects Research (Part C) 69:363–374, 2003. © 2003 Wiley‐Liss, Inc.
Roles of FGF receptors in mammalian development and congenital diseases
Authors: Coumoul Xavier , Deng Chu‐Xia
Published: December 2003

Four fibroblast growth factor receptors (FGFR1–4) constitute a family of transmembrane tyrosine kinases that serve as high affinity receptors for at least 22 FGF ligands. Gene targeting in mice has yielded valuable insights into the functions of this important gene family in multiple biological processes. These include mesoderm induction and patterning; cell growth, migration, and differentiation; organ formation and maintenance; neuronal differentiation and survival; wound healing; and malignant transformation. Furthermore, discoveries that mutations in three of the four receptors result in more than a dozen human congenital diseases highlight the importance of these genes in skeletal development. In this review, we will discuss recent progress on the roles of FGF receptors in mammalian development and congenital diseases, with an emphasis on signal transduction pathways. Birth Defects Research (Part C) 69:286–304, 2003. Published 2003 Wiley‐Liss, Inc.
Wnts and wing: Wnt signaling in vertebrate limb development and musculoskeletal morphogenesis
Authors: Yang Yingzi
Published: December 2003

In the past twenty years, secreted signaling molecules of the Wnt family have been found to play a central role in controlling embryonic development from hydra to human. In the developing vertebrate limb, Wnt signaling is required for limb bud initiation, early limb patterning (which is governed by several well‐characterized signaling centers), and, finally, late limb morphogenesis events. Wnt ligands are unique, in that they can activate several different receptor‐mediated signal transduction pathways. The most extensively studied Wnt pathway is the canonical Wnt pathway, which controls gene expression by stabilizing β‐catenin in regulating a diverse array of biological processes. Recently, more attention has been given to the noncanonical Wnt pathway, which is β‐catenin–independent. The noncanonical Wnt pathway signals through activating Ca2+ flux, JNK activation, and both small and heterotrimeric G proteins, to induce changes in gene expression, cell adhesion, migration, and polarity. Abnormal Wnt signaling leads to developmental defects and human diseases affecting either tissue development or homeostasis. Further understanding of the biological function and signaling mechanism of Wnt signaling is essential for the development of novel preventive and therapeutic approaches of human diseases. This review provides a critical perspective on how Wnt signaling regulates different developmental processes. As Wnt signaling in tumor formation has been reviewed extensively elsewhere, this part is not included in the review of the clinical significance of Wnt signaling. Birth Defects Research (Part C) 69:305–317, 2003. Published 2003 Wiley‐Liss, Inc.
Nodal signaling and vertebrate germ layer formation
Authors: Weng Wei , Stemple Derek L.
Published: December 2003

The understanding of germ layer formation in vertebrates began with classical experimental embryology. Early in the 20th century, Spemann and Mangold (1924) identified a region of the early embryo capable of inducing an entire embryonic axis. Termed the dorsal organizer, the tissue and the activity have been shown to exist in all vertebrates examined. In mice, for example, the activity resides in a region of the gastrula embryo known as the node. Experiments by the Dutch embryologist Nieuwkoop (1967a, 1967b, 1973, 1977) showed that a signal derived from the vegetal half of the amphibian embryo is responsible for the formation of mesoderm. Nieuwkoop's results allowed the development of in vitro assays that led, in the late 1980s and early 1990s, to the identification of growth factors essential for germ layer formation. Through more recent genetic investigations in mice and zebrafish, we now know that one class of secreted growth factor, called Nodal because of its localized expression in the mouse node, is essential for formation of mesoderm and endoderm and for the morphological rearrangements that occur during gastrulation. Birth Defects Research (Part C) 69:325–332, 2003. © 2003 Wiley‐Liss, Inc.
PTHrP, PTH, and the PTH/PTHrP receptor in endochondral bone development
Authors: Schipani Ernestina , Provot Sylvain
Published: December 2003

