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Null
Kinds of Null Terms modified by Null Selected AbstractsThe use of transient pressure analysis at the Dounreay Shaft Isolation Project.GEOMECHANICS AND TUNNELLING, Issue 5 2009Die Verwendung der Analyse instationärer Druckentwicklung am Dounreay Schachtabdichtungsprojekt Grouting; Innovative methods; Injektionen; Neue Verfahren Abstract This paper provides an assessment of the use of pressure fall-off data during the Dounreay Shaft Isolation Project. The instrumentation controlling the injection of grout monitors and records both the pressure and the flow rate throughout the process, so pressure fall-off data is collected during any pauses to, and at the end of, each grout injection. The shapes of the pressure fall-off vs time curves have been examined qualitatively and categorised. The fall-off data has also been examined using PanSystem well test software, which creates the pressure change and pressure derivative curves, then attempts to simulate the fall-off curve by iteration after selection of a flow and boundary model chosen from the wide range available. The implications that the shapes of the pressure and derivative curves and the flow and boundary models have for the grout curtain have been examined. The caveats that surround the quantitative use of results from Pan-System analyses for a cement grout rather than a Newtonian fluid are discussed. Diese Veröffentlichung handelt von der Beurteilung des Einsatzes und der Analyse von Daten zum Druckabfall im Zuge der Injektion am Schachtabdichtungsprojekt Dounreay, Schottland, UK. Die Instrumentation der Baustelle war darauf ausgelegt, Messwerte von Druck und Injektionsrate anzuzeigen, aufzuzeichnen und als Diagramm darzustellen. Damit war es möglich, in jeder Injektionsunterbrechung (also bei Rate = Null) und zu jedem Passenende Druckabfalldaten aufzuzeichnen. Die Form dieser Druckabfallkurven gegen die Zeit wurde qualitativ untersucht und kategorisiert. Eine weitere Interpretation dieser Daten erfolgte mittels des Programms "PanSystem". Bei dieser Methodik werden die Druckänderungen über kleine Zeitinkremente errechnet und deren Ableitung über die Zeit in Kurvenform dargestellt. Durch iterative Simulation und Eingabe von Randbedingungen ("boundaries") für das jeweilige Strömungsmodell , ausgewählt aus einer weiten Bandbreite von Möglichkeiten , ergibt sich die Möglichkeit, u. a. die Strömungsdimension, Strömungshindernisse und Reichweite der Injektion zu prognostizieren. Die daraus gezogenen Schlüsse für den Injektionsschirm wurden für die qualitative Abnahme der Arbeiten mitverwendet. In dem vorliegenden Artikel wird auch auf die möglichen Vorbehalte eingegangen, die sich aus den rheologischen Abweichungen von Injektionsmischungen gegenüber einer Newtonschen Flüssigkeit ergeben. [source] MPowering ecologists: community assembly tools for community assembly rulesOIKOS, Issue 7 2010Joshua Ladau Null model tests of presence,absence data (,NMTPAs') provide important tools for inferring effects of competition, facilitation, habitat filtering, and other ecological processes from observational data. Many NMTPAs have been developed, but they often yield conflicting conclusions when applied to the same data. Type I and II error rates, size, power, robustness and bias provide important criteria for assessing which tests are valid, but these criteria need to be evaluated contingent on the sample size, null hypothesis of interest, and assumptions that are appropriate for the data set that is being analyzed. In this paper, we confirm that this is the case using the software MPower, evaluating the validity of NMTPAs contingent on the null hypothesis being tested, assumptions that can be made, and sample size. Evaluating the validity of NMTPAs contingent on these factors is important towards ensuring that reliable inferences are drawn from observational data about the processes controlling community assembly. [source] Delayed embryonic development and impaired cell growth and survival in Actg1 null mice,CYTOSKELETON, Issue 9 2010Tina M. Bunnell Abstract Actins are among the most highly expressed proteins in eukaryotes and play a central role in nearly all aspects of cell biology. While the intricate process of development undoubtedly requires a properly regulated actin cytoskeleton, little is known about the contributions of different actin isoforms during embryogenesis. Of the six actin isoforms, only the two cytoplasmic actins, ,cyto - and ,cyto -actin, are ubiquitously expressed. We found that ,cyto -actin null (Actg1,/,) mice were fully viable during embryonic development, but most died within 48 h of birth due to respiratory failure and cannibalization by the parents. While no morphogenetic defects were identified, Actg1,/, mice exhibited stunted growth during embryonic and postnatal development as well as delayed cardiac outflow tract formation that resolved by birth. Using primary mouse embryonic fibroblasts, we confirm that ,cyto -actin is not required for cell migration. The Actg1,/, cells, however, exhibited growth impairment and reduced cell viability, defects which perhaps contribute to the stunted growth and developmental delays observed in Actg1,/, embryos. Since the total amount of actin protein was maintained in Actg1,/, cells, our data suggests a distinct requirement for ,cyto -actin in cell growth and survival. © 2010 Wiley-Liss, Inc. [source] Expression, functional, and structural analysis of proteins critical for otoconia developmentDEVELOPMENTAL DYNAMICS, Issue 10 2010Yinfang Xu Abstract Otoconia, developed during late gestation and perinatal stages, couple mechanic force to the sensory hair cells in the vestibule for motion detection and bodily balance. In the present work, we have investigated whether compensatory deposition of another protein(s) may have taken place to partially alleviate the detrimental effects of Oc90 deletion by analyzing a comprehensive list of plausible candidates, and have found a drastic increase in the deposition of Sparc-like 1 (aka