bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple levels of transcriptional and post-transcriptional regulation are required to define the domain of Hoxb4 expression
Authors: Brend Tim , Gilthorpe Jonathan , Summerbell Dennis , Rigby Peter W. J.
Published: May 2003

Hox genes are key determinants of anteroposterior patterning of animal embryos, and spatially restricted expression of these genes is crucial to this function. In this study, we demonstrate that expression of Hoxb4 in the paraxial mesoderm of the mouse embryo is transcriptionally regulated in several distinct phases, and that multiple regulatory elements interact to maintain the complete expression domain throughout embryonic development. An enhancer located within the intron of the gene (region C) is sufficient for appropriate temporal activation of expression and the establishment of the correct anterior boundary in the paraxial mesoderm (somite 6/7). However, the Hoxb4 promoter is required to maintain this expression beyond 8.5 dpc. In addition, sequences within the 3′ untranslated region (region B)are necessary specifically to maintain expression in somite 7 from 9.0 dpc onwards. Neither the promoter nor region B can direct somitic expression independently, indicating that the interaction of regulatory elements is crucial for the maintenance of the paraxial mesoderm domain of Hoxb4expression. We further report that the domain of Hoxb4 expression is restricted by regulating transcript stability in the paraxial mesoderm and by selective translation and/or degradation of protein in the neural tube. Moreover, the absence of Hoxb4 3′-untranslated sequences from transgene transcripts leads to inappropriate expression of some Hoxb4transgenes in posterior somites, indicating that there are sequences within region B that are important for both transcriptional and post-transcriptional regulation.
Tbx5 is required for forelimb bud formation and continued outgrowth
Authors: Rallis Charalampos , Bruneau Benoit G. , Del Buono Jo , Seidman Christine E. , Seidman J. G. , Nissim Sahar , Tabin Clifford J. , Logan Malcolm P. O.
Published: May 2003

Tbx5 is a T-box transcription factor expressed exclusively in the developing forelimb but not in the developing hindlimb of vertebrates. Tbx5 is first detected in the prospective forelimb mesenchyme prior to overt limb bud outgrowth and its expression is maintained throughout later limb development stages. Direct evidence for a role of Tbx5 in forelimb development was provided by the discovery that mutations in human TBX5 cause Holt-Oram Syndrome (HOS), a dominant disorder characterised predominantly by upper(fore) limb defects and heart abnormalities. Misexpression studies in the chick have demonstrated a role for this gene in limb-type specification. Using a conditional knockout strategy in the mouse to delete Tbx5 gene function in the developing forelimb, we demonstrate that this gene is also required at early limb bud stages for forelimb bud development. In addition, by misexpressing dominant-negative and dominant-activated forms of Tbx5 in the chick wing we provide evidence that this gene is also required at later stages of limb bud development for continued limb outgrowth. Our results provide a context to understand the defects observed in HOS caused by haploinsufficiency of TBX5 in human. Moreover, our results also demonstrate that limb bud outgrowth and specification of limb identity are linked by a requirement for Tbx5.
Tbx5 and Tbx4 trigger limb initiation through activation of the Wnt/Fgf signaling cascade
Authors: Takeuchi Jun K. , Koshiba-Takeuchi Kazuko , Suzuki Takayuki , Kamimura Mika , Ogura Keiko , Ogura Toshihiko
Published: May 2003

A tight loop between members of the fibroblast growth factor and the Wnt families plays a key role in the initiation of vertebrate limb development. We show for the first time that Tbx5 and Tbx4 are directly involved in this process. When dominant-negative forms of these Tbx genes were misexpressed in the chick prospective limb fields, a limbless phenotype arose with repression of both Wnt and Fgf genes By contrast, when Tbx5 and Tbx4 were misexpressed in the flank, an additional wing-like and an additional leg-like limbs were induced, respectively. This additional limb formation was accompanied by the induction of both Wnt and Fgf genes These results highlight the pivotal roles of Tbx5 and Tbx4 during limb initiation, specification of forelimb/hindlimb and evolution of tetrapod limbs, placing Tbx genes at the center of a highly conserved genetic program.
Ectopic expression of Kruppel like factor 4(Klf4)accelerates formation of the epidermal permeability barrier
Authors: Jaubert Jean , Cheng Jun , Segre Julia A.
Published: May 2003

Dysfunction of the epidermal permeability barrier can result in dehydration, electrolyte imbalance and poor thermoregulation. Immature skin is a portal of entry for infectious agents and potential toxins in topically applied substances. As the skin is one of the last organs to mature in utero,premature infants born before 34 weeks gestation are at great risk for complications. The transcription factor kruppel-like factor 4 (Klf4),has been shown by a targeted ablation, to have an essential function in barrier acquisition. We investigated whether Klf4 expression in utero is sufficient to establish the epidermal barrier. Specifically, we generated lines of mice that express Klf4 from a tetracycline inducible promoter when crossed with transgenic mice expressing the tetracycline transactivator tTA from the epidermal keratin 5 promoter. These mice exhibit acceleration in barrier acquisition as manifest by the exclusion of a dye solution one day earlier in development than controls. Underlying this dye impermeability are morphological changes, including an increased number of stratified layers, expression of terminal differentiation markers and assembly of cornified envelopes. By all criteria, Klf4 ectopic expression accelerates the normal process of terminal differentiation. Premature barrier acquisition in these mice follows the normal pattern rather than the pattern of the transgene promoter, indicating that there are fields of competence in which KLF4 acts. Although other transgenic mice have perturbed barrier acquisition, these mice are the first to accelerate the process of barrier establishment. These studies show that KLF4 regulates barrier acquisition and provides an animal model for studying how to accelerate the process of barrier acquisition for the premature infant.
Elevated SMAD1/β-catenin molecular complexes and renal medullary cystic dysplasia in ALK3 transgenic mice
Authors: Hu Ming Chang , Piscione Tino D. , Rosenblum Norman D.
Published: May 2003