Endochondral bone development is a fascinating story of proliferation, maturation, and death. An understanding of this process at the molecular level is emerging. In particular, significant advances have been made in understanding the role of parathyroid‐hormone‐related peptide (PTHrP), parathyroid hormone (PTH), and the PTH/PTHrP receptor in endochondral bone development. Mutations of the PTH/PTHrP receptor have been identified in Jansen metaphyseal chondrodysplasia, Blomstrand's lethal chondrodysplasia, and enchondromatosis. Furthermore, genetic manipulations of the PTHrP, PTH, and the PTH/PTHrP receptor genes, respectively, have demonstrated the critical role of these proteins in regulating both the switch between proliferation and differentiation of chondrocytes, and their replacement by bone cells. A future area of investigation will be the identification of downstream effectors of PTH, PTHrP, and PTH/PTHrP receptor activities. Furthermore, it will be of critical importance to study how these proteins cooperate and integrate with other molecules that are essential for growth plate development. Birth Defects Research (Part C) 69:352–362, 2003. © 2003 Wiley‐Liss, Inc.
Planar cell polarity genes and neural tube closure
Authors: Ueno Naoto , Greene Nicholas D.E.
Published: December 2003

Closure of the neural tube is essential for normal development of the brain and spinal cord. Failure of closure results in neural tube defects (NTDs), common and clinically severe congenital malformations whose molecular mechanisms remain poorly understood. On the other hand, it is increasingly well established that common molecular mechanisms are employed to regulate morphogenesis of multicellular organisms. For example, signaling triggered by polypeptide growth factors is highly conserved among species and utilized in multiple developmental processes. Recent studies have revealed that the Drosophila planar cell polarity (PCP) pathway, which directs position and direction of wing hairs on the surface of the fly wing, is well conserved, and orthologs of several genes encoding components of the pathway are also found in vertebrates. Interestingly, in vertebrates, this signaling pathway appears to be co‐opted to regulate “convergent extension” cell movements during gastrulation. Disruption of vertebrate PCP genes in Xenopus laevis or zebrafish causes severe gastrulation defects or the shortening of the trunk, as well as mediolateral expansion of somites. In Xenopus, in which the neural tube closes by elevation and fusion of neural folds, inhibition of convergent extension can also prevent neural tube closure causing a “spina bifida‐like” appearance. Furthermore, several of the genes involved in the PCP pathway have recently been shown to be required for neural tube closure in the mouse, since mutation of these genes causes NTDs. Therefore, understanding the mechanisms underlying the establishment of cell polarity in Drosophila may provide important clues to the molecular basis of NTDs. Birth Defects Research (Part C) 69:318–324, 2003. © 2003 Wiley‐Liss, Inc.
Biology of platelet‐derived growth factors in development
Authors: Betsholtz Christer
Published: December 2003

Platelet‐derived growth factor (PDGF) was one of the first growth factors to be characterized, and the PDGF family of ligand and receptors has remained an archetype system for studies of the mechanisms of action of growth factors and receptor tyrosine kinases for more than two decades. The small size of the family has also facilitated genetic studies and, in particular, manipulations of the mouse PDGF and PDGF receptor genes have given important insights into the role of this family during mammalian development. These studies have shown that discrete populations of mesenchymal and neuroectodermal progenitor cells depend on PDGF signaling for their growth and distribution within developing organs. Other studies suggest that the same, or similar, cells may be targeted by exaggerated PDGF signaling in a number of pathological processes, including different types of cancer. The present review summarizes current views on the roles of PDGFs in developmental processes, and discusses the critical importance of the amount, spatial distribution, and bioavailability of the PDGF proteins for acquisition of the correct number and location of target cells. Birth Defects Research (Part C) 69:272–285, 2003. © 2003 Wiley‐Liss, Inc.
Ventral striatopallidal oxytocin and vasopressin V1a receptors in the monogamous prairie vole (Microtus ochrogaster)
Authors: Lim Miranda M. , Murphy Anne Z. , Young Larry J.
Published: December 2003

