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Sample records for dominant negative basic

  1. Negativity bias and basic values.

    PubMed

    Schwartz, Shalom H

    2014-06-01

    Basic values explain more variance in political attitudes and preferences than other personality and sociodemographic variables. The values most relevant to the political domain are those likely to reflect the degree of negativity bias. Value conflicts that represent negativity bias clarify differences between what worries conservatives and liberals and suggest that relations between ideology and negativity bias are linear. PMID:24970450

  2. Osmosensation in TRPV2 dominant negative expressing skeletal muscle fibres

    PubMed Central

    Zanou, Nadège; Mondin, Ludivine; Fuster, Clarisse; Seghers, François; Dufour, Inès; de Clippele, Marie; Schakman, Olivier; Tajeddine, Nicolas; Iwata, Yuko; Wakabayashi, Shigeo; Voets, Thomas; Allard, Bruno; Gailly, Philippe

    2015-01-01

    Abstract Increased plasma osmolarity induces intracellular water depletion and cell shrinkage followed by activation of a regulatory volume increase (RVI). In skeletal muscle, this is accompanied by transverse tubule (TT) dilatation and by a membrane depolarization responsible for a release of Ca2+ from intracellular pools. We observed that both hyperosmotic shock-induced Ca2+ transients and RVI were inhibited by Gd3+, ruthenium red and GsMTx4 toxin, three inhibitors of mechanosensitive ion channels. The response was also completely absent in muscle fibres overexpressing a non-permeant, dominant negative (DN) mutant of the transient receptor potential, V2 isoform (TRPV2) ion channel, suggesting the involvement of TRPV2 or of a TRP isoform susceptible to heterotetramerization with TRPV2. The release of Ca2+ induced by hyperosmotic shock was increased by cannabidiol, an activator of TRPV2, and decreased by tranilast, an inhibitor of TRPV2, suggesting a role for the TRPV2 channel itself. Hyperosmotic shock-induced membrane depolarization was impaired in TRPV2-DN fibres, suggesting that TRPV2 activation triggers the release of Ca2+ from the sarcoplasmic reticulum by depolarizing TTs. RVI requires the sequential activation of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and NKCC1, a Na+–K+–Cl− cotransporter, allowing ion entry and driving osmotic water flow. In fibres overexpressing TRPV2-DN as well as in fibres in which Ca2+ transients were abolished by the Ca2+ chelator BAPTA, the level of P-SPAKSer373 in response to hyperosmotic shock was reduced, suggesting a modulation of SPAK phosphorylation by intracellular Ca2+. We conclude that TRPV2 is involved in osmosensation in skeletal muscle fibres, acting in concert with P-SPAK-activated NKCC1. Key points Increased plasma osmolarity induces intracellular water depletion and cell shrinkage (CS) followed by activation of a regulatory volume increase (RVI). In skeletal muscle, the hyperosmotic shock

  3. Dominant negative retinoic acid receptor initiates tumor formation in mice

    PubMed Central

    Kupumbati, Tara S; Cattoretti, Giorgio; Marzan, Christine; Farias, Eduardo F; Taneja, Reshma; Mira-y-Lopez, Rafael

    2006-01-01

    Background Retinoic acid suppresses cell growth and promotes cell differentiation, and pharmacological retinoic acid receptor (RAR) activation is anti-tumorigenic. This begs the question of whether chronic physiological RAR activation by endogenous retinoids is likewise anti-tumorigenic. Results To address this question, we generated transgenic mice in which expression of a ligand binding defective dominant negative RARα (RARαG303E) was under the control of the mouse mammary tumor virus (MMTV) promoter. The transgene was expressed in the lymphoid compartment and in the mammary epithelium. Observation of aging mice revealed that transgenic mice, unlike their wild type littermates, developed B cell lymphomas at high penetrance, with a median latency of 40 weeks. MMTV-RARαG303E lymphomas were high grade Pax-5+, surface H+L Ig negative, CD69+ and BCL6- and cytologically and phenotypically resembled human adult high grade (Burkitt's or lymphoblastic) lymphomas. We postulated that mammary tumors might arise after a long latency period as seen in other transgenic models of breast cancer. We tested this idea by transplanting transgenic epithelium into the cleared fat pads of wild type hosts, thus bypassing lymphomagenesis. At 17 months post-transplantation, a metastatic mammary adenocarcinoma developed in one of four transplanted glands whereas no tumors developed in sixteen of sixteen endogenous glands with wild type epithelium. Conclusion These findings suggest that physiological RAR activity may normally suppress B lymphocyte and mammary epithelial cell growth and that global RAR inactivation is sufficient to initiate a stochastic process of tumor development requiring multiple transforming events. Our work makes available to the research community a new animal resource that should prove useful as an experimental model of aggressive sporadic lymphoma in immunologically uncompromised hosts. We anticipate that it may also prove useful as a model of breast cancer. PMID

  4. Enhanced tumor radiosensitivity by a survivin dominant-negative mutant.

    PubMed

    Yuan, Qing-Zhong; Wang, Chun-Ting; Mao, Yong-Qiu; Zhang, Peng; Shi, Hua-Shan; Li, Zhi-Yong; Pan, Li; Yu, Dan-Dan; Leng, Fei; Chen, Xiang; Ying, Wei; Xu, Jing-Hui; Li, Wei; Wu, Fan; Wen, Yuan; Ma, Tian-Tai; Wei, Yu-Quan

    2010-01-01

    Radiosensitivity of tumors is due to a complex interaction of various factors, it has been reported that survivin also acts as a constitutive and inducible radioresistance factor in a panel of tumor cells and approaches designed to inhibit survivin expression or function may lead to tumor sensitisation to chemical and physical agents. Previously, we found that the plasmid encoding the phosphorylation-defective mouse survivin threonine 34-->alanine mutant complexed to DOTAP-chol liposome (Lip-mS) can suppress murine primary breast carcinoma. However, little is known regarding the biological effect of Lip-mS combined with radiation. The present study was designed to determine whether Lip-mS could enhance the anti-tumor activity of radiation. The Lewis Lung Carcinoma (LLC) cells treated with a combination of Lip-mS and radiation displayed apparently increased apoptosis compared with those treated with Lip-mS or radiation alone. Mice bearing LLC tumors were treated with intravenous injections of Lip-mS and radiation, the combined treatment significantly reduced mean tumor volume compared with either treatment alone. Moreover, the anti-tumor effect of Lip-mS combined with radiation was greater than their additive effect when compared with the expected effect of the combined treatment. These data suggest that inhibition of survivin using a dominant-negative mutant, survivin T34A, could sensitize LLC cells to radiation efficiently and the synergistic anti-tumor activity may in part result from increasing the apoptosis of tumor cells, inhibiting tumor angiogenesis and inducing a tumor-protective immune response in the combined treatment. PMID:19956869

  5. Right Hemispheric Dominance in Processing of Unconscious Negative Emotion

    ERIC Educational Resources Information Center

    Sato, Wataru; Aoki, Satoshi

    2006-01-01

    Right hemispheric dominance in unconscious emotional processing has been suggested, but remains controversial. This issue was investigated using the subliminal affective priming paradigm combined with unilateral visual presentation in 40 normal subjects. In either left or right visual fields, angry facial expressions, happy facial expressions, or…

  6. A recurring dominant negative mutation causes autosomal dominant growth hormone deficiency - a clinical research center study

    SciTech Connect

    Cogan, J.D.; Prince, M.; Phillips, J.