Sc1 or hevin) in Oc90 null versus wt otoconia. We show that such up-regulation is specific to Sc1, and that stable transfection of Oc90 and Sc1 full-length expression constructs in NIH/3T3 cells indeed promotes matrix calcification. Analysis and modeling of Oc90 and Sc1 protein structures show common features that may be critical requirements for the otoconial matrix backbone protein. Such information will serve as the foundation for future regenerative purposes. Developmental Dynamics 239:2659,2673, 2010. © 2010 Wiley-Liss, Inc. [source] Asator, a tau-tubulin kinase homolog in Drosophila localizes to the mitotic spindleDEVELOPMENTAL DYNAMICS, Issue 12 2009Hongying Qi Abstract We have used a yeast two-hybrid interaction assay to identify Asator, a tau-tubulin kinase homolog in Drosophila that interacts directly with the spindle matrix protein Megator. Using immunocytochemical labeling by an Asator-specific mAb as well as by transgenic expression of a GFP-labeled Asator construct, we show that Asator is localized to the cytoplasm during interphase but redistributes to the spindle region during mitosis. Determination of transcript levels using qRT-PCR suggested that Asator is expressed throughout development but at relatively low levels. By P-element excision, we generated a null or strong hypomorphic Asatorexc allele that resulted in complete adult lethality when homozygous, indicating that Asator is an essential gene. That the observed lethality was caused by impaired Asator function was further supported by the partial restoration of viability by transgenic expression of Asator-GFP in the Asatorexc homozygous mutant background. The finding that Asator localizes to the spindle region during mitosis and directly can interact with Megator suggests that its kinase activity may be involved in regulating microtubule dynamics and microtubule spindle function. Developmental Dynamics 238:3248,3256, 2009. © 2009 Wiley-Liss, Inc. [source] Targeted deletion of Dicer disrupts lens morphogenesis, corneal epithelium stratification, and whole eye developmentDEVELOPMENTAL DYNAMICS, Issue 9 2009Yan Li Abstract Dicer, a ribonuclease essential for miRNA processing, is expressed abundantly in developing mouse cornea and lens. We studied the roles of Dicer and miRNAs in eye development by conditionally deleting the Dicer gene in the mouse lens and corneal epithelium. Adult Dicer conditional null (DicerCN) mice had severe microphthalmia with no discernible lens and a poorly stratified corneal epithelium. Targeted deletion of Dicer effectively inhibited miRNA processing in the developing lens at 12.5 day of embryogenesis (E12.5). Lens development initiated normally but underwent progressive dystrophy between E14.5 and E18.5. Microarray analysis revealed activation of P53 signaling in DicerCN lenses at E13.5, consistent with increased apoptosis and reduced cell proliferation between E12.5 and E14.5. Expression of Pax6 and other lens developmental transcription factors were not greatly affected between E12.5 and E14.5 but decreased as the lens degenerated. Our data indicated an indispensible role for Dicer and miRNAs in lens and corneal development. Developmental Dynamics 238:2388,2400, 2009. © 2009 Wiley-Liss, Inc. [source] Neurotrophin-3 signaling in mammalian Merkel cell developmentDEVELOPMENTAL DYNAMICS, Issue 4 2003Viktor Szeder Abstract Merkel cells are sensory cells of neural crest origin. Because little is known about the mechanisms that direct their differentiation, we have investigated the potential role of a candidate regulatory factor, neurotrophin-3 (NT-3). At embryonic day 16.5 (E 16.5), neither NT-3 nor its primary receptors, TrkC and p75NTR are expressed by Merkel cells in the murine whisker. At the time of birth, however, Merkel cells are immunoreactive for NT-3, TrkC and p75NTR. In TrkC null and NT-3 null mice, Merkel cells differentiate initially, but undergo apoptosis perinatally. These results show that NT-3 signaling is not required for the differentiation of Merkel cells, but that it is essential for their postnatal survival. Developmental Dynamics 228:623,629, 2003. © 2003 Wiley-Liss, Inc. [source] An SNF2 factor involved in mammalian development and cellular proliferationDEVELOPMENTAL DYNAMICS, Issue 1 2001Eric H. Raabe Abstract Members of the SNF2 (Sucrose Non-Fermenter) family of chromatin-remodeling proteins function in processes ranging from DNA repair to transcription to methylation. Using differential display, we recently identified a novel member of the SNF2 family that is highly expressed at the mRNA level in proliferating cells and is down-regulated during apoptosis. We have named this gene PASG (Proliferation-Associated SNF2-like Gene). Northern blot analysis of adult mouse tissues shows PASG to be highly expressed in proliferating organs such as thymus, bone marrow, and testis and absent from nonproliferative tissues such as brain and heart. In situ hybridization analysis of mouse embryos shows that PASG is differentially expressed during development, with highest expression in developing face, limbs, skeletal muscle, heart, and tail. In vitro, PASG expression correlates with a shift from a quiescent to a proliferative state. Mice null for PASG (also known as LSH or Hells) are reported to die perinatally, although the mechanism for lethality is unclear (Geiman and Muegge, 2000). To test the hypothesis that PASG functions in cell proliferation, we compared 5-bromodeoxyuridine (BrdU) incorporation in C33A cells transiently transfected with PASG versus empty vector and found that PASG transfected cells showed a significant decrease in the amount of BrdU incorporation. These findings suggest that PASG plays a role in cell proliferation and may function in the development of multiple cell lineages during murine embryogenesis. © 2001 Wiley-Liss, Inc. [source] Administration of myostatin does not alter fat mass in adult miceDIABETES OBESITY & METABOLISM, Issue 2 2008L. E. Stolz Aim: Myostatin, a member of the TGF-beta superfamily, is produced by skeletal muscle and acts as