Oxytocin receptors (OTR) and vasopressin V1a receptors (V1aR) in the ventral forebrain play critical roles in the formation of pair bonds in the monogamous prairie vole. Previous reports have been inconsistent in the identification of the specific brain regions in the ventral forebrain that express these receptors. To delineate more clearly the neuroanatomical boundaries of the OTR and V1aR fields in this species, we compared OTR and V1aR binding in adjacent brain sections and also with markers that delineate neuroanatomical boundaries in the ventral forebrain. OTR binding displayed an overlapping distribution with substance P mRNA and preproenkephalin mRNA, both markers for the shell and core of the nucleus accumbens. V1aR binding was nonoverlapping with each of these markers but colocalized with iron accumulation as shown by Perls' iron stain as well as leucine‐enkephalin immunoreactivity, both markers for the ventral pallidum. OTR and V1aR mRNA were also restricted within the nucleus accumbens and ventral pallidum, respectively. Furthermore, destruction of ventral striatal dopaminergic terminals with 6‐hydroxydopamine infusions into the nucleus accumbens did not alter OTR binding. Immunocytochemical analysis of oxytocin and vasopressin in the ventral forebrain demonstrated the presence of oxytocin‐immunoreactive fibers in the nucleus accumbens and vasopressin‐immunoreactive fibers in the ventral pallidum, with males showing a greater density of vasopressin fibers than females, but there was no such sex difference in the oxytocin system. Based on these results, we discuss potential neural mechanisms by which receptors in these brain regions mediate pair bond formation in this monogamous species. J. Comp. Neurol. 468:555–570, 2004. © 2003 Wiley‐Liss, Inc.
Morphology and molecular organization of the adult neuromuscular junction of Drosophila
Authors: Rivlin Patricia K. , St. Clair Ryan M. , Vilinsky Ilya , Deitcher David L.
Published: December 2003

While the larval neuromuscular junction (NMJ) of Drosophila has emerged as a model system to study synaptic function and development, little attention has been given to the study of the adult NMJ. Here we report an immunocytochemical and morphological characterization of an adult NMJ preparation of the prothorax. All muscles examined were innervated by small, uniform type II terminals (0.5–1.5 μm), a subset of which contained octopamine. Terminals classified as type I varied in their morphology across different muscles, ranging from strings or clusters of boutons (0.8–5.5 μm) to an elongate terminal (80–100 μm long) with few branches and contiguous swellings (3–15 μm) along its length. Analysis of the molecular composition of the NMJs during the first 5 days after eclosion revealed four major findings: 1) type I boutons increase in size during early adulthood; 2) Fasciclin II‐immunoreactivity is not detectable at type I terminals, while DLG‐immunoreactivity is observed at the synapse; 3) a Shaker‐GFP fusion protein that localizes to all type I boutons in the larva is differentially localized at adult prothoracic NMJs; and 4) while all type I terminals contain glutamate, the glutamate receptor subunits, DGluRIIA and DGluRIIB, are expressed and clustered in only a subset of muscles. These findings suggest that maturation of the adult NMJ occurs during early adulthood and that muscle‐specific properties may play a role in organizing synaptic components in the adult. Furthermore, these results demonstrate that there are major differences in the molecular organization of the adult and larval NMJs. J. Comp. Neurol. 468:596–613, 2004. © 2003 Wiley‐Liss, Inc.
Types of bipolar cells in the mouse retina
Authors: Ghosh Krishna K. , Bujan Sascha , Haverkamp Silke , Feigenspan Andreas , Wässle Heinz
Published: December 2003

We studied the morphology of bipolar cells in fixed vertical tissue sections (slices) of the mouse retina by injecting the cells with Lucifer Yellow and Neurobiotin. Nine different cone bipolar cell types and one rod bipolar cell type were distinguished. The major criteria for classifying the cells were the branching pattern and stratification level of their axon terminals in the inner plexiform layer (IPL). To assess this, the IPL was subdivided into five strata of equal width. The slices were immunostained for calretinin, which labels three horizontal bands serving as a standard measure for the precise localization of the axon terminals. Immunostaining the retina with antibodies against the G‐protein Gγ13, a marker for ON‐bipolar cells, made it possible to separate OFF‐ and ON‐bipolar cells. At least two OFF‐cone bipolar cells (Types 1 and 2) were immunolabeled with antibodies against the neurokinin 3 receptors (NK3R). A further OFF‐ and an ON‐cone bipolar cell (Types 3 and 5) were immunostained with antibodies against the calcium‐binding protein CaB5. The bipolar cell types described here were compared with previous schemes of rat and primate bipolar cells. Homologous types between the three species are discussed. J. Comp. Neurol. 469:70–82, 2004. © 2003 Wiley‐Liss, Inc.
A design of reflection‐type polarization control device using ferroelectric liquid crystals
Authors: Ogawa Noriyuki , Machida Kosuke , Okada Yusuke , Nakagami Takakiyo
Published: December 2003