    1995-12-01

    Familial isolated GH deficiency type II (IGHD-II) is an autosomal dominant disorder that has been previously shown in some patients to be caused by heterogeneous GH gene defects that affect GH messenger RNA (mRNA) splicing. We report here our findings of multiple G{r_arrow}A transitions of the first base of the donor splice site of IVS 3 (+1G{r_arrow}A) in IGHD II subjects from three nonrelated kindreds from Sweden, North America, and South Africa. This + 1G{r_arrow}A substitution creates an NlaIII site that was used to demonstrate that all affected individuals in all three families were heterozygous for the mutation. To determine the effect of this mutation of GH mRNA processing, HeLa cells were transfected with expression plasmids containing normal or mutant +1G{r_arrow}A alleles, and complementary DNAs from the resulting GH mRNAs were sequenced. The mutation was found to destroy the GH IVS3 donor splice site, causing skipping of exon 3 and loss of the codons for amino acids 32-71 of the mature GH peptide from the mutant GH mRNA. Our finding of exon 3 skipping in transcripts of the +1G{r_arrow}A mutant allele is identical to our previous report of a different sixth base transition (+6T{r_arrow}C) mutation of the IVS 3 donor splice site that also causes IGHD II. Microsatellite analysis of an affected subjects` DNA from each of the three nonrelated kindreds indicates that the +1G{r_arrow}A mutation arose independently in each family. Finding that neither grandparent has the mutation in the first family suggests that it arose de novo in that family. Our data indicate that (1) +1G{r_arrow}A IVS 3 mutations perturb GH mRNA splicing and cause IGHD II; and (2) these mutations can present as de novo GHD cases. 13 refs., 4 figs., 1 tab.

  7. Mutational Analysis of Bovine Leukemia Virus Rex: Identification of a Dominant-Negative Inhibitor

    PubMed Central

    Choi, Eun-A; Hope, Thomas J.

    2005-01-01

    The Rex proteins of the delta-retroviruses act to facilitate the export of intron-containing viral RNAs. The Rex of bovine leukemia virus (BLV) is poorly characterized. To gain a better understanding of BLV Rex, we generated a reporter assay to measure BLV Rex function and used it to screen a series of point and deletion mutations. Using this approach, we were able to identify the nuclear export signal of BLV Rex. Further, we identified a dominant-negative form of BLV Rex. Protein localization analysis revealed that wild-type BLV Rex had a punctate nuclear localization and was associated with nuclear pores. In contrast, the dominant-negative BLV Rex mutation had a diffuse nuclear localization and no nuclear pore association. Overexpression of the dominant-negative BLV Rex altered the localization of the wild-type protein. This dominant-negative derivative of BLV Rex could be a useful tool to test the concept of intracellular immunization against viral infection in a large animal model. PMID:15890956

  8. Modeling of surface-dominated plasmas: From electric thruster to negative ion source

    SciTech Connect

    Taccogna, F.; Schneider, R.; Longo, S.; Capitelli, M.

    2008-02-15

    This contribution shows two important applications of the particle-in-cell/monte Carlo technique on ion sources: modeling of the Hall thruster SPT-100 for space propulsion and of the rf negative ion source for ITER neutral beam injection. In the first case translational degrees of freedom are involved, while in the second case inner degrees of freedom (vibrational levels) are excited. Computational results show how in both cases, plasma-wall and gas-wall interactions play a dominant role. These are secondary electron emission from the lateral ceramic wall of SPT-100 and electron capture from caesiated surfaces by positive ions and atoms in the rf negative ion source.

  9. Molecular basis of the dominant negative effect of a glycine transporter 2 mutation associated with hyperekplexia.

    PubMed

    Arribas-González, Esther; de Juan-Sanz, Jaime; Aragón, Carmen; López-Corcuera, Beatriz

    2015-01-23

    Hyperekplexia or startle disease is a rare clinical syndrome characterized by an exaggerated startle in response to trivial tactile or acoustic stimuli. This neurological disorder can have serious consequences in neonates, provoking brain damage and/or sudden death due to apnea episodes and cardiorespiratory failure. Hyperekplexia is caused by defective inhibitory glycinergic neurotransmission. Mutations in the human SLC6A5 gene encoding the neuronal GlyT2 glycine transporter are responsible for the presynaptic form of the disease. GlyT2 mediates synaptic glycine recycling, which constitutes the main source of releasable transmitter at glycinergic synapses. Although the majority of GlyT2 mutations detected so far are recessive, a dominant negative mutant that affects GlyT2 trafficking does exist. In this study, we explore the properties and structural alterations of the S512R mutation in GlyT2. We analyze its dominant negative effect that retains wild-type GlyT2 in the endoplasmic reticulum (ER), preventing surface expression. We show that the presence of an arginine rather than serine 512 provoked transporter misfolding, enhanced association to the ER-chaperone calnexin, altered association with the coat-protein complex II component Sec24D, and thereby impeded ER exit. The S512R mutant formed oligomers with wild-type GlyT2 causing its retention in the ER. Overexpression of calnexin rescued wild-type GlyT2 from the dominant negative effect of the mutant, increasing the amount of transporter that reached the plasma membrane and dampening the interaction between the wild-type and mutant GlyT2. The ability of chemical chaperones to overcome the dominant negative effect of the disease mutation on the wild-type transporter was demonstrated in heterologous cells and primary neurons.

  10. Expression of dominant negative cadherin in the adult mouse brain modifies rearing behavior.

    PubMed

    Edsbagge, Josefina; Zhu, Shunwei; Xiao, Min-Yi; Wigström, Holger; Mohammed, Abdul H; Semb, Henrik

    2004-03-01

    The cadherin superfamily of cell-cell adhesion molecules (CAM) are crucial regulators of morphogenesis and axonal guidance during development of the nervous system and have been suggested to play important roles in neural plasticity of the brain. To study the latter, we created a mouse model that expressed a dominant negative classical cadherin in the brain of adult mice. The mice were tested for spontaneous motor activity and exploratory behavior in the open field, anxiety in the plus-maze, and spatial learning and memory in the water-T maze. Mice expressing the dominant negative cadherin displayed reduced rearing behavior, but no change in motor activity, in the open field, indicating deficits in exploratory behavior. In the water maze, animals expressing the mutant cadherin showed normal escape latencies and were indistinguishable from control littermates. Similarly, LTP in hippocampal slices of cadherin mutant and control mice were indistinguishable. These findings demonstrate intact spatial learning in mice expressing a dominant negative cadherin but altered rearing behavior, suggesting the involvement of classical cadherins in mechanisms mediating rearing behavior.