a negative regulator of muscle mass. It has also been suggested that low-dose administration of myostatin (2 ,g/day) in rodents can reduce fat mass without altering muscle mass. In the current study, we attempted to further explore the effects of myostatin on adipocytes and its potential to reduce fat mass, since myostatin administration could potentially be a useful strategy to treat obesity and its complications in humans. Methods: Purified myostatin protein was examined for its effects on adipogenesis and lipolysis in differentiated 3T3-L1 adipocytes as well as for effects on fat mass in wild-type, myostatin null and obese mice. Results: While myostatin was capable of inhibiting adipogenesis in 3T3-L1 cells, it did not alter lipolysis in fully differentiated adipocytes. Importantly, pharmacological administration of myostatin over a range of doses (2,120 ,g/day) did not affect fat mass in wild-type or genetically obese (ob/ob, db/db) mice, although muscle mass was significantly reduced at the highest myostatin dose. Conclusions: Our results suggest that myostatin does not reduce adipose stores in adult animals. Contrary to prior indications, pharmacological administration of myostatin does not appear to be an effective strategy to treat obesity in vivo. [source] Does constrained oviposition influence offspring sex ratio in the solitary parasitoid wasp Venturia canescens?ECOLOGICAL ENTOMOLOGY, Issue 2 2008MARIE METZGER Abstract 1.,In haplodiploid organisms, virgin or sperm-depleted females can reproduce but are constrained to produce only male progeny. According to Godfray's constrained model, when p, the proportion of females constrained to produce only male progeny, is not null in a panmictic population, unconstrained females should bias their sex allocation towards females to compensate for the excess of males. These unconstrained females should be able to adjust the sex ratio in response to local variation of p. 2.,In this paper an experimental approach is used to test the hypotheses of this model in the solitary endoparasitoid Venturia canescens under both field and laboratory conditions. Specifically, it is tested whether unconstrained females use their encounters with conspecifics (either male or female) to estimate p and then adjust their sex ratio accordingly. 3.,As assumed by Godfray's model, constrained females actively search for host patches in the field and under laboratory conditions produce the same number of offspring during their lifetime as unconstrained females. As predicted by the model, unconstrained females produce a sex ratio biased towards females both in the laboratory and in the field. 4.,The results show that this bias is not a response to encounters with conspecifics previous to oviposition. The hypothesis that the bias is due to differential mortality between sexes during ontogeny is also rejected. The proportions of constrained ovipositions estimated in two natural populations explain only a small fraction of the sex ratio bias observed in V. canescens. [source] Profitable self-superparasitism in an infanticidal parasitoid when conspecifics are present: self-superparasitism deters later attackers from probing for infanticideECOLOGICAL ENTOMOLOGY, Issue 6 2005Emi Ito Abstract., 1.,To reveal the profitability of self-superparasitism when conspecifics are present, the total combined fitness returns from the first and second ovipositions under triple parasitism were compared with fitness returns from the first oviposition under double parasitism, using the small brown hopper Laodelphax striatellus and its semi-solitary infanticidal parasitoid Echthrodelphax fairchildii. 2.,The total combined survival rate of the first and second comers under triple parasitism with oviposition intervals of 1/24 h (where 1 and 24 h represent the first-to-second and second-to-third oviposition intervals respectively) was nearly double the survival rate of the first comer under double parasitism with a 25-h oviposition interval, although there was no difference between these triple and double parasitisms in terms of head width and developmental time. Under the conditions of other oviposition intervals, self-superparasitism produced null (1/1- and 24/24-h intervals) or negative fitness returns (24/1-h intervals). This suggests that self-superparasitism on hosts that were self-parasitised 1 h previously is profitable when conspecifics are present. 3.,When the female parasitoid laid an egg on a host harbouring the earlier comer(s) on the non-oviposition side, she often probed the non-oviposition side for infanticide, i.e. killing the first offspring. When the first and second comers were on different sides, the probing frequency at the third oviposition in triple parasitism with 1/24-h oviposition intervals was lower than that at the second oviposition in double parasitism with a 25-h oviposition interval. This difference was responsible for the above difference in survival rate between the triple and double parasitisms. [source] Understanding biodiversity effects on prey in multi-enemy systemsECOLOGY LETTERS, Issue 9 2006Paolo Casula Abstract Biodiversity,ecosystem functioning theory would predict that increasing natural enemy richness should enhance prey consumption rate due to functional complementarity of enemy species. However, several studies show that ecological interactions among natural enemies may result in complex effects of enemy diversity on prey consumption. Therefore, the challenge in understanding natural enemy diversity effects is to predict consumption rates of multiple enemies taking into account effects arising from patterns of prey use together with species interactions. Here, we show how complementary and redundant prey use patterns result in additive and saturating effects, respectively, and how ecological interactions such as phenotypic niche shifts, synergy and intraguild predation enlarge the range of outcomes to include null, synergistic and antagonistic effects. This study provides a simple theoretical framework that can be applied to experimental