Renal dysplasia, the most frequent cause of childhood renal failure in humans, arises from perturbations in a complex series of morphogenetic events during embryonic renal development. The molecular pathogenesis of renal dysplasia is largely undefined. While investigating the role of a BMP-dependent pathway that inhibits branching morphogenesis in vitro, we generated a novel model of renal dysplasia in a transgenic (Tg) model of ALK3receptor signaling. We report the renal phenotype, and our discovery of molecular interactions between effectors in the BMP and WNT signaling pathways in dysplastic kidney tissue. Expression of the constitutively active ALK3 receptor ALK3QD, in two independent transgenic lines caused renal aplasia/severe dysgenesis in 1.5% and 8.4% of hemizygous and homozygous Tg mice, respectively, and renal medullary cystic dysplasia in 49% and 74% of hemizygous and homozygous Tg mice, respectively. The dysplastic phenotype,which included a decreased number of medullary collecting ducts, increased medullary mesenchyme, collecting duct cysts and decreased cortical thickness,was apparent by E18.5. We investigated the pathogenesis of dysplasia in these mice, and demonstrated a 30% decrease in branching morphogenesis at E13.5 before the appearance of histopathogical features of dysplasia, and the formation of β-catenin/SMAD1/SMAD4 molecular complexes in dysplastic renal tissue. Increased transcriptional activity of a β-catenin reporter gene in ALK3QD;Tcf-gal mice demonstrated functional cooperativity between the ALK3 and β-catenin-dependent signaling pathways in kidney tissue. Together with our results in the dysplastic mouse kidney,our findings that phospho-SMAD1 and β-catenin are overexpressed in human fetal dysplastic renal tissue suggest that dysregulation of these signaling effectors is pathogenic in human renal dysplasia. Our work provides novel insights into the role that crucial developmental signaling pathways may play during the genesis of malformed renal tissue elements.
Translational repression of aC. elegansNotch mRNA by the STAR/KH domain protein GLD-1
Authors: Marin Veronica A. , Evans Thomas C.
Published: May 2003

In C. elegans, the Notch receptor GLP-1 is localized within the germline and early embryo by translational control of glp-1 mRNA. RNA elements in the glp-1 3′untranslated region (3′ UTR) are necessary for repression of glp-1 translation in germ cells, and for localization of translation to anterior cells of the early embryo. The direct regulators of glp-1 mRNA are not known. Here, we show that a 34 nucleotide region of the glp-1 3′ UTR contains two regulatory elements, an element that represses translation in germ cells and posterior cells of the early embryo, and an element that inhibits repressor activity to promote translation in the embryo. Furthermore, we show that the STAR/KH domain protein GLD-1 binds directly and specifically to the repressor element. Depletion of GLD-1 activity by RNA interference causes loss of endogenous glp-1 mRNA repression in early meiotic germ cells, and in posterior cells of the early embryo. Therefore, GLD-1 is a direct repressor of glp-1 translation at two developmental stages. These results suggest a new function for GLD-1 in regulating early embryonic asymmetry. Furthermore,these observations indicate that precise control of GLD-1 activity by other regulatory factors is important to localize this Notch receptor, and contributes to the spatial organization of Notch signaling.
Oriented cell divisions asymmetrically segregate aPKC and generate cell fate diversity in the earlyXenopusembryo
Authors: Chalmers Andrew D. , Strauss Bernhard , Papalopulu Nancy
Published: May 2003

A key feature of early vertebrate development is the formation of superficial, epithelial cells that overlie non-epithelial deep cells. In Xenopus, deep and superficial cells show a range of differences,including a different competence for primary neurogenesis. We show that the two cell populations are generated during the blastula stages by perpendicularly oriented divisions. These take place during several cell divisions, in a variable pattern, but at a percentage that varies little between embryos and from one division to the next. The orientation of division correlates with cell shape suggesting that simple geometric rules may control the orientation of division in this system. We show that dividing cells are molecularly polarised such that aPKC is localised to the external, apical,membrane. Membrane localised aPKC can be seen as early as the one-cell stage and during the blastula divisions, it is preferentially inherited by superficial cells. Finally, we show that when 64-cell stage isolated blastomeres divide perpendicularly and the daughters are cultured separately,only the progeny of the cells that inherit the apical membrane turn on the bHLH gene, ESR6e. We conclude that oriented cell divisions generate the superficial and deep cells and establish cell fate diversity between them.
Analysis of PINCH function inDrosophilademonstrates its requirement in integrin-dependent cellular processes
Authors: Clark Kathleen A. , McGrail Maura , Beckerle Mary C.
Published: May 2003