  11. Structure of the dominant negative S17N mutant of Ras

    PubMed Central

    Nassar, Nicolas; Singh, Kavita; Garcia-Diaz, Miguel

    2010-01-01

    The use of the dominant negative mutant of Ras has been crucial in elucidating the cellular signaling of Ras in response to the activation of various membrane-bound receptors. Although several point mutants of Ras exhibit a dominant negative effect, the asparagine to serine mutation at position 17 (S17N) remains the most popular and the most effective at inhibiting the activation of endogenous Ras. It is now widely accepted that the dominant negative effect is due to the ability of the mutant to sequester upstream activators and its inability to activate downstream effectors. Here, we present the crystal structure of RasS17N in the GDP-bound form. In the three molecules that populate the asymmetric unit, the Mg2+ ion that normally coordinates the β-phosphate is absent because of steric hindrance from the Asn17 side chain. Instead, a Ca2+ ion is coordinating the α-phosphate. Also absent from one molecule is electron density for Phe28, a conserved residue that normally stabilizes the nucleotide’s guanine base. Except for Phe28, the nucleotide makes conserved interactions with Ras. Combined, the inability of Phe28 to stabilize the guanine base and the absence of a Mg2+ ion to neutralize the negative charges on the phosphates explain the weaker affinity of GDP for Ras. Our data suggest that the absence of the Mg2+ should also dramatically affect GTP binding to Ras and the proper positioning of Thr35 necessary for the activation of switch 1 and the binding to downstream effectors, a prerequisite for the triggering of signaling pathways. PMID:20131908

  12. Negative transcriptional regulation of the interferon-gamma promoter by glucocorticoids and dominant negative mutants of c-Jun.

    PubMed

    Cippitelli, M; Sica, A; Viggiano, V; Ye, J; Ghosh, P; Birrer, M J; Young, H A

    1995-05-26

    Interferon-gamma (IFN-gamma) is an immunoregulatory cytokine expressed in large granular lymphocytes and T cells. However, the molecular mechanisms underlying IFN-gamma gene transcription have not been fully defined. Here, we analyze the mechanisms responsible for the inhibition of IFN-gamma promoter activity by the glucocorticoid hormone dexamethasone. Cotransfection assays performed in Jurkat T cells demonstrated that the activity of the initial 108 base pairs of the IFN-gamma promoter was down-regulated in the presence of dexamethasone. Furthermore, utilizing electrophoretic mobility shift analysis, we identified activator protein 1 AP-1-cAMP response element binding protein-activating transcription factor (CREB-ATF) binding elements situated in positions of the IFN-gamma promoter previously identified as essential for promoter activity. Moreover, dominant negative mutants of the c-Jun proto-oncogene were able to mimic the same down-regulatory effect exerted by dexamethasone, and mutations that abolished the binding of the AP-1 CREB-ATF factors were able to block the glucocorticoid effect. These results suggest a model involving the inhibition of IFN-gamma AP-1 CREB-ATF DNA binding complexes as one of the mechanisms involved in the negative regulatory action of glucocorticoids on IFN-gamma gene expression and support the relevance of AP-1 CREB-ATF binding factors during the transcriptional activation of the IFN-gamma promoter in T cells. PMID:7759501

  13. Negative-dominance phenomenon with genetic variants of the cardiac sodium channel Nav1.5.

    PubMed

    Sottas, Valentin; Abriel, Hugues

    2016-07-01

    During the past two decades, many pathological genetic variants in SCN5A, the gene encoding the pore-forming subunit of the cardiac (monomeric) sodium channel Na(v)1.5, have been described. Negative dominance is a classical genetic concept involving a "poison" mutant peptide that negatively interferes with the co-expressed wild-type protein, thus reducing its cellular function. This phenomenon has been described for genetic variants of multimeric K(+) channels, which mechanisms are well understood. Unexpectedly, several pathologic SCN5A variants that are linked to Brugada syndrome also demonstrate such a dominant-negative (DN) effect. The molecular determinants of these observations, however, are not yet elucidated. This review article summarizes recent findings that describe the mechanisms underlying the DN phenomenon of genetic variants of K(+), Ca(2+), Cl(-) and Na(+) channels, and in particular Brugada syndrome variants of Na(v)1.5. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

  14. Cardioselective Dominant-negative Thyroid Hormone Receptor (Δ337T) Modulates Myocardial Metabolism and Contractile Dfficiency

    SciTech Connect

    Hyyti, Outi M.; Olson, Aaron; Ge, Ming; Ning, Xue-Han; Buroker, Norman E.; Chung, Youngran; Jue, Thomas; Portman, Michael A.

    2008-06-03

    Dominant- negative thyroid hormone receptors (TRs) show elevated expression relative to ligand-binding TRs during cardiac hypertrophy. We tested the hypothesis that overexpression of a dominant-negative TR alters cardiac metabolism and contractile efficiency (CE). We used mice expressing the cardioselective dominant-negative TRβ1 mutation Δ337T. Isolated working Δ337T hearts and nontransgenic control (Con) hearts were perfused with 13C-labeled free fatty acids (FFA), acetoacetate (ACAC), lactate, and glucose at physiological concentrations for 30 min. 13C NMR spectroscopy and isotopomer analyses were used to determine substrate flux and fractional contributions (Fc) of acetyl-CoA to the citric acid cycle (CAC). Δ337T hearts exhibited rate depression but higher developed pressure and CE, defined as work per oxygen consumption (MV˙ O2). Unlabeled substrate Fc from endogenous sources was higher in Δ337T, but ACAC Fc was lower. Fluxes through CAC, lactate, ACAC, and FFA were reduced in Δ337T. CE and Fc differences were reversed by pacing Δ337T to Con rates, accompanied by an increase in FFA Fc. Δ337T hearts lacked the ability to increase MV˙ O2. Decreases in protein expression for glucose transporter-4 and hexokinase-2 and increases in pyruvate dehydrogenase kinase-2 and -4 suggest that these hearts are unable to increase carbohydrate oxidation in response to stress. These data show that Δ337T alters the metabolic phenotype in murine heart by reducing substrate flux for multiple pathways. Some of these changes are heart rate dependent, indicating that the substrate shift may represent an accommodation to altered contractile protein kinetics, which can be disrupted by pacing stress.

  15. Dominant-Negative Mutants of a Toxin Subunit: An Approach to Therapy of Anthrax

    NASA Astrophysics Data System (ADS)

    Sellman, Bret R.; Mourez, Michael; John Collier, R.

    2001-04-01

    The protective antigen moiety of anthrax toxin translocates the toxin's enzymic moieties to the cytosol of mammalian cells by a mechanism that depends on its ability to heptamerize and insert into membranes. We identified dominant-negative mutants of protective antigen that co-assemble with the wild-type protein and block its ability to translocate the enzymic moieties across membranes. These mutants strongly inhibited toxin action in cell culture and in an animal intoxication model, suggesting that they could be useful in therapy of anthrax.