studies to infer the biological mechanisms underlying natural enemy diversity effects on prey. [source] Cytochrome P450 2D6 and glutathione S-transferase M1 genotypes and migraineEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 4 2000Mattsson Background Migraine is thought to be a disease of the brain and trigeminovascular system. Migraine patients often claim that stress, food, and beverages trigger their attacks. Chemical substances in these foodstuffs with the property of triggering migraine attacks have not yet been characterised. Cytochrome P450 2D6 (CYP2D6) and glutathione S-transferase M1 (GSTM1) are thought to be present in the brain. They metabolise numerous environmental compounds. The genes exhibit genetic polymorphism that is associated with altered enzyme activity. The aim of this study was to determine if the genotypes of these two enzymes are associated with migraine. Materials and methods The study included 100 female patients and 245 female controls from the general population. Genomic DNA was isolated from whole blood. Allele specific PCR methods were used to identify the normal CYP2D6*1 allele and the mutated CYP2D6*3 and CYP2D6*4 alleles. Initially all samples were genotyped only for GSTM1 plus (+) and GSTM1 null (,) variants. All samples positive for GSTM1 were further analysed for the presence of allelic variants GSTM1*A and GSTM1*B. Results None of the CYP2D6 and GSTM1 genotypes was associated with migraine. We observed an odds ratio (OR) for the poor metaboliser genotype of CYP2D6 of 1.4 (95% CI = 0.5,3.6) and for the GSTM1 null genotype of 1.0 (95% CI = 0.6,1.5). Conclusion The results of this study indicate that deficient metabolism because of mutated CYP2D6 alleles or GSTM1 allele variants is not important in the aetiology of migraine. [source] Consequences for enamel development and mineralization resulting from loss of function of ameloblastin or enamelinEUROPEAN JOURNAL OF ORAL SCIENCES, Issue 5 2009Charles E. Smith Although the nonamelogenin proteins, ameloblastin and enamelin, are both low-abundance and rapidly degrading components of forming enamel, they seem to serve essential developmental functions, as suggested by findings that an enamel layer fails to appear on teeth of mice genetically engineered to produce either a truncated form of ameloblastin (exons 5 and 6 deleted) or no enamelin at all (null). The purpose of this study was to characterize, by direct micro weighing, changes in enamel mineralization occurring on maxillary and mandibular incisors of mice bred for these alterations in nonamelogenin function (Ambn+/+, +/,5,6, ,5,6/,5,6, Enam+/+, +/, ,,/,). The results indicated similar changes to enamel-mineralization patterns within the altered genotypes, including significant decreases by as much as 50% in the mineral content of maturing enamel from heterozygous mice and the formation of a thin, crusty, and disorganized mineralized layer, rather than true enamel, on the labial (occlusal) surfaces of incisors and molars along with ectopic calcifications within enamel organ cells in Ambn,5,6/,5,6 and Enam,/, homozygous mice. These findings confirm that both ameloblastin and enamelin are required by ameloblasts to create an enamel layer by appositional growth as well as to assist in achieving its unique high level of mineralization. [source] POSTCOPULATORY FERTILIZATION BIAS AS A FORM OF CRYPTIC SEXUAL SELECTIONEVOLUTION, Issue 5 2008Ryan Calsbeek Males and females share most of their genetic material yet often experience very different selection pressures. Some traits that are adaptive when expressed in males may therefore be maladaptive when expressed in females. Recent studies demonstrating negative correlations in fitness between parents and their opposite-sex progeny suggest that natural selection may favor a reduction in trait correlations between the sexes to partially mitigate intralocus sexual conflict. We studied sex-specific forms of selection acting in Anolis lizards in the Greater Antilles, a group for which the importance of natural selection has been well documented in species-level diversification, but for which less is known about sexual selection. Using the brown anole (Anolis sagrei), we measured fitness-related variation in morphology (body size), and variation in two traits reflecting whole animal physiological condition: running endurance and immune function. Correlations between body size and physiological traits were opposite between males and females and the form of natural selection acting on physiological traits significantly differed between the sexes. Moreover, physiological traits in progeny were correlated with the body-size of their sires, but correlations were null or even negative between parents and their opposite-sex progeny. Although results based on phenotypic and genetic correlations, as well as the action of natural selection, suggest the potential for intralocus sexual conflict, females used sire body size as a cue to sort sperm for the production of either sons or daughters. Our results suggest that intralocus sexual conflict may be at least partly resolved through post-copulatory sperm choice in A. sagrei. [source] Casein phosphopeptide promotion of calcium uptake in HT-29 cells , relationship between biological activity and supramolecular structureFEBS JOURNAL, Issue 19 2007Claudia Gravaghi Casein phosphopeptides (CPPs) form aggregated complexes with calcium phosphate and induce Ca2+ influx into HT-29 cells that have been shown to be differentiated in culture. The relationship between the aggregation of CPPs assessed by laser light scattering and their biological effect was studied using the CPPs ,-CN(1,25)4P and ,s1 -CN(59,79)5P, the commercial mixture CPP DMV, the ,cluster sequence' pentapeptide, typical of CPPs, and dephosphorylated ,-CN(1,25)4P, [,-CN(1,25)0P]. The biological effect was found to be: (a) maximal with ,-CN(1,25)4P and null with the ,cluster sequence'; (b) independent of the presence of inorganic phosphate; and (c) maximal at 4 mmol·L,1 Ca2+. The aggregation of CPP had