Integrins play a crucial role in cell motility, cell proliferation and cell survival. The evolutionarily conserved LIM protein PINCH is postulated to act as part of an integrin-dependent signaling complex. In order to evaluate the role of PINCH in integrin-mediated cellular events, we have tested directly the in vivo function of PINCH in Drosophila melanogaster. We demonstrate that the steamer duck (stck) alleles that were first identified in a screen for potential integrin effectors represent mutations in Drosophila pinch. stck mutants die during embryogenesis,revealing a key role for PINCH in development. Muscle cells within embryos that have compromised PINCH function display disturbed actin organization and cell-substratum adhesion. Mutation of stck also causes failure of integrin-dependent epithelial cell adhesion in the wing. Consistent with the idea that PINCH could contribute to integrin function, PINCH protein colocalizes with βPS integrin at sites of actin filament anchorage in both muscle and wing epithelial cells. Furthermore, we show that integrins are required for proper localization of PINCH at the myotendinous junction. The integrin-linked kinase, ILK, is also essential for integrin function. We demonstrate that Drosophila PINCH and ILK are complexed in vivo and are coincident at the integrin-rich muscle-attachment sites in embryonic muscle. Interestingly, ILK localizes appropriately in stck mutant embryos, therefore the phenotypes exhibited by the stck mutants are not attributable to mislocalization of ILK. Our results provide direct genetic evidence that PINCH is essential for Drosophila development and is required for integrin-dependent cell adhesion.
Clonal expansion of ovarian germline stem cells during niche formation inDrosophila
Authors: Zhu Chun-Hong , Xie Ting
Published: May 2003

Stem cell niches are specific regulatory microenvironments formed by neighboring stromal cells. Owing to difficulties in identifying stem cells and their niches in many systems, mechanisms that control niche formation and stem cell recruitment remain elusive. In the Drosophila ovary, two or three germline stem cells (GSCs) have recently been shown to reside in a niche, in which terminal filaments (TFs) and cap cells are two major components. We report that signals from newly formed niches promote clonal expansion of GSCs during niche formation in the Drosophila ovary. After the formation of TFs and cap cells, anterior primordial germ cells(PGCs) adjacent to TFs/cap cells can develop into GSCs at the early pupal stage while the rest directly differentiate. The anterior PGCs are very mitotically active and exhibit two division patterns with respect to cap cells. One of these patterns generates two daughters that both contact cap cells and potentially become GSCs. Our lineage tracing study confirms that one PGC can generate two or three GSCs to occupy a whole niche (`clonal expansion'). decapentaplegic (dpp), the Drosophilahomolog of human bone morphogenetic protein 2/4, is expressed in anterior somatic cells of the gonad, including TFs/cap cells. dppoverexpression promotes PGC proliferation and causes the accumulation of more PGCs in the gonad. A single PGC mutant for thick veins, encoding an essential dpp receptor, loses the ability to clonally populate a niche. Therefore, dpp is probably one of the mitotic signals that promote the clonal expansion of GSCs in a niche. This study also suggests that signals from newly formed niche cells are important for expanding stem cells and populating niches.
The C. elegans LIM homeobox gene lin-11 specifies multiple cell fates during vulval development
Authors: Gupta Bhagwati P. , Wang Minqin , Sternberg Paul W.
Published: May 2003

LIM homeobox family members regulate a variety of cell fate choices during animal development. In C. elegans, mutations in the LIM homeobox gene lin-11 have previously been shown to alter the cell division pattern of a subset of the 2° lineage vulval cells. We demonstrate multiple functions of lin-11 during vulval development. We examined the fate of vulval cells in lin-11 mutant animals using five cellular markers and found that lin-11 is necessary for the patterning of both 1°and 2° lineage cells. In the absence of lin-11 function, vulval cells fail to acquire correct identity and inappropriately fuse with each other. The expression pattern of lin-11 reveals dynamic changes during development. Using a temporally controlled overexpression system, we show that lin-11 is initially required in vulval cells for establishing the correct invagination pattern. This process involves asymmetric expression of lin-11 in the 2° lineage cells. Using a conditional RNAi approach, we show that lin-11 regulates vulval morphogenesis. Finally, we show that LDB-1, a NLI/Ldb1/CLIM2 family member,interacts physically with LIN-11, and is necessary for vulval morphogenesis. Together, these findings demonstrate that temporal regulation of lin-11 is crucial for the wild-type vulval patterning.
The zebrafish forkhead transcription factor Foxi1 specifies epibranchial placode-derived sensory neurons
Authors: Lee Susie A. , Shen Ellen L. , Fiser Andras , Sali Andrej , Guo Su
Published: May 2003