  16. Under-dominance constrains the evolution of negative autoregulation in diploids.

    PubMed

    Stewart, Alexander J; Seymour, Robert M; Pomiankowski, Andrew; Reuter, Max

    2013-01-01

    Regulatory networks have evolved to allow gene expression to rapidly track changes in the environment as well as to buffer perturbations and maintain cellular homeostasis in the absence of change. Theoretical work and empirical investigation in Escherichia coli have shown that negative autoregulation confers both rapid response times and reduced intrinsic noise, which is reflected in the fact that almost half of Escherichia coli transcription factors are negatively autoregulated. However, negative autoregulation is rare amongst the transcription factors of Saccharomyces cerevisiae. This difference is surprising because E. coli and S. cerevisiae otherwise have similar profiles of network motifs. In this study we investigate regulatory interactions amongst the transcription factors of Drosophila melanogaster and humans, and show that they have a similar dearth of negative autoregulation to that seen in S. cerevisiae. We then present a model demonstrating that this striking difference in the noise reduction strategies used amongst species can be explained by constraints on the evolution of negative autoregulation in diploids. We show that regulatory interactions between pairs of homologous genes within the same cell can lead to under-dominance--mutations which result in stronger autoregulation, and decrease noise in homozygotes, paradoxically can cause increased noise in heterozygotes. This severely limits a diploid's ability to evolve negative autoregulation as a noise reduction mechanism. Our work offers a simple and general explanation for a previously unexplained difference between the regulatory architectures of E. coli and yeast, Drosophila and humans. It also demonstrates that the effects of diploidy in gene networks can have counter-intuitive consequences that may profoundly influence the course of evolution.

  17. Study of Vaccinia and Cowpox viruses' replication in Rac1-N17 dominant-negative cells

    PubMed Central

    Salgado, Ana Paula Carneiro; Soares-Martins, Jamária Adriana Pinheiro; Andrade, Luciana Garcia; Albarnaz, Jonas Dutra; Ferreira, Paulo César Peregrino; Kroon, Erna Geessien; Bonjardim, Cláudio Antônio

    2013-01-01

    Interfering with cellular signal transduction pathways is a common strategy used by many viruses to create a propitious intracellular environment for an efficient replication. Our group has been studying cellular signalling pathways activated by the orthopoxviruses Vaccinia (VACV) and Cowpox (CPXV) and their significance to viral replication. In the present study our aim was to investigate whether the GTPase Rac1 was an upstream signal that led to the activation of MEK/ERK1/2, JNK1/2 or Akt pathways upon VACV or CPXV' infections. Therefore, we generated stable murine fibroblasts exhibiting negative dominance to Rac1-N17 to evaluate viral growth and the phosphorylation status of ERK1/2, JNK1/2 and Akt. Our results demonstrated that VACV replication, but not CPXV, was affected in dominant-negative (DN) Rac1-N17 cell lines in which viral yield was reduced in about 10-fold. Viral late gene expression, but not early, was also reduced. Furthermore, our data showed that Akt phosphorylation was diminished upon VACV infection in DN Rac1-N17 cells, suggesting that Rac1 participates in the phosphoinositide-3 kinase pathway leading to the activation of Akt. In conclusion, our results indicate that while Rac1 indeed plays a role in VACV biology, perhaps another GTPase may be involved in CPXV replication. PMID:23903969

  18. The positive and negative framing of affirmative action: a group dominance perspective.

    PubMed

    Haley, Hillary; Sidanius, Jim

    2006-05-01

    Using a sample of 328 White, Latino, and Black Los Angeles County adults, the authors examined the tendency to employ various affirmative action "frames" (e.g., affirmative action as a "tie-breaking" device or as a quota-based policy). All three groups agreed about which frames cast affirmative action in a positive light and which cast it in a negative light. Although minorities had a tendency to frame affirmative action in terms that most people find morally acceptable, Whites had a tendency to frame affirmative action in terms most people find unacceptable. In addition, compared to minorities, Whites were less supportive of affirmative action regardless of how it was framed. LISREL modeling also was employed to test two competing models regarding predictors of the tendency to use frames that one personally finds to be relatively negative versus positive. Consistent with the expectations of social dominance theory and a motivated cognition perspective, the authors found that social dominance orientation (SDO) had significant net direct and indirect effects on one's framing of affirmative action. PMID:16702158

  19. Targeted Disruption of Chlamydia trachomatis Invasion by in Trans Expression of Dominant Negative Tarp Effectors

    PubMed Central

    Parrett, Christopher J.; Lenoci, Robert V.; Nguyen, Brenda; Russell, Lauren; Jewett, Travis J.

    2016-01-01

    Chlamydia trachomatis invasion of eukaryotic host cells is facilitated, in part, by the type III secreted effector protein, Tarp. The role of Tarp in chlamydiae entry of host cells is supported by molecular approaches that examined recombinant Tarp or Tarp effectors expressed within heterologous systems. A major limitation in the ability to study the contribution of Tarp to chlamydial invasion of host cells was the prior absence of genetic tools for chlamydiae. Based on our knowledge of Tarp domain structure and function along with the introduction of genetic approaches in C. trachomatis, we hypothesized that Tarp function could be disrupted in vivo by the introduction of dominant negative mutant alleles. We provide evidence that transformed C. trachomatis produced epitope tagged Tarp, which was secreted into the host cell during invasion. We examined the effects of domain specific Tarp mutations on chlamydial invasion and growth and demonstrate that C. trachomatis clones harboring engineered Tarp mutants lacking either the actin binding domain or the phosphorylation domain had reduced levels of invasion into host cells. These data provide the first in vivo evidence for the critical role of Tarp in C. trachomatis pathogenesis and indicate that chlamydial invasion of host cells can be attenuated via the introduction of engineered dominant negative type three effectors.

  20. Targeted Disruption of Chlamydia trachomatis Invasion by in Trans Expression of Dominant Negative Tarp Effectors.

    PubMed

    Parrett, Christopher J; Lenoci, Robert V; Nguyen, Brenda; Russell, Lauren; Jewett, Travis J

    2016-01-01

    Chlamydia trachomatis invasion of eukaryotic host cells is facilitated, in part, by the type III secreted effector protein, Tarp. The role of Tarp in chlamydiae entry of host cells is supported by molecular approaches that examined recombinant Tarp or Tarp effectors expressed within heterologous systems. A major limitation in the ability to study the contribution of Tarp to chlamydial invasion of host cells was the prior absence of genetic tools for chlamydiae. Based on our knowledge of Tarp domain structure and function along with the introduction of genetic approaches in C. trachomatis, we hypothesized that Tarp function could be disrupted in vivo by the introduction of dominant negative mutant alleles. We provide evidence that transformed C. trachomatis produced epitope tagged Tarp, which was secreted into the host cell during invasion. We examined the effects of domain specific Tarp mutations on chlamydial invasion and growth and demonstrate that C. trachomatis clones harboring engineered Tarp mutants lacking either the actin binding domain or the phosphorylation domain had reduced levels of invasion into host cells. These data provide the first in vivo evidence for the critical role of Tarp in C. trachomatis pathogenesis and indicate that chlamydial invasion of host cells can be attenuated via the introduction of engineered dominant negative type three effectors. PMID:27602332

  1. Targeted Disruption of Chlamydia trachomatis Invasion by in Trans Expression of Dominant Negative Tarp Effectors

    PubMed Central

    Parrett, Christopher J.; Lenoci, Robert V.; Nguyen, Brenda; Russell, Lauren; Jewett, Travis J.