the following features: (a) rapid occurrence; (b) maximal aggregation by ,-CN(1,25)4P with aggregates of 60 nm hydrodynamic radius; (c) need for the concomitant presence of Ca2+ and CPP for optimal aggregation; (d) lower aggregation in Ca2+ -free Krebs/Ringer/Hepes; (e) formation of bigger aggregates (150 nm radius) with ,-CN(1,25)0P. With both ,-CN(1,25)4P and CPP DMV, the maximum biological activity and degree of aggregation were reached at 4 mmol·L,1 Ca2+. [source] Transcriptional profiling of the Candida albicans Ssk1p receiver domain point mutants and their virulenceFEMS YEAST RESEARCH, Issue 5 2008Veena Menon Abstract The Ssk1p response regulator of Candida albicans is required for oxidant adaptation, survival in human neutrophils, and virulence in a disseminated murine model of candidiasis. We have previously shown that the amino acid residues D556 and D513 of the Ssk1p receiver domain are critical to the Ssk1p in oxidant stress adaptation and morphogenesis. Herein, transcriptional profiling is used to explain the oxidant sensitivity and morphogenesis defect of two point mutants (D556N and D513K, respectively) compared with a WT strain. In the D556N mutant, during oxidative stress (5 mM H2O2), a downregulation of genes associated with redox homeostasis and oxidative stress occurred, which accounted for about 5% of all gene changes, including among others, SOD1 (superoxide dismutase), CAP1 (required for some types of oxidant stress), and three genes encoding glutathione biosynthesis proteins (GLR1, GSH1, and GSH2). Mutant D513K was not sensitive to peroxide but was impaired in its yeast $/to hyphal transition. We noted downregulation of genes associated with morphogenesis and cell elongation. Virulence of each mutant was also evaluated in a rat vaginitis model of candidiasis. Clearance of an SSK1 null and the D556N mutants from the vaginal canal was significantly greater than wild type or the D513K mutant, indicating that a change in a single amino acid of the Ssk1p alters the ability of this strain to colonize the rat vaginal mucosa. [source] EDEM accelerates ERAD by preventing aberrant dimer formation of misfolded ,1-antitrypsinGENES TO CELLS, Issue 5 2006Nobuko Hosokawa Misfolded glycoproteins are degraded by a mechanism known as ERAD (ER-associated degradation) after retrotranslocation out of the endoplasmic reticulum (ER). This mechanism plays an important role in ER quality control. We previously reported that an ER membrane protein, EDEM, accelerates ERAD of a misfolded ,1-antitrypsin variant, null (Hong Kong) (NHK), suggesting that EDEM may function as an acceptor of terminally misfolded glycoproteins. In this study, we constructed several genetically manipulated cell lines to test this hypothesis. EDEM expression did not alter the secretion rate of properly folded molecules and the forced retention of wild-type ,1-antitrypsin in the ER did not cause its association with EDEM, suggesting that EDEM may function as a molecular chaperone. To examine this possibility, we analyzed the effect of EDEM over-expression on the structure of NHK, and found that the accumulation of covalent NHK dimers was selectively prevented by the over-expression of EDEM. Co-expression of NHK with two other ER membrane proteins, calnexin and H+/K+ -ATPase (, subunit), did not inhibit NHK dimer formation or accelerate NHK ERAD. These results indicate that EDEM may maintain the retrotranslocation competence of NHK by inhibiting aggregation so that unstable misfolded proteins can be accommodated by the dislocon for ERAD. [source] Hyperactivity, startle reactivity and cell-proliferation deficits are resistant to chronic lithium treatment in adult Nr2e1frc/frc miceGENES, BRAIN AND BEHAVIOR, Issue 7 2010B. K. Y. Wong The NR2E1 region on Chromosome 6q21-22 has been repeatedly linked to bipolar disorder (BP) and NR2E1 has been associated with BP, and more specifically bipolar I disorder (BPI). In addition, patient sequencing has shown an enrichment of rare candidate-regulatory variants. Interestingly, mice carrying either spontaneous (Nr2e1frc) or targeted (Tlx,) deletions of Nr2e1 (here collectively known as Nr2e1 -null) show similar neurological and behavioral anomalies, including hypoplasia of the cerebrum, reduced neural stem cell proliferation, extreme aggression and deficits in fear conditioning; these are the traits that have been observed in some patients with BP. Thus, NR2E1 is a positional and functional candidate for a role in BP. However, no Nr2e1 -null mice have been fully evaluated for behaviors used to model BP in rodents or pharmacological responses to drugs effective in treating BP symptoms. In this study we examine Nr2e1frc/frc mice, homozygous for the spontaneous deletion, for abnormalities in activity, learning and information processing, and cell proliferation; these are the phenotypes that are either affected in patients with BP or commonly assessed in rodent models of BP. The effect of lithium, a drug used to treat BP, was also evaluated for its ability to attenuate Nr2e1frc/frc behavioral and neural stem cell-proliferation phenotypes. We show for the first time that Nr2e1 -null mice exhibit extreme hyperactivity in the open field as early as postnatal day 18 and in the home cage, deficits in open-field habituation and passive avoidance, and surprisingly, an absence of acoustic startle. We observed a reduction in neural stem/progenitor cell proliferation in Nr2e1frc/frc mice, similar to that seen in other Nr2e1 -null strains. These behavioral and cell-proliferation phenotypes were resistant to chronic-adult-lithium treatment. Thus, Nr2e1frc/frc mice exhibit behavioral traits used to model BP in rodents, but our results do not support Nr2e1frc/frc mice as pharmacological models for BP. [source] Perception of sweet taste is important for voluntary alcohol consumption in miceGENES, BRAIN AND BEHAVIOR, Issue 1 2008Y. A. Blednov To directly evaluate the association between taste perception and alcohol intake, we used three different mutant mice, each lacking a gene expressed in taste