Vertebrate epibranchial placodes give rise to visceral sensory neurons that transmit vital information such as heart rate, blood pressure and visceral distension. Despite the pivotal roles they play, the molecular program underlying their development is not well understood. Here we report that the zebrafish mutation no soul, in which epibranchial placodes are defective, disrupts the fork headrelated, winged helix domain-containing protein Foxi1. Foxi1 is expressed in lateral placodal progenitor cells. In the absence of foxi1 activity, progenitor cells fail to express the basic helix-loop-helix gene neurogenin that is essential for the formation of neuronal precursors, and the paired homeodomain containing gene phox2a that is essential for neuronal differentiation and maintenance. Consequently, increased cell death is detected indicating that the placodal progenitor cells take on an apoptotic pathway. Furthermore,ectopic expression of foxi1 is sufficient to induce phox2a-positive and neurogenin-positive cells. Taken together, these findings suggest that Foxi1 is an important determination factor for epibranchial placodal progenitor cells to acquire both neuronal fate and subtype visceral sensory identity.
Targeted ablation of CCAP neuropeptide-containing neurons ofDrosophilacauses specific defects in execution and circadian timing of ecdysis behavior
Authors: Park Jae H. , Schroeder Andrew J. , Helfrich-Förster Charlotte , Jackson F. Rob , Ewer John
Published: May 2003

Insect growth and metamorphosis is punctuated by molts, during which a new cuticle is produced. Every molt culminates in ecdysis, the shedding of the remains of the old cuticle. Both the timing of ecdysis relative to the molt and the actual execution of this vital insect behavior are under peptidergic neuronal control. Based on studies in the moth, Manduca sexta, it has been postulated that the neuropeptide Crustacean cardioactive peptide (CCAP)plays a key role in the initiation of the ecdysis motor program. We have used Drosophila bearing targeted ablations of CCAP neurons (CCAP KO animals) to investigate the role of CCAP in the execution and circadian regulation of ecdysis. CCAP KO animals showed specific defects at ecdysis, yet the severity and nature of the defects varied at different developmental stages. The majority of CCAP KO animals died at the pupal stage from the failure of pupal ecdysis, whereas larval ecdysis and adult eclosion behaviors showed only subtle defects. Interestingly, the most severe failure seen at eclosion appeared to be in a function required for abdominal inflation, which could be cardioactive in nature. Although CCAP KO populations exhibited circadian eclosion rhythms, the daily distribution of eclosion events (i.e.,gating) was abnormal. Effects on the execution of ecdysis and its circadian regulation indicate that CCAP is a key regulator of the behavior. Nevertheless, an unexpected finding of this work is that the primary functions of CCAP as well as its importance in the control of ecdysis behaviors may change during the postembryonic development of Drosophila.
Loss of Tbx4 blocks hindlimb development and affects vascularization and fusion of the allantois
Authors: Naiche L. A. , Papaioannou Virginia E.
Published: May 2003

Tbx4 is a member of the T-box family of transcription factor genes, which have been shown to play important roles in development. We have ablated Tbx4 function using targeted mutagenesis in the mouse. Embryos homozygous for the null allele fail to undergo chorioallantoic fusion and die by 10.5 days post coitus. The allantoises of Tbx4-mutant embryos are stunted, apoptotic and display abnormal differentiation. Endothelial cells within mutant allantoises do not undergo vascular remodeling. Heterozygous embryos show a mild, transient growth defect in the allantois. Induction of a hindlimb field occurs normally in Tbx4mutants and initial patterning of the hindlimb bud appears normal. However,hindlimb buds from Tbx4 mutants fail to develop either in vivo or in vitro and do not maintain Fgf10 expression in the mesenchyme. The expression of another, closely-linked, T-box gene, Tbx2, is reduced in both the hindlimb and the allantois of Tbx4-mutant embryos prior to the development of overt morphological abnormalities, which suggests that Tbx4 regulates Tbx2 in these tissues.
Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development
Authors: Ivkovic Sanja , Yoon Byeong S. , Popoff Steven N. , Safadi Fayez F. , Libuda Diana E. , Stephenson Robert C. , Daluiski Aaron , Lyons Karen M.
Published: May 2003

Coordinated production and remodeling of the extracellular matrix is essential during development. It is of particular importance for skeletogenesis, as the ability of cartilage and bone to provide structural support is determined by the composition and organization of the extracellular matrix. Connective tissue growth factor (CTGF, CCN2) is a secreted protein containing several domains that mediate interactions with growth factors,integrins and extracellular matrix components. A role for CTGF in extracellular matrix production is suggested by its ability to mediate collagen deposition during wound healing. CTGF also induces neovascularization in vitro, suggesting a role in angiogenesis in vivo. To test whether CTGF is required for extracellular matrix remodeling and/or angiogenesis during development, we examined the pattern of Ctgf expression and generated Ctgf-deficient mice. Ctgf is expressed in a variety of tissues in midgestation embryos, with highest levels in vascular tissues and maturing chondrocytes. We confirmed that CTGF is a crucial regulator of cartilage extracellular matrix remodeling by generating Ctgf-/- mice. Ctgf deficiency leads to skeletal dysmorphisms as a result of impaired chondrocyte proliferation and extracellular matrix composition within the hypertrophic zone. Decreased expression of specific extracellular matrix components and matrix metalloproteinases suggests that matrix remodeling within the hypertrophic zones in Ctgf mutants is defective. The mutant phenotype also revealed a role for Ctgf in growth plate angiogenesis. Hypertrophic zones of Ctgf mutant growth plates are expanded, and endochondral ossification is impaired. These defects are linked to decreased expression of vascular endothelial growth factor (VEGF) in the hypertrophic zones of Ctgf mutants. These results demonstrate that CTGF is important for cell proliferation and matrix remodeling during chondrogenesis, and is a key regulator coupling extracellular matrix remodeling to angiogenesis at the growth plate.
Ogon/Secreted Frizzled functions as a negative feedback regulator of Bmp signaling
Authors: Yabe Taijiro , Shimizu Takashi , Muraoka Osamu , Bae Young-Ki , Hirata Tsutomu , Nojima Hideaki , Kawakami Atsushi , Hirano Toshio , Hibi Masahiko
Published: May 2003