For a planar polarization control optical switch proposed by the authors for optical communication networks, a reflection‐type liquid crystal polarization control device (PCD) that can emit the incident wave in the same direction as the incident after totally reflected on the back side and can accurately switch the polarization direction of the optical wave by 90° in response to an applied voltage is needed. The authors have previously derived and reported a design theory for accurate switching of the polarization direction for an obliquely incident ferroelectric liquid crystal polarization control device (FLC‐PCD) in which the light wave is obliquely incident upon the device surface at an arbitrary angle and transmits to the back side. In the present paper, based on this theory, the polarization control characteristics are theoretically analyzed by means of the Jones matrix with respect to the reflection‐type FLC‐PCD, in which the incident wave is totally reflected at the back side of the device and is returned to the incident side. The condition for accurate switching of the polarization direction of the output wave by 90° is derived. Based on this condition, a method for derivation of the optimum design values of the liquid crystal layer thickness and liquid crystal optical axis angle is presented. The polarization control characteristics of the device fabricated for trial are measured, demonstrating the validity of the present design method. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 87(1): 43–53, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10038
Monolithic integration of lasers and passive elements using selective QW disordering by rapid thermal annealing with SiO2 caps of different thicknesses
Authors: Shimada Naoyuki , Fukumoto Yutaka , Uemukai Masahiro , Suhara Toshiaki , Nishihara Hiroshi , Larsson Anders
Published: December 2003

We have investigated the use of rapid thermal annealing of InGaAs strained quantum well structures through SiO2 caps with two different thicknesses to selectively disorder the quantum well, as a way to implement the monolithic integration of low‐loss passive devices such as optical waveguides with quantum well lasers. In these investigations, we first selectively disordered a quantum well by depositing a 300‐nm SiO2 cap in one region and a 30‐nm SiO2 cap in another region, followed by rapid thermal annealing. We then fabricated lasers in the two regions, and found that the oscillation wavelengths of lasers fabricated in the region with the 300‐nm SiO2 cap differed from the oscillation wavelengths of those in the region with the 30‐nm SiO2 cap. By using this technique to integrate passive waveguides with a Fabry‐Perot laser, we were able to evaluate the optical loss in the passive waveguides. We found that we could reduce the loss by a large amount, from 40 cm−1 for the case of no disordering to only 3 cm−1. We also fabricated a distributed Bragg reflector laser using selective disordering of the quantum well in the grating region, and succeeded in obtaining a remarkable improvement in the laser characteristics compared to those of an undisordered laser. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 87(1): 34–42, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10039
Fabrication and electrical properties of ferroelectric‐gate FETS with epitaxial gate structures
Authors: Migita Shinji , Sakamaki Kazuo , Xiong Si Bei , Ota Hiroyuki , Tarui Yasuo , Sakai Shigeki
Published: December 2003

We have fabricated ferroelectric‐gate FETs with an epitaxially grown insulator‐ferroelectric gate structure. Our prior success in growing epitaxial layers of SrBi2Ta2O9 with the c‐axis oriented at a 45° angle to the normal of the substrate plane enabled us to grow diode structures whose C–V characteristics exhibited memory effects arising from the ferroelectric's remanent polarization. We confirmed that data encoded as capacitance changes arising from the layer's ferroelectricity could be preserved for periods of over 10 days. We then grew FET structures, and examined their Id–Vg characteristics. Our examination revealed a five‐order‐of‐magnitude value for the on/off drain current ratio, as well as memory characteristics. We confirmed that data encoded as drain current changes based on ferroelectricity could be stored for over 2 hours. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 87(1): 24–33, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10043
Low‐voltage, 208 contiguous subfield addressing of AC PDPs by using erase address technique with space charge priming
Authors: Ishii Makoto , Shiga Tomokazu , Igarashi Kiyoshi , Mikoshiba Shigeo
Published: December 2003

Both low‐voltage addressing and high‐speed addressing are achieved in AC plasma display panels (PDPs) by using the priming effect due to space charges and the wall charges generated by erase addressing. When we set the interval between the priming pulse and the scan pulse to 1 µs and the widths of the scan pulse and the data pulse to 0.33 µs, the lowest address voltage decreased to 75 V. Furthermore, we developed a drive technique capable of a 208 contiguous subfield display for VGA panels. Thus, high‐image‐quality, low‐cost plasma displays could be implemented. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 87(1): 16–23, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10106
Formation of β‐FeSi2 with electron beam evaporation
Authors: Misaki Takashi , Ohsawa Jun
Published: December 2003