buds and critical to taste transduction: ,-gustducin (Gnat3), Tas1r3 or Trpm5. Null mutant mice lacking any of these three genes showed lower preference score for alcohol and consumed less alcohol in a two-bottle choice test, as compared with wild-type littermates. These null mice also showed lower preference score for saccharin solutions than did wild-type littermates. In contrast, avoidance of quinine solutions was less in Gnat3 or Trpm5 knockout mice than in wild-type mice, whereas Tas1r3 null mice were not different from wild type in their response to quinine solutions. There were no differences in null vs. wild-type mice in their consumption of sodium chloride solutions. To determine the cause for reduction of ethanol intake, we studied other ethanol-induced behaviors known to be related to alcohol consumption. There were no differences between null and wild-type mice in ethanol-induced loss of righting reflex, severity of acute ethanol withdrawal or conditioned place preference for ethanol. Weaker conditioned taste aversion (CTA) to alcohol in null mice may have been caused by weaker rewarding value of the conditioned stimulus (saccharin). When saccharin was replaced by sodium chloride, no differences in CTA to alcohol between knockout and wild-type mice were seen. Thus, deletion of any one of three different genes involved in detection of sweet taste leads to a substantial reduction of alcohol intake without any changes in pharmacological actions of ethanol. [source] Mutation and evolutionary analyses identify NR2E1- candidate-regulatory mutations in humans with severe cortical malformationsGENES, BRAIN AND BEHAVIOR, Issue 6 2007R. A. Kumar Nuclear receptor 2E1 (NR2E1) is expressed in human fetal and adult brains; however, its role in human brain,behavior development is unknown. Previously, we have corrected the cortical hypoplasia and behavioral abnormalities in Nr2e1,/, mice using a genomic clone spanning human NR2E1, which bolsters the hypothesis that NR2E1 may similarly play a role in human cortical and behavioral development. To test the hypothesis that humans with abnormal brain,behavior development may have null or hypomorphic NR2E1 mutations, we undertook the first candidate mutation screen of NR2E1 by sequencing its entire coding region, untranslated, splice site, proximal promoter and evolutionarily conserved non-coding regions in 56 unrelated patients with cortical disorders, namely microcephaly. We then genotyped the candidate mutations in 325 unrelated control subjects and 15 relatives. We did not detect any coding region changes in NR2E1; however, we identified seven novel candidate regulatory mutations that were absent from control subjects. We used in silico tools to predict the effects of these candidate mutations on neural transcription factor binding sites (TFBS). Four candidate mutations were predicted to alter TFBS. To facilitate the present and future studies of NR2E1, we also elucidated its molecular evolution, genetic diversity, haplotype structure and linkage disequilibrium by sequencing an additional 94 unaffected humans representing Africa, the Americas, Asia, Europe, the Middle East and Oceania, as well as great apes and monkeys. We detected strong purifying selection, low genetic diversity, 21 novel polymorphisms and five common haplotypes at NR2E1. We conclude that protein-coding changes in NR2E1 do not contribute to cortical and behavioral abnormalities in the patients examined here, but that regulatory mutations may play a role. [source] A statistical method for scanning the genome for regions with rare disease allelesGENETIC EPIDEMIOLOGY, Issue 5 2010Chad GarnerArticle first published online: 21 JUN 2010 Abstract Studying the role of rare alleles in common disease has been prevented by the impractical task of determining the DNA sequence of large numbers of individuals. Next-generation DNA sequencing technologies are being developed that will make it possible for genetic studies of common disease to study the full frequency spectrum of genetic variation, including rare alleles. This report describes a method for scanning the genome for disease susceptibility regions that show an increased number of rare alleles among a sample of disease cases versus an ethnically matched sample of controls. The method was based on a hidden Markov model and the statistical support for a disease susceptibility region characterized by rare alleles was measured by a likelihood ratio statistic. Due to the lack of empirical data, the method was evaluated through simulation. The performance of the method was tested under the null and alternative hypotheses under a range of sequence generating and hidden Markov models parameters. The results showed that the statistical method performs well at identifying true disease susceptibility regions and that performance was primarily affected by the amount of variation in the neutral sequence and the number of rare disease alleles found in the disease susceptibility region. Genet. Epidemiol. 34: 386,395, 2010. © 2010 Wiley-Liss, Inc. [source] Examining the statistical properties of fine-scale mapping in large-scale association studiesGENETIC EPIDEMIOLOGY, Issue 3 2008Steven Wiltshire Abstract Interpretation of dense single nucleotide polymorphism (SNP) follow-up of genome-wide association or linkage scan signals can be facilitated by establishing expectation for the behaviour of primary mapping signals upon fine-mapping, under both null and alternative hypotheses. We examined the inferences that can be made regarding the posterior probability of a real genetic effect and considered different disease-mapping strategies and prior probabilities of association. We investigated the impact of the extent of linkage disequilibrium between the disease SNP and the primary analysis signal and the extent to which the disease gene can be physically localised under these scenarios. We found that large increases in significance (>2 orders of magnitude) appear in the exclusive domain of genuine genetic effects, especially in the follow-up of genome-wide association scans or consensus regions from multiple linkage scans. Fine-mapping significant association signals that reside directly under linkage peaks yield little improvement in an already high posterior probability of a real effect. Following fine-mapping, those signals that increase in significance also demonstrate improved localisation. We found local linkage disequiliptium patterns around the primary analysis signal(s) and tagging efficacy of typed markers to play an important role in determining a suitable interval for fine-mapping. Our findings help inform the interpretation and design of dense SNP-mapping follow-up studies, thus facilitating discrimination between a genuine genetic effect and chance fluctuation (false positive). Genet. Epidemiol. 