The zebrafish mutant ogon (also called mercedes and short tail) displays ventralized phenotypes similar to the chordino (dino) mutant, in which the gene for the Bmp antagonist Chordin is mutated. We isolated the gene responsible for ogon by a positional cloning strategy and found that the ogon locus encodes a zebrafish homolog of Secreted Frizzled(Sizzled), which has sequence similarity to a Wnt receptor, Frizzled. Unlike other secreted Frizzled-related proteins (sFrps) and the Wnt inhibitor Dickkopf1, the misexpression of Ogon/Sizzled dorsalized, but did not anteriorize, the embryos, suggesting a role for Ogon/Sizzled in Bmp inhibition. Ogon/Sizzled did not inhibit a Wnt8-dependent transcription in the zebrafish embryo. ogon/sizzled was expressed on the ventral side from the late blastula through the gastrula stages. The ventral ogon/sizzled expression in the gastrula stage was reduced or absent in the swirl/bmp2b mutants but expanded in the chordinomutants. Misexpression of ogon/sizzled did not dorsalize the chordino mutants, suggesting that Ogon/Sizzled required Chordin protein for dorsalization and Bmp inhibition. These data indicate that Ogon/Sizzled functions as a negative regulator of Bmp signaling and reveal a novel role for a sFrp in dorsoventral patterning.
Disc brake judder considering instantaneous disc thickness and spatial friction variation
Authors: Jacobsson H
Published: May 2003

Brake judder is a braking-induced vibration. The character of judder is typical of forced vibrations passing through a critical speed. No specific friction characteristic is needed for judder to occur. In two previous models, i.e. a rotor-stator model and a whole vehicle model, the vibration during a brake application was simulated. The vibrations were assumed to be driven by a brake torque variation (BTV) during a wheel revolution. The BTV was assumed to be proportional to the brake pressure variation (BPV) which was measured. Moreover, the proportionality constant was assumed to be independent of the braking conditions. Verifying measurements were made on a street going vehicle with strong disc thickness variation (DTV) on one of its front wheels. The measured vibration variation during braking was predicted almost exactly by the models. However, the maximum measured vibration level could only be approximated. In the present paper a more accurate analysis of the measurements was found to improve strongly the agreement between predicted and measured vibrations. Hence, the deviation in slope between measured and experimentally generated curves was markedly reduced by replacing the overall mean values of brake pressure level, etc. by slowly varying time functions. The new extended model of the present paper takes into account that the BTV may be generated by variations in normal force (i.e. BPV) and other synchronous variations (called BXV), e.g. spatial friction variation and variation of the equivalent brake radius. The result indicates that BXV may be induced by high BPV levels. Even at judder vibrations primarily caused by heavy DTV (20 μm or more in the cold state), there may be considerable contributions to the vibration level from other synchronous disturbances, i.e. BXV. Further, it was found that the pad stiffness increases with the brake pressure. For such a pad stiffness characteristic, an increase of the DTV level (for whatever reason) by 50 per cent might result in more than a 100 per cent increase in the corresponding BPV and BTV levels. Hence, a progressive pad is more sensitive to increases of the DTV level than a linear pad would be.
Validation of an indentor system for evaluating truck seat cushions
Authors: Seigler M , Ahmadian M , Boggs C
Published: May 2003

The objective of this study was to validate an indentor system—called a cushion loading indentor (CLI)—for use in objectively evaluating seat cushion performance for heavy truck seats. Included in this study is a detailed description of the five-component indentor design, with major components being a polyurethane buttocks mould and a variable weighting system. Validation of the CLI was performed by comparing its interface pressure distribution with five human test subjects for four different seating surfaces. The results demonstrate that the CLI is both more repeatable than the human test subjects and provides similar pressure distribution to that of a seated person. Furthermore, it is shown that the CLI is valid for dynamic testing of heavy truck seat cushions owing to the inclusion of the seat suspension, which significantly reduces the dynamic complexity between the cushion and the seated person.
Behavioural modelling and analysis of hybrid vehicle steering systems
Authors: Mills V D , Wagner J R
Published: May 2003

Hybrid vehicles integrate an internal combustion engine, electric motor with accompanying battery pack and generator, and potentially fuel cells to realize greater fuel economy and reduced emission levels. A variety of powertrain operating scenarios exist including engine with belt-driven generator, electric motor using battery pack and/or fuel cell and, finally, engine and electric motor. Automotive subsystems such as hydraulic power steering cannot be consistently powered by a conventional belt-driven hydraulic pump since the engine may be frequently turned off to conserve energy. Thus, a need exists to investigate the dynamic behaviour of various steering systems for hybrid vehicles in terms of platform steering characteristics and power consumption. In this paper, empirical and analytical mathematical models will be presented for power (e.g. hydraulic, electric and steer by wire) rack and pinion steering units. The influence of chassis, tyre-road interface and steering system non-linearities are introduced. Representative numerical results will be presented and discussed to investigate a vehicle's transient response for each steering system configuration.
Tractive efficiency of four-wheel-drive vehicles: An analysis for non-uniform traction conditions
Authors: Besselink B C
Published: May 2003