In the formation of β‐FeSi2 by means of FeSi2 alloy evaporation, there are problems that the vapor pressure of Fe and Si is low and that there is a vapor pressure difference of close to one order of magnitude between Fe and Si. In this paper, by using electron beam (EB) evaporation equipment, these problems are resolved and the success of β‐FeSi2 formation is reported. First, the Fe and Si composition ratio of the EB evaporated film of FeSi2 alloy is analyzed by XPS. It is confirmed that the ratio is almost 1 to 2. Next, a sample with FeSi2 alloy EB evaporated on a Si substrate is annealed within a nitrogen environment by using an infrared heating furnace (at 700 to 900 °C) so that β‐FeSi2 is synthesized. Also, it is found that the β‐FeSi2 layer is made thicker and the optical absorption characteristic is improved by vapor‐depositing an Fe layer between the FeSi2 alloy layer and a Si substrate. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 87(1): 9–15, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10118
Numerical analysis of a modified rooftop mirror using mode interference
Authors: Ando Takashi , Fukuda Daisuke , Takeuchi Masanori , Yamauchi Junji , Nakano Hisamatsu
Published: December 2003

In this paper, an improved rooftop mirror is proposed and its characteristics are evaluated by numerical analysis. First, it is shown by FDTD analysis that it is not easy to obtain a high reflection characteristic with fundamental mode incidence in the conventional structure. Next, the reflection characteristics are analyzed for an improved structure in which the incident single‐mode waveguide is connected to a multimode interference waveguide inside the rooftop. In such a process, comparison with the results obtained by FDTD analysis demonstrates that the simple guided mode propagation method neglecting the radiation mode is effective for design of a mode interference section. A reflectivity of 96% is attained by introduction of the mode interference section for both fundamental TE and TM mode incidence. Further, the wavelength characteristics of the reflection coefficient are studied. The effects of misalignment of the waveguide axis and shift of the apex angle of the rooftop on the reflection characteristics are discussed. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 87(1): 1–8, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10172
A statistical language model for conventional speech reflecting the previous utterance of the other participant
Authors: Yamamoto Hirofumi , Tanigaki Koichi , Sagisaka Yoshinori
Published: December 2003

This paper proposes the construction of a language model for speech recognition in speech translation. The proposed language model is intended to improve speech recognition performance by taking account of the previous utterance content of the counterpart speaker. The previous utterance content of the counterpart speaker is represented by the intermediate language which is generally used by C‐star (Spoken Language Translation Research Group). The proposed model is based on a language model that is dependent on the intermediate language representation. An experiment concerning the conversation of hotel reservations shows that the rate of incorrect word recognition is reduced by approximately 5.4% (from 14.7% to 13.9%), and the usefulness of the proposed model is demonstrated. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 87(1): 54–62, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10211
Task scheduling method considered the communication time by critical path: Application to various kinds of network topology
Authors: Iijima Nobukazu , Suwa Kazunori , Sone Mototaka
Published: December 2003

In parallel processing in a multiprocessor system, it is necessary to partition the user program and data to be distributed to the processors, that is, to apply scheduling. It is difficult to realize the scheduling under arbitrary conditions without any restriction of precedence constraints, number of employed processors, the multiprocessor configuration, and the communication time, by an algorithm with optimized polynomial time. Thus, the application of a heuristic algorithm is considered. This paper is based on the critical path (CP) method, and proposes a scheduling method which can be used in multiprocessor systems with various topologies, including perfect and imperfect connections. The proposed method resembles the existing method in that the task is assigned, but has the feature that the assignment is corrected and optimized from the viewpoint of the communication time. The allocation of processors and adequate modification of hopping are also considered. The effectiveness of the proposed method is evaluated through comparison to existing methods using the same task graph. In order to evaluate its effectiveness when applied to a large‐scale system, the method was implemented on a real system (a system with 32 DSP), and an analysis program for an electrical power system was run. The proposed method was demonstrated to be uniformly useful for various topologies, and exhibits sufficient performance in practice. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 87(1): 63–75, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.10212