2007. © 2007 Wiley-Liss, Inc. [source] Quantifying bias due to allele misclassification in case-control studies of haplotypesGENETIC EPIDEMIOLOGY, Issue 7 2006Usha S. Govindarajulu Abstract Objectives Genotyping errors can induce biases in frequency estimates for haplotypes of single nucleotide polymorphisms (SNPs). Here, we considered the impact of SNP allele misclassification on haplotype odds ratio estimates from case-control studies of unrelated individuals. Methods We calculated bias analytically, using the haplotype counts expected in cases and controls under genotype misclassification. We evaluated the bias due to allele misclassification across a range of haplotype distributions using empirical haplotype frequencies within blocks of limited haplotype diversity. We also considered simple two- and three-locus haplotype distributions to understand the impact of haplotype frequency and number of SNPs on misclassification bias. Results We found that for common haplotypes (>5% frequency), realistic genotyping error rates (0.1,1% chance of miscalling an allele), and moderate relative risks (2,4), the bias was always towards the null and increases in magnitude with increasing error rate, increasing odds ratio. For common haplotypes, bias generally increased with increasing haplotype frequency, while for rare haplotypes, bias generally increased with decreasing frequency. When the chance of miscalling an allele is 0.5%, the median bias in haplotype-specific odds ratios for common haplotypes was generally small (<4% on the log odds ratio scale), but the bias for some individual haplotypes was larger (10,20%). Bias towards the null leads to a loss in power; the relative efficiency using a test statistic based upon misclassified haplotype data compared to a test based on the unobserved true haplotypes ranged from roughly 60% to 80%, and worsened with increasing haplotype frequency. Conclusions The cumulative effect of small allele-calling errors across multiple loci can induce noticeable bias and reduce power in realistic scenarios. This has implications for the design of candidate gene association studies that utilize multi-marker haplotypes. Genet. Epidemiol. 2006. © 2006 Wiley-Liss, Inc. [source] A mouse embryonic stem cell model of Schwann cell differentiation for studies of the role of neurofibromatosis type 1 in Schwann cell development and tumor formationGLIA, Issue 11 2007Therese M. Roth Abstract The neurofibromatosis Type 1 (NF1) gene functions as a tumor suppressor gene. One known function of neurofibromin, the NF1 protein product, is to accelerate the slow intrinsic GTPase activity of Ras to increase the production of inactive rasGDP, with wide-ranging effects on p21ras pathways. Loss of neurofibromin in the autosomal dominant disorder NF1 is associated with tumors of the peripheral nervous system, particularly neurofibromas, benign lesions in which the major affected cell type is the Schwann cell (SC). NF1 is the most common cancer predisposition syndrome affecting the nervous system. We have developed an in vitro system for differentiating mouse embryonic stem cells (mESC) that are NF1 wild type (+/+), heterozygous (+/,), or null (,/,) into SC-like cells to study the role of NF1 in SC development and tumor formation. These mES-generated SC-like cells, regardless of their NF1 status, express SC markers correlated with their stage of maturation, including myelin proteins. They also support and preferentially direct neurite outgrowth from primary neurons. NF1 null and heterozygous SC-like cells proliferate at an accelerated rate compared to NF1 wild type; this growth advantage can be reverted to wild type levels using an inhibitor of MAP kinase kinase (Mek). The mESC of all NF1 types can also be differentiated into neuron-like cells. This novel model system provides an ideal paradigm for studies of the role of NF1 in cell growth and differentiation of the different cell types affected by NF1 in cells with differing levels of neurofibromin that are neither transformed nor malignant. © 2007 Wiley-Liss, Inc. [source] Early onset of degenerative changes at nodes of Ranvier in alpha-motor axons of Cntf null (,/,) mutant miceGLIA, Issue 4 2003Kliment P. Gatzinsky Abstract The nodes of Ranvier are sites of specific interaction between Schwann cells and axons. Besides their crucial role in transmission of action potentials, the nodes of Ranvier and in particular the paranodal axon-Schwann cell networks (ASNs) are thought to function as local centers in large motor axons for removal, degradation, and disposal of organelles. In order to test whether ciliary neurotrophic factor (CNTF), which is present at high levels in the Schwann cell cytoplasm, is involved in the maintenance of these structures, we have examined lumbar ventral root nerve fibers of alpha-motor neurons by electron microscopy in 3- and 9-month-old Cntf null (,/,) mutant mice. Nerve fibers and nodes of Ranvier in 3-month-old Cntf,/, mutants appeared morphologically normal, except that ASNs were more voluminous in the mutants than in wild-type control animals at this age. In 9-month-old Cntf,/, animals, morphological changes, such as reduction in nerve fiber and axon diameter, myelin sheath disruption, and loss of ASNs at nodes of Ranvier, were observed. These findings suggest that endogenous CNTF, in addition to its role in promoting motor neuron survival and regeneration, is needed for long-term maintenance of alpha-motor nerve fibers. The premature loss of paranodal ASNs in animals lacking CNTF, which seems to be a defect related to a disturbed interaction in the nodal region between the axon and its myelinating Schwann cells, could impede the maintenance of a normal milieu in the motor axon, preceding more general neuronal damage. GLIA 42:340,349, 2003. © 2003 Wiley-Liss, Inc. [source] Above-ground forest biomass is not consistently related to wood density in tropical forestsGLOBAL ECOLOGY, Issue 5 2009James C. Stegen ABSTRACT Aim, It is increasingly accepted that the mean wood density of trees within a forest is tightly coupled to above-ground forest biomass. It is unknown, however, if a positive relationship between forest biomass and mean community wood density is a general phenomenon across forests. Understanding spatial variation in biomass as a function of wood density both within and among forests is important for predicting changes in stored carbon in response to global change, and here we evaluated the generality of a positive biomass,wood density relationship within and among six tropical forests. Location, Costa Rica, Panama, Puerto Rico and Ecuador. Methods, Individual stem data, including diameter at breast height and spatial position, for six forest dynamics plots were merged with an extensive wood density database. Individual stem biomass values were calculated from these data using published statistical models. Total above ground biomass, total basal area and mean community wood density were also quantified across a range of subcommunity plot sizes within each forest. Results, Among forests, biomass did not vary with mean community wood density. The relationship between subcommunity biomass and mean wood density within a forest varied from negative to null to positive depending on the size of subcommunities and forest identity. The direction of correlation was determined by the associated total basal area,mean wood density correlation, the slope of which increased strongly with whole forest mean wood density. Main conclusions, There is no general relationship between forest biomass and wood density, and in some forests, stored carbon is highest where wood density is lowest. Our results suggest that declining wood density, due to global change, will result in decreased or increased stored carbon in forests with high or low mean wood density, respectively. [source] The geography of hospital admission in a national health service with patient choiceHEALTH ECONOMICS, Issue 9 2010Daniele Fabbri Abstract Each year about 20% of the 10 million hospital inpatients in Italy get admitted to hospitals outside the Local Health Authority of residence. In this paper we carefully explore this phenomenon and estimate gravity equations for ,trade' in hospital care using a Poisson pseudo-maximum likelihood method. Consistency of the PPML estimator is guaranteed under the null of independence provided that the conditional mean is correctly specified. In our case we find that patients' flows are affected by network autocorrelation. We correct for it by relying upon spatial filtering. Our results suggest that the gravity model is a good framework for explaining patient mobility in most of the examined diagnostic groups. We find that the ability to restrain patients' outflows increases with the size of the pool of enrollees. Moreover, the ability to attract patients' inflows is reduced by the size of pool of enroless for all LHAs except for the very big LHAs. For LHAs in the top quintile of size of enrollees, the ability to attract inflows increases with the size of the pool. Copyright © 2010 John Wiley & Sons, Ltd. [source] Active and passive behaviors of soft tissues: Pelvic floor musclesINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING, Issue 6 2010M. P. M. Pato Abstract A new active-contraction visco-elastic numerical model of the pelvic floor (skeletal) muscle is presented. Our model includes all elements that represent the muscle constitutive behavior, contraction and relaxation. In contrast with the previous models, the activation function can be null. The complete equations are shown and exactly linearized. Small verification and validation tests are performed and the pelvis is modeled using the data from the intra-abdominal pressure tests. Copyright © 2009 John Wiley & Sons, Ltd. [source] Adaptive pattern nulling design of linear array antenna by phase-only perturbations using memetic algorithmsINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING, Issue 11 2008Chao-Hsing Hsu Abstract In this paper, the pattern nulling of a linear array for interference cancellation is derived by phase-only perturbations using memetic algorithms (MAs). The MAs uses improvement procedures which is obtained by incorporating local search into the genetic algorithms. It is proposed to improve the search ability of genetic algorithms. MA is a kind of an improved type of the traditional genetic algorithms. By using local search procedure, it can avoid the shortcoming of the traditional genetic algorithms, whose termination criteria are set up by using the trial and error method. The MA is applied to find the pattern nulling of the proposed adaptive antenna. This design for radiation pattern nulling of an adaptive antenna can suppress interference by placing a null at the direction of the interfering source, i.e. to increase the signal to interference ratio. This proposed method is that an innovative adaptive antenna optimization technique is also able to solve the multipath problem which exists in practical wireless communication systems. Two examples are provided to justify the proposed phase-only perturbations approach based on MAs. Computer simulation results are given to demonstrate the effectiveness of the proposed method. Copyright © 2007 John Wiley & Sons, Ltd. [source] | ||||||||||||||||||||||||||||||||||||||||||||||