An analysis of the tractive efficiency of four-wheel-drive vehicles is conducted from the perspective of maximizing efficiency of slip with respect to non-uniform traction conditions in particular. The analysis is conducted using a more rigorous mathematical analysis than previously and using a thorough graphical analysis to substantiate the mathematical analysis. Previous studies concluded that under all traction conditions efficiency of slip will be a maximum when the slip of each wheel is equal. The analysis revealed that, contrary to the previous literature, efficiency of slip will not be a maximum when the slip of each wheel is equal under non-uniform traction conditions. When applied to a vehicle with an interaxle fixed ratio coupling, this means that the optimum theoretical speed ratio is not always equal to 1. An example of non-uniform traction conditions is the situation where two drive wheels are on soil and the other two are on tarmac. The improvement in the efficiency of slip, in this example, when using the correct theoretical speed ratio (as opposed to that equal to 1) is particularly marked at high drawbar loads. The method by which the correct theoretical speed ratio is to be achieved when non-uniform traction conditions occur is problematic. The drive system would require a drive mechanism and a level of intelligence not currently found in off-road vehicles.
Feedforward-plus-proportional-integral-derivative controller for an off-road vehicle electrohydraulic steering system
Authors: Qiu H , Zhang Q
Published: May 2003

This paper presents the use of a feedforward-plus-proportional-integral-derivative (FPID) controller for improving the control performance of the electrohydraulic steering system on an offroad vehicle. The FPID controller used an inverse valve transform in the feedforward loop to compensate for an electrohydraulic steering system deadband and used a conventional PID feedback loop to minimize the tracking error in steering control. On-simulator evaluation tests verified that the FPID resulted in a superior steering rate tracking performance over both a feedforward controller and a PID controller. On-vehicle evaluation tests verified that this FPID controller could achieve prompt and accurate steering angle tracking for agricultural vehicle automated guidance applications.
Multidimensional simulation of the air-flow and fuel transport process in the air-assisted injection system of a new, low-emission two-stroke engine
Authors: Bakshi S , Ravikrishna R V
Published: May 2003

The aim of this work is to model the air and fuel flow process in the air-assisted injection system of a new, low emission two-stroke engine with a view to determine the critical features in the system that influence the engine performance. A computational method for multidimensional, compressible, two-phase flow using a Lagrangian-Eulerian approach is developed and used for this analysis. Good agreement is observed between computations and measurements of fuel consumption and pressure recovery in the injection system of the current prototype. The results show a strong dependence of the typical air flow characteristics of the injection system on engine speed. Significant fuelling after inlet port closure, higher fuel transport efficiency at low speeds and a substantial impingement of liquid fuel on the solid walls of the injection system are also evident from the results of the computations. This suggests a delayed transient response and strong speed dependence of the quality of mixture preparation in this system, which explains certain observed trends in the current prototype of the engine.
Combustion characteristics of natural-gas direct-injection combustion under various fuel injection timings
Authors: Huang Z , Shiga S , Ueda T , Nakamura H , Ishima T , Obokata T , Tsue M , Kono M
Published: May 2003

The characteristics of natural-gas direct-injection combustion under various fuel injection timings were studied by using a rapid compression machine. Results show that natural-gas direct injection can result in combustion that is much faster than homogeneous combustion while shortening the time interval between injection timing and ignition timing can markedly decrease the combustion duration. Unburned hydrocarbon would increase over a wide range of equivalence ratios, shortening the time interval between injection timing and ignition timing can decrease the value to that of homogeneous-mixture combustion. The NOx level is high but the CO level is low over a wide range of equivalence ratios and is little affected by fuel injection timing. High values of pressure rise due to combustion can be realized and it is insensitive to the variation in fuel injection timing. High combustion efficiency can be achieved, which is also independent of injection timing.
A numerical study on soot formation and oxidation for a direct injection diesel engine
Authors: Sung N , Lee S , Kim H , Kim B
Published: May 2003

A numerical cycle model is developed to investigate the soot production in a direct injection (DI) diesel engine. The Surovikin and Fusco models for soot formation and the Nagle model for soot oxidation are used with the KIVA-3V code. In the Surovikin model, carbon radicals are produced from pyrolysis of fuel and soot particles grow through collisions with fuel molecules. In the Fusco model, the carbon radicals and acetylene are formed from pyrolysis of fuel. There, acetylene works for the growth of soot particles. From investigation of the e. ects of the operating conditions on soot formation and oxidation, it is found that soot formation is mainly governed by fuel concentration and combustion temperature and soot oxidation is more dependent on combustion temperature. The air-fuel ratio a. ects soot formation more than injection timing. For a stoichiometric mixture ratio, soot formation is increased because of the high combustion temperature.
Topical Corticosteroid Prescribing Patterns following Changes in Drug Benefit Status
Authors: Campbell Chole A , Cooke Charmaine A , Weerasinghe Swarna DS , Sketris Ingrid S , McLean-Veysey Pam R , Skedgel Chris D
Published: May 2003

OBJECTIVE:

To examine changes in prescribing patterns for topical corticosteroid products dispensed to elderly patients in Nova Scotia, Canada, after all but 2 combination topical corticosteroid products were removed from the Nova Scotia Seniors' Pharmacare Program benefit list.

METHODS:

Administrative prescription claims from the Nova Scotia Seniors' Pharmacare Program were used to identify the number and costs of topical corticosteroid, antifungal, antibiotic, and combination corticosteroid products dispensed. Time-series analysis was used to compare the periods before (April 1, 1999–March 31, 2000) and after (April 1, 2000–March 31, 2001) the delisting.

RESULTS:

In 1999–2000, 26 031 of 103 400 eligible elderly patients (25%) and in 2000–2001, 22 837 of 95 550 eligible elderly (24%) received a prescription for a defined topical product. Nova Scotia Seniors' Pharmacare Program expenditures for all topical products decreased from $11.88 to $10.60 (CND) per beneficiary per year (11%) after the policy revision. Topical combination products decreased from 18% of all topical products dispensed to 14%, while the percentage of potent corticosteroid products dispensed increased from 24% to 27% over the study period. Pre- and post-policy time–trend analysis showed statistically significant increasing trends in cost per beneficiary for all topical products and potent corticosteroid products. Combination corticosteroid products showed no change in trends for costs per beneficiary before, and a slight increasing trend after, the policy revision.

CONCLUSIONS:

Prescribing of topical corticosteroid combination products in Nova Scotia decreased following the formulary revision. There was an increase in potent topical corticosteroid prescribing. Future study involving evaluation of patient outcomes would be useful.
Chromium as Adjunctive Treatment for Type 2 Diabetes
Authors: Ryan Gina J , Wanko Nancy S , Redman Andrea R , Cook Curtiss B
Published: May 2003

OBJECTIVE:

To review the chemistry, pharmacology, efficacy, and safety of trivalent chromium in the treatment of type 2 diabetes and hyperlipidemia.

DATA SOURCES:

The English literature was searched from 1966 through May 2002 using MEDLINE, International Pharmaceutical Abstracts, and EMBASE. The key words included chromium, glucose, lipids, and diabetes. Pertinent references from review articles and studies were used as additional sources.

DATA SYNTHESIS:

Trivalent chromium is an essential nutrient and has a key role in lipid and glucose metabolism. Supplementation with chromium does not appear to reduce glucose levels in euglycemia. It may, however, have some efficacy in reducing glucose levels in hyperglycemia. The effects of chromium on lipid levels are variable. Chromium in doses <1000 μg/d appears to be safe for short-term administration. Kidney function and dermatologic changes need to be monitored.

CONCLUSIONS:

Chromium appears to be a safe supplement and may have a role as adjunctive therapy for treatment of type 2 diabetes. Additional large-scale, long-term, randomized, double-blind studies examining the effect of various doses and forms of chromium are needed.
Glycoprotein IIb/IIIa Receptor Inhibitors in Percutaneous Coronary Intervention and Acute Coronary Syndrome
Authors: Crouch Michael A , Nappi Jean M , Cheang Kai I
Published: May 2003

OBJECTIVE:

To review the contemporary role of the glycoprotein (GYP) IIb/IIIa receptor inhibitors abciximab, eptifibatide, and tirofiban in patients undergoing percutaneous coronary intervention (PCI) and those with an acute coronary syndrome (ACS), and to provide an algorithm based on currently available evidence for specific agents.

DATA SOURCES:

Primary articles were identified by a MEDLINE search (1966–January 2003); references cited in these articles provided additional resources.

STUDY SELECTION AND DATA EXTRACTION:

All of the articles identified from data sources were considered for relevant information; this article primarily addresses large, controlled or comparative studies, and meta-analyses.

DATA SYNTHESIS:

The role of GYP IIb/IIIa inhibitors in patients undergoing PCI and those with ACS has progressed markedly. To date, abciximab has the most robust data in patients undergoing PCI, particularly high-risk individuals. In PCI patients with lower risk (e.g., elective stenting), eptifibatide is a reasonable first-line option. Data do not support tirofiban for routine use in patients undergoing PCI. For individuals with signs and symptoms of ACS, specifically unstable angina or non–ST-segment elevation myocardial infarction (MI), eptifibatide or tirofiban is recommended in high-risk patients when a conservative approach is used (PCI is not planned). Abciximab is not recommended in this situation. In patients with ST-segment elevation MI (STEMI), abciximab is the only GYP IIb/IIIa inhibitor evaluated in large, well-designed investigations. For medical management in combination with a fibrinolytic agent, the role of abciximab remains unclear. For patients undergoing primary PCI for the management of STEMI, the available evidence supports the use of abciximab, albeit further investigation is warranted.

CONCLUSIONS:

The role of GYP IIb/IIIa inhibitors in clinical cardiology continues to evolve. Choice of the agent depends on situation of use, patient-specific characteristics and risk stratification, and, in the case of ACS, chosen management strategy (medical management or intervention).
Enoxaparin-Induced Retroperitoneal Hematoma
Authors: Melde Stephen L
Published: May 2003

OBJECTIVE:

To report 2 cases of retroperitoneal hematoma in elderly patients receiving enoxaparin.

CASE SUMMARIES:

Two white men, aged 70 and 71 years, received enoxaparin 80 mg subcutaneously twice a day for 8 and 4 days, respectively. Baseline hemoglobin and hematocrit values were 9.5 g/dL and 28.9% and 11.2 g/dL and 32.8%, respectively. In both cases, after the hemoglobin and hematocrit values decreased to 6.6 g/dL and 20.4% and 5.1 g/dL and 15.2%, respectively, a computed tomography scan revealed a retroperitoneal hematoma.

DISCUSSION:

Enoxaparin is a frequently used anticoagulant. Major bleeding episodes are reported to occur at a rate of up to 5.2%. Factors that increase the risk of bleeding in patients receiving enoxaparin are the use of high doses of enoxaparin, advanced age, renal impairment, and the concomitant use of drugs affecting hemostasis. Both of these patients received relatively high doses of 0.80 and 0.94 mg/kg subcutaneously twice a day, were elderly, and had mild renal impairment; 1 received aspirin concomitantly, while the other received aspirin 4 days prior and warfarin 1 day prior to bleeding.

CONCLUSIONS:

There are very few published reports implicating enoxaparin as a factor in retroperitoneal hematoma. It is hoped that the addition of these 2 cases to the medical literature creates more awareness that retroperitoneal hematoma should be considered in the differential diagnosis in patients receiving enoxaparin and experiencing unexplained decreases in hemoglobin and hematocrit.
Applications and computational strategies for the two‐point mixture index of fit
Authors: Dayton C. Mitchell
Published: May 2003

Although numerous descriptive measures have been proposed for assessing model fit when analysing frequency tables, the two‐point mixture index of fit proposed by Rudas, Clogg, and Lindsay possesses features that make this index especially appealing in many applied research settings. In particular, the index has an intuitive interpretation that does not depend upon the specific nature of the model being assessed and is not sensitive to sample size. Also, the index can be applied when models are fitted to virtually any frequency table. This paper summarizes the underlying theory and addresses issues of estimation for goodness‐of‐fit tests for one‐way or multi‐way frequency tables as well as for certain latent variable models. In addition, a new approach for estimating a lower confidence bound for the index is presented.
Repeated measures one‐way ANOVA based on a modified one‐step M‐estimator
Authors: Wilcox Rand R. , Keselman H. J.
Published: May 2003

Wilcox, Keselman, Muska and Cribbie (2000) found a method for comparing the trimmed means of dependent groups that performed well in simulations, in terms of Type I errors, with a sample size as small as 21. Theory and simulations indicate that little power is lost under normality when using trimmed means rather than untrimmed means, and trimmed means can result in substantially higher power when sampling from a heavy‐tailed distribution. However, trimmed means suffer from two practical concerns described in this paper. Replacing trimmed means with a robust M‐estimator addresses these concerns, but control over the probability of a Type I error can be unsatisfactory when the sample size is small. Methods based on a simple modification of a one‐step M‐estimator that address the problems with trimmed means are examined. Several omnibus tests are compared, one of which performed well in simulations, even with a sample size of 11.
Dynamical system approach to factor analysis parameter estimation
Authors: Trendafilov Nikolay T.
Published: May 2003

A new unified approach to solving and studying the factor analysis parameter estimation problem is proposed. The maximum likelihood and least squares formulations of factor analysis are considered. The approach leads to globally convergent procedures for simultaneous estimation of the factor analysis parameters. The method presented necessarily leads to proper factor analysis estimations.
A method of moments technique for fitting interaction effects in structural equation models
Authors: Wall Melanie M. , Amemiya Yasuo
Published: May 2003

The desire to fit structural equation models containing an interaction term has received much methodological attention in the social science literature. This paper presents a technique for the cross‐product structural model that utilizes factor score estimates and results in closed‐form moments‐type estimators. The technique, which does not require normality for the underlying factors, was originally introduced in a very general form by Wall and Amemiya (2000) for any polynomial structural model. In this paper, the practical implementation of this method, including standard error estimation, is presented specifically for the cross‐product model. The procedure is applied to an example from social/behavioural epidemiology where the flexibility of the cross‐product model provides a useful description of the underlying theory. A simulation study is also presented comparing the method of moments for the cross‐product model with three other procedures.
Stochastic EM for estimating the parameters of a multilevel IRT model
Authors: Fox J.‐P.
Published: May 2003

An item response theory (IRT) model is used as a measurement error model for the dependent variable of a multilevel model. The dependent variable is latent but can be measured indirectly by using tests or questionnaires. The advantage of using latent scores as dependent variables of a multilevel model is that it offers the possibility of modelling response variation and measurement error and separating the influence of item difficulty and ability level. The two‐parameter normal ogive model is used for the IRT model. It is shown that the stochastic EM algorithm can be used to estimate the parameters which are close to the maximum likelihood estimates. This algorithm is easily implemented. The estimation procedure will be compared to an implementation of the Gibbs sampler in a Bayesian framework. Examples using real data are given.