    2016-01-01

    Chlamydia trachomatis invasion of eukaryotic host cells is facilitated, in part, by the type III secreted effector protein, Tarp. The role of Tarp in chlamydiae entry of host cells is supported by molecular approaches that examined recombinant Tarp or Tarp effectors expressed within heterologous systems. A major limitation in the ability to study the contribution of Tarp to chlamydial invasion of host cells was the prior absence of genetic tools for chlamydiae. Based on our knowledge of Tarp domain structure and function along with the introduction of genetic approaches in C. trachomatis, we hypothesized that Tarp function could be disrupted in vivo by the introduction of dominant negative mutant alleles. We provide evidence that transformed C. trachomatis produced epitope tagged Tarp, which was secreted into the host cell during invasion. We examined the effects of domain specific Tarp mutations on chlamydial invasion and growth and demonstrate that C. trachomatis clones harboring engineered Tarp mutants lacking either the actin binding domain or the phosphorylation domain had reduced levels of invasion into host cells. These data provide the first in vivo evidence for the critical role of Tarp in C. trachomatis pathogenesis and indicate that chlamydial invasion of host cells can be attenuated via the introduction of engineered dominant negative type three effectors. PMID:27602332

  2. Dominant-Negative CK2α Induces Potent Effects on Circadian Rhythmicity

    PubMed Central

    Smith, Elaine M; Lin, Jui-Ming; Meissner, Rose-Anne; Allada, Ravi

    2008-01-01

    Circadian clocks organize the precise timing of cellular and behavioral events. In Drosophila, circadian clocks consist of negative feedback loops in which the clock component PERIOD (PER) represses its own transcription. PER phosphorylation is a critical step in timing the onset and termination of this feedback. The protein kinase CK2 has been linked to circadian timing, but the importance of this contribution is unclear; it is not certain where and when CK2 acts to regulate circadian rhythms. To determine its temporal and spatial functions, a dominant negative mutant of the catalytic alpha subunit, CK2αTik, was targeted to circadian neurons. Behaviorally, CK2αTik induces severe period lengthening (∼33 h), greater than nearly all known circadian mutant alleles, and abolishes detectable free-running behavioral rhythmicity at high levels of expression. CK2αTik, when targeted to a subset of pacemaker neurons, generates period splitting, resulting in flies exhibiting both long and near 24-h periods. These behavioral effects are evident even when CK2αTik expression is induced only during adulthood, implicating an acute role for CK2α function in circadian rhythms. CK2αTik expression results in reduced PER phosphorylation, delayed nuclear entry, and dampened cycling with elevated trough levels of PER. Heightened trough levels of per transcript accompany increased protein levels, suggesting that CK2αTik disturbs negative feedback of PER on its own transcription. Taken together, these in vivo data implicate a central role of CK2α function in timing PER negative feedback in adult circadian neurons. PMID:18208335

  3. Dental enamel structure is altered by expression of dominant negative RhoA in ameloblasts.

    PubMed

    Li, Yong; Pugach, Megan K; Kuehl, Melissa A; Peng, Li; Bouchard, Jessica; Hwang, Soon Y; Gibson, Carolyn W

    2011-01-01

    Using in vitrotooth germ cultures and analysis by confocal microscopy, ameloblasts treated with sodium fluoride were found to have elevated amounts of filamentous actin. Because this response is reduced by inhibitors of the Rho/ROCK signaling pathway, we generated mice that express dominant negative RhoA (RhoA(DN)) in ameloblasts for in vivo analysis. Expression of the EGFP-RhoA(DN) fusion protein was evaluated by RT-PCR and immunohistochemistry, and teeth were analyzed by scanning electron microscopy. The 3 strains expressed at either low (TgEGFP-RhoA(DN)-8), intermediate (TgEGFP-RhoA(DN)-2), or high (TgEGFP-RhoA(DN)-13) levels, and the molar teeth from the 3 strains had enamel hypoplasia and surface defects. We conclude that RhoA(DN) expressed in ameloblasts interferes with normal enamel development through the pathway that is induced by sodium fluoride.

  4. Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect

    PubMed Central

    Romanelli Tavares, Vanessa L; Gordon, Christopher T; Zechi-Ceide, Roseli M; Kokitsu-Nakata, Nancy Mizue; Voisin, Norine; Tan, Tiong Y; Heggie, Andrew A; Vendramini-Pittoli, Siulan; Propst, Evan J; Papsin, Blake C; Torres, Tatiana T; Buermans, Henk; Capelo, Luciane Portas; den Dunnen, Johan T; Guion-Almeida, Maria L; Lyonnet, Stanislas; Amiel, Jeanne; Passos-Bueno, Maria Rita

    2015-01-01

    Auriculocondylar syndrome is a rare craniofacial disorder comprising core features of micrognathia, condyle dysplasia and question mark ear. Causative variants have been identified in PLCB4, GNAI3 and EDN1, which are predicted to function within the EDN1–EDNRA pathway during early pharyngeal arch patterning. To date, two GNAI3 variants in three families have been reported. Here we report three novel GNAI3 variants, one segregating with affected members in a family previously linked to 1p21.1-q23.3 and two de novo variants in simplex cases. Two variants occur in known functional motifs, the G1 and G4 boxes, and the third variant is one amino acid outside of the G1 box. Structural modeling shows that all five altered GNAI3 residues identified to date cluster in a region involved in GDP/GTP binding. We hypothesize that all GNAI3 variants lead to dominant negative effects. PMID:25026904

  5. Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect.

    PubMed

    Romanelli Tavares, Vanessa L; Gordon, Christopher T; Zechi-Ceide, Roseli M; Kokitsu-Nakata, Nancy Mizue; Voisin, Norine; Tan, Tiong Y; Heggie, Andrew A; Vendramini-Pittoli, Siulan; Propst, Evan J; Papsin, Blake C; Torres, Tatiana T; Buermans, Henk; Capelo, Luciane Portas; den Dunnen, Johan T; Guion-Almeida, Maria L; Lyonnet, Stanislas; Amiel, Jeanne; Passos-Bueno, Maria Rita

    2015-04-01

    Auriculocondylar syndrome is a rare craniofacial disorder comprising core features of micrognathia, condyle dysplasia and question mark ear. Causative variants have been identified in PLCB4, GNAI3 and EDN1, which are predicted to function within the EDN1-EDNRA pathway during early pharyngeal arch patterning. To date, two GNAI3 variants in three families have been reported. Here we report three novel GNAI3 variants, one segregating with affected members in a family previously linked to 1p21.1-q23.3 and two de novo variants in simplex cases. Two variants occur in known functional motifs, the G1 and G4 boxes, and the third variant is one amino acid outside of the G1 box. Structural modeling shows that all five altered GNAI3 residues identified to date cluster in a region involved in GDP/GTP binding. We hypothesize that all GNAI3 variants lead to dominant negative effects.

  6. Tissue-specific Expression of Dominant Negative Mutant Drosophila HSC70 Causes Developmental Defects and Lethality

    PubMed Central

    Elefant, Felice; Palter, Karen B.

    1999-01-01

    The Drosophila melanogaster HSC3 and HSC4 genes encode Hsc70 proteins homologous to the mammalian endoplasmic reticulum (ER) protein BiP and the cytoplasmic clathrin uncoating ATPase, respectively. These proteins possess ATP binding/hydrolysis activities that mediate their ability to aid in protein folding by coordinating the sequential binding and release of misfolded proteins. To investigate the roles of HSC3 (Hsc3p) and HSC4 (Hsc4p) proteins during development, GAL4-targeted gene expression was used to analyze the effects of producing dominant negatively acting Hsc3p (D231S, K97S) and Hsc4p (D206S, K71S) proteins, containing single amino acid substitutions in their ATP-binding domains, in specific tissues of Drosophila throughout development. We show that the production of each mutant protein results in lethality over a range of developmental stages, depending on the levels of protein produced and which tissues are targeted. We demonstrate that the functions of both Hsc3p and Hsc4p are required for proper tissue establishment and maintenance. Production of mutant Hsc4p, but not Hsc3p, results in induction of the stress-inducible Hsp70 at normal temperatures. Evidence is presented that lethality is caused by tissue-specific defects that result from a global accumulation of misfolded protein caused by lack of functional Hsc70. We show that both mutant Hsc3ps are defective in ATP-induced substrate release, although Hsc3p(D231S) does undergo an ATP-induced conformational change. We believe that the amino acid substitutions in Hsc3p interfere with the structural coupling of ATP binding to substrate release, and this defect is the basis for the mutant proteins’ dominant negative effects in vivo. PMID:10397752

  7. Reduced striatal dopamine DA D2 receptor function in dominant-negative GSK-3 transgenic mice.

    PubMed

    Gomez-Sintes, Raquel; Bortolozzi, Analia; Artigas, Francesc; Lucas, José J

    2014-09-01

    Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with constitutive activity involved in cellular architecture, gene expression, cell proliferation, fate decision and apoptosis, among others. GSK-3 expression is particularly high in brain where it may be involved in neurological and psychiatric disorders such as Alzheimer׳s disease, bipolar disorder and major depression. A link with schizophrenia is suggested by the antipsychotic drug-induced GSK-3 regulation and by the involvement of the Akt/GSK-3 pathway in dopaminergic neurotransmission. Taking advantage of the previous development of dominant negative GSK-3 transgenic mice (Tg) showing a selective reduction of GSK-3 activity in forebrain neurons but not in dopaminergic neurons, we explored the relationship between GSK-3 and dopaminergic neurotransmission in vivo. In microdialysis experiments, local quinpirole (DA D2-R agonist) in dorsal striatum reduced dopamine (DA) release significantly less in Tg mice than in wild-type (WT) mice. However, local SKF-81297 (selective DA D1-R agonist) in dorsal striatum reduced DA release equally in both control and Tg mice indicating a comparable function of DA D1-R in the direct striato-nigral pathway. Likewise, systemic quinpirole administration - acting preferentially on presynaptic DA D2- autoreceptors to modulate DA release-reduced striatal DA release similarly in both control and Tg mice. Quinpirole reduced locomotor activity and induced c-fos expression in globus pallidus (both striatal DA D2-R-mediated effects) significantly more in WT than in Tg mice. Taking together, the present results show that dominant negative GSK-3 transgenic mice show reduced DA D2-R-mediated function in striatum and further support a link between dopaminergic neurotransmission and GSK-3 activity.

  8. Generic and personalized RNAi-based therapeutics for a dominant-negative epidermal fragility disorder.

    PubMed

    Leslie Pedrioli, Deena M; Fu, Dun Jack; Gonzalez-Gonzalez, Emilio; Contag, Christopher H; Kaspar, Roger L; Smith, Frances J D; McLean, W H Irwin

    2012-06-01

    Epidermolytic palmoplantar keratoderma (EPPK) is one of >30 autosomal-dominant human keratinizing disorders that could benefit from RNA interference (RNAi)-based therapy. EPPK is caused by mutations in the keratin 9 (KRT9) gene, which is exclusively expressed in thick palm and sole skin where there is considerable keratin redundancy. This, along with the fact that EPPK is predominantly caused by a few hotspot mutations, makes it an ideal proof-of-principle model skin disease to develop gene-specific, as well as mutation-specific, short interfering RNA (siRNA) therapies. We have developed a broad preclinical RNAi-based therapeutic package for EPPK containing generic KRT9 siRNAs and allele-specific siRNAs for four prevalent mutations. Inhibitors were systematically identified in vitro using a luciferase reporter gene assay and validated using an innovative dual-Flag/Strep-TagII quantitative immunoblot assay. siKRT9-1 and siKRT9-3 were the most potent generic K9 inhibitors, eliciting >85% simultaneous knockdown of wild-type and mutant K9 protein synthesis at picomolar concentrations. The allele-specific inhibitors displayed similar potencies and, importantly, exhibited strong specificities for their target dominant-negative alleles with little or no effect on wild-type K9. The most promising allele-specific siRNA, siR163Q-13, was tested in a mouse model and was confirmed to preferentially inhibit mutant allele expression in vivo.

  9. A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells.

    PubMed

    Boisson, Bertrand; Wang, Yong-Dong; Bosompem, Amma; Ma, Cindy S; Lim, Annick; Kochetkov, Tatiana; Tangye, Stuart G; Casanova, Jean-Laurent; Conley, Mary Ellen

    2013-11-01

    Approximately 90% of patients with isolated agammaglobulinemia and failure of B cell development have mutations in genes required for signaling through the pre–B cell and B cell receptors. The nature of the gene defect in the majority of remaining patients is unknown. We recently identified 4 patients with agammaglobulinemia and markedly decreased numbers of peripheral B cells. The B cells that could be detected had an unusual phenotype characterized by the increased expression of CD19 but the absence of a B cell receptor. Genetic studies demonstrated that all 4 patients had the exact same de novo mutation in the broadly expressed transcription factor E47. The mutant protein (E555K) was stable in patient-derived EBV-transformed cell lines and cell lines transfected with expression vectors. E555K in the transfected cells localized normally to the nucleus and resulted in a dominant negative effect when bound to DNA as a homodimer with wild-type E47. Mutant E47 did permit DNA binding by a tissue-specific heterodimeric DNA-binding partner, myogenic differentiation 1 (MYOD). These findings document a mutational hot-spot in E47 and represent an autosomal dominant form of agammaglobulinemia. Further, they indicate that E47 plays a critical role in enforcing the block in development of B cell precursors that lack functional antigen receptors. PMID:24216514

  10. CLAVATA1 dominant-negative alleles reveal functional overlap between multiple receptor kinases that regulate meristem and organ development.

    PubMed

    Diévart, Anne; Dalal, Monica; Tax, Frans E; Lacey, Alexzandria D; Huttly, Alison; Li, Jianming; Clark, Steven E

    2003-05-01

    The CLAVATA1 (CLV1) receptor kinase controls stem cell number and differentiation at the Arabidopsis shoot and flower meristems. Other components of the CLV1 signaling pathway include the secreted putative ligand CLV3 and the receptor-like protein CLV2. We report evidence indicating that all intermediate and strong clv1 alleles are dominant negative and likely interfere with the activity of unknown receptor kinase(s) that have functional overlap with CLV1. clv1 dominant-negative alleles show major differences from dominant-negative alleles characterized to date in animal receptor kinase signaling systems, including the lack of a dominant-negative effect of kinase domain truncation and the ability of missense mutations in the extracellular domain to act in a dominant-negative manner. We analyzed chimeric receptor kinases by fusing CLV1 and BRASSINOSTEROID INSENSITIVE1 (BRI1) coding sequences and expressing these in clv1 null backgrounds. Constructs containing the CLV1 extracellular domain and the BRI1 kinase domain were strongly dominant negative in the regulation of meristem development. Furthermore, we show that CLV1 expressed within the pedicel can partially replace the function of the ERECTA receptor kinase. We propose the presence of multiple receptors that regulate meristem development in a functionally related manner whose interactions are driven by the extracellular domains and whose activation requires the kinase domain.

  11. CLAVATA1 Dominant-Negative Alleles Reveal Functional Overlap between Multiple Receptor Kinases That Regulate Meristem and Organ Development

    PubMed Central

    Diévart, Anne; Dalal, Monica; Tax, Frans E.; Lacey, Alexzandria D.; Huttly, Alison; Li, Jianming; Clark, Steven E.

    2003-01-01

    The CLAVATA1 (CLV1) receptor kinase controls stem cell number and differentiation at the Arabidopsis shoot and flower meristems. Other components of the CLV1 signaling pathway include the secreted putative ligand CLV3 and the receptor-like protein CLV2. We report evidence indicating that all intermediate and strong clv1 alleles are dominant negative and likely interfere with the activity of unknown receptor kinase(s) that have functional overlap with CLV1. clv1 dominant-negative alleles show major differences from dominant-negative alleles characterized to date in animal receptor kinase signaling systems, including the lack of a dominant-negative effect of kinase domain truncation and the ability of missense mutations in the extracellular domain to act in a dominant-negative manner. We analyzed chimeric receptor kinases by fusing CLV1 and BRASSINOSTEROID INSENSITIVE1 (BRI1) coding sequences and expressing these in clv1 null backgrounds. Constructs containing the CLV1 extracellular domain and the BRI1 kinase domain were strongly dominant negative in the regulation of meristem development. Furthermore, we show that CLV1 expressed within the pedicel can partially replace the function of the ERECTA receptor kinase. We propose the presence of multiple receptors that regulate meristem development in a functionally related manner whose interactions are driven by the extracellular domains and whose activation requires the kinase domain. PMID:12724544

  12. Recurring dominant-negative mutations in the AVP-NPII gene cause neurohypophyseal diabetes insipidus

    SciTech Connect

    Repaske, D.R.; Phillips, J.A.; Krishnamani, M.R.S.

    1994-09-01

    Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a familial form of arginine vasopressin (or antidiuretic hormone) deficiency that is usually manifest in early childhood with polyuria, polydipsia and an antidiuretic response to exogenous vasopressin or its analogs. The phenotype is postulated to arise from gliosis and depletion of the magnocellular neurons that produce vasopressin in the supraoptic and paraventricular nuclei of the hypothalamus. ADNDI is caused by heterozygosity for a variety of mutations in the AVP-NPII gene which encodes vasopressin, its carrier protein (NPII) and a glycoprotein (copeptin) of unknown function. These mutations include: (1) Ala 19{r_arrow}Thr (G279A) in AVP`s signal peptide, (2) Gly 17{r_arrow}Val (G1740T), (3) Pro 24{r_arrow}Leu (C1761T), (4) Gly 57{r_arrow}Ser (G1859A) and (5) del Glu 47({delta}AGG 1824-26), all of which occur in NPII. In characterizing the AVP-NPII mutations in five non-related ADNDI kindreds, we have detected two kindreds having mutation 1 (G279A), two having mutation 3 (C1761T) and one having mutation 4 (G1859A) without any other allelic changes being detected. Two of these recurring mutations (G279A and G1859A) are transitions that occur at CpG dinucleotides while the third (C1761T) does not. Interestingly, families with the same mutations differed in their ethnicity or in their affected AVP-NPII allele`s associated haplotype of closely linked DNA polymorphisms. Our data indicated that at least three of five known AVP-NPII mutations causing ADNDI tend to recur but the mechanisms by which these dominant-negative mutations cause variable or progressive expression of the ADNDI phenotype remain unclear.

  13. Dominant-negative effect on adhesion by myelin Po protein truncated in its cytoplasmic domain

    PubMed Central

    1996-01-01

    The myelin Po protein is believed to hold myelin together via interactions of both its extracellular and cytoplasmic domains. We have already shown that the extracellular domains of Po can interact in a homophilic manner (Filbin, M.T., F.S. Walsh, B.D. Trapp, J.A. Pizzey, and G.I. Tennekoon. 1990. Nature (Lond.). 344:871-872). In addition, we have shown that for this homophilic adhesion to take place, the cytoplasmic domain of Po must be intact and most likely interacting with the cytoskeleton; Po proteins truncated in their cytoplasmic domains are not adhesive (Wong, M.H., and M.T. Filbin, 1994. J. Cell Biol. 126:1089-1097). To determine if the presence of these truncated forms of Po could have an effect on the functioning of the full-length Po, we coexpressed both molecules in CHO cells. The adhesiveness of CHO cells expressing both full-length Po and truncated Po was then compared to cells expressing only full-length Po. In these coexpressors, both the full-length and the truncated Po proteins were glycosylated. They reached the surface of the cell in approximately equal amounts as shown by an ELISA and surface labeling, followed by immunoprecipitation. Furthermore, the amount of full-length Po at the cell surface was equivalent to other cell lines expressing only full-length Po that we had already shown to be adhesive. Therefore, there should be sufficient levels of full-length Po at the surface of these coexpressors to measure adhesion of Po. However, as assessed by an aggregation assay, the coexpressors were not adhesive. By 60 min they had not formed large aggregates and were indistinguishable from the control transfected cells not expressing Po. In contrast, in the same time, the cells expressing only the full-length Po had formed large aggregates. This indicates that the truncated forms of Po have a dominant-negative effect on the adhesiveness of the full-length Po. Furthermore, from cross-linking studies, full-length Po, when expressed alone but not when

  14. Sonic Hedgehog Mutations Identified in Holoprosencephaly Patients Can Act in a Dominant Negative Manner

    PubMed Central

    Singh, Samer; Tokhunts, Robert; Baubet, Valerie; Goetz, John A.; Huang, Zhen Jane; Schilling, Neal S.; Black, Kendall E.; MacKenzie, Todd A.; Dahmane, Nadia; Robbins, David J.

    2009-01-01

    Sonic Hedgehog (SHH) plays an important instructional role in vertebrate development, as exemplified by the numerous developmental disorders that occur when the SHH pathway is disrupted. Mutations in the SHH gene are the most common cause of sporadic and inherited Holoprosencephaly (HPE), a developmental disorder that is characterized by defective prosencephalon development. SHH HPE mutations provide a unique opportunity to better understand SHH biogenesis and signaling, and to decipher its role in the development of HPE. Here, we analyzed a panel of SHH HPE missense mutations that encode changes in the amino-terminal active domain of SHH. Our results show that SHH HPE mutations affect SHH biogenesis and signaling at multiple steps, which broadly results in low levels of protein expression, defective processing of SHH into its active form and protein with reduced activity. Additionally, we found that some inactive SHH proteins were able to modulate the activity of wt SHH in a dominant negative manner, both in vitro and in vivo. These findings show for the first time the susceptibility of SHH driven developmental processes to perturbations by low-activity forms of SHH. In conclusion, we demonstrate that SHH mutations found in HPE patients affect distinct steps of SHH biogenesis to attenuate SHH activity to different levels, and suggest that these variable levels of SHH activity might contribute to some of the phenotypic variation found in HPE patients. PMID:19057928

  15. Negative dominance in gene lamB: random assembly of secreted subunits issued from different polysomes.

    PubMed Central

    Marchal, C; Hofnung, M

    1983-01-01

    lamB is the structural gene for the lambda receptor, an oligomeric outer membrane protein from Escherichia coli K12 involved in phage lambda adsorption. We show that, under certain conditions, in a strain diploid for gene lamB, all the missense lamB mutations conferring lambda resistance that we have tested are dominant with respect to wild-type. We propose a model which allows a quantitative interpretation of the data. It is based on negative complementation at the level of oligomerisation. Wild-type and mutant subunits would assemble at random forming homo- and hetero-oligomers. Only wild-type homo-oligomers would be efficient for phage inactivation. For some classes of missense mutations the hetero-oligomers would have the capacity to bind, but not to inactivate the phage. The model confirms that active lambda receptor is a trimer and implies that for this secreted protein there is no preferential assembly of subunits originating from the same polysome. Images Fig. 2. PMID:11894914

  16. Inhibition of elastase-pulmonary emphysema in dominant-negative MafB transgenic mice.

    PubMed

    Aida, Yasuko; Shibata, Yoko; Abe, Shuichi; Inoue, Sumito; Kimura, Tomomi; Igarashi, Akira; Yamauchi, Keiko; Nunomiya, Keiko; Kishi, Hiroyuki; Nemoto, Takako; Sato, Masamichi; Sato-Nishiwaki, Michiko; Nakano, Hiroshi; Sato, Kento; Kubota, Isao

    2014-01-01

    Alveolar macrophages (AMs) play important roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously demonstrated upregulation of the transcription factor MafB in AMs of mice exposed to cigarette smoke. The aim of this study was to elucidate the roles of MafB in the development of pulmonary emphysema. Porcine pancreatic elastase was administered to wild-type (WT) and dominant-negative (DN)-MafB transgenic (Tg) mice in which MafB activity was suppressed only in macrophages. We measured the mean linear intercept and conducted cell differential analysis of bronchoalveolar lavage (BAL) cells, surface marker analysis using flow cytometry, and immunohistochemical staining using antibodies to matrix metalloproteinase (MMP)-9 and MMP-12. Airspace enlargement of the lungs was suppressed significantly in elastase-treated DN-MafB Tg mice compared with treated WT mice. AMs with projected pseudopods were decreased in DN-MafB Tg mice. The number of cells intermediately positive for F4/80 and weakly or intermediately positive for CD11b, which are considered cell subsets of matured AMs, decreased in the BAL of DN-MafB Tg mice. Furthermore, MMP-9 and -12 were significantly downregulated in BAL cells of DN-MafB Tg mice. Because MMPs exacerbate emphysema, MafB may be involved in pulmonary emphysema development through altered maturation of macrophages and MMP expression.

  17. A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51

    PubMed Central

    Ameziane, Najim; May, Patrick; Haitjema, Anneke; van de Vrugt, Henri J.; van Rossum-Fikkert, Sari E.; Ristic, Dejan; Williams, Gareth J.; Balk, Jesper; Rockx, Davy; Li, Hong; Rooimans, Martin A.; Oostra, Anneke B.; Velleuer, Eunike; Dietrich, Ralf; Bleijerveld, Onno B.; Maarten Altelaar, A. F.; Meijers-Heijboer, Hanne; Joenje, Hans; Glusman, Gustavo; Roach, Jared; Hood, Leroy; Galas, David; Wyman, Claire; Balling, Rudi; den Dunnen, Johan; de Winter, Johan P.; Kanaar, Roland; Gelinas, Richard; Dorsman, Josephine C.

    2015-01-01

    Fanconi anaemia (FA) is a hereditary disease featuring hypersensitivity to DNA cross-linker-induced chromosomal instability in association with developmental abnormalities, bone marrow failure and a strong predisposition to cancer. A total of 17 FA disease genes have been reported, all of which act in a recessive mode of inheritance. Here we report on a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in one allele of the homologous recombination DNA repair gene RAD51 in an FA-like patient. This heterozygous mutation causes a novel FA subtype, ‘FA-R', which appears to be the first subtype of FA caused by a dominant-negative mutation. The patient, who features microcephaly and mental retardation, has reached adulthood without the typical bone marrow failure and paediatric cancers. Together with the recent reports on RAD51-associated congenital mirror movement disorders, our results point to an important role for RAD51-mediated homologous recombination in neurodevelopment, in addition to DNA repair and cancer susceptibility. PMID:26681308

  18. Cell-type specific expression of a dominant negative PKA mutation in mice.

    PubMed

    Willis, Brandon S; Niswender, Colleen M; Su, Thomas; Amieux, Paul S; McKnight, G Stanley

    2011-01-01

    We employed the Cre recombinase/loxP system to create a mouse line in which PKA activity can be inhibited in any cell-type that expresses Cre recombinase. The mouse line carries a mutant Prkar1a allele encoding a glycine to aspartate substitution at position 324 in the carboxy-terminal cAMP-binding domain (site B). This mutation produces a dominant negative RIα regulatory subunit (RIαB) and leads to inhibition of PKA activity. Insertion of a loxP-flanked neomycin cassette in the intron preceding the site B mutation prevents expression of the mutant RIαB allele until Cre-mediated excision of the cassette occurs. Embryonic stem cells expressing RIαB demonstrated a reduction in PKA activity and inhibition of cAMP-responsive gene expression. Mice expressing RIαB in hepatocytes exhibited reduced PKA activity, normal fasting induced gene expression, and enhanced glucose disposal. Activation of the RIαB allele in vivo provides a novel system for the analysis of PKA function in physiology. PMID:21533282

  19. A cancer-predisposing "hot spot" mutation of the fumarase gene creates a dominant negative protein.

    PubMed

    Lorenzato, Annalisa; Olivero, Martina; Perro, Mario; Brière, Jean Jacques; Rustin, Pierre; Di Renzo, Maria Flavia

    2008-02-15

    The Fumarase (Fumarate Hydratase, FH) is a tumor suppressor gene whose germline heterozygous mutations predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). The FH gene encodes an enzyme of the Krebs cycle, functioning as a homotetramer and catalyzing the hydration of fumarate to malate. Among the numerous FH mutations reported so far, the R190H missense mutation is the most frequent in HLRCC patients. Here we show the functional analyses of the R190H, in comparison to the better characterized E319Q mutation. We first expressed wild-type and mutated proteins in FH deficient human skin fibroblasts, using lentiviral vectors. The wild-type transgene was able to restore the FH enzymatic activity in cells, while the R190H- and E319Q-FH were not. More interestingly, when the same transgenes were expressed in normal, FH-proficient cells, only the R190H-FH reduced the endogenous FH enzymatic activity. By enforcing the expression of equal amount of wild-type and R190H-FH in the same cell, we showed that the mutated FH protein directly inhibited enzymatic activity by nearly abrogating the FH homotetramer formation. These data demonstrate the dominant negative effect of the R190H missense mutation in the FH gene and suggest that the FH tumor-suppressing activity might be impaired in cells carrying a heterozygous mutation.

  20. Alternative Splice Variants Modulates Dominant-Negative Function of Helios in T-Cell Leukemia

    PubMed Central

    Zhao, Shaorong; Liu, Wei; Li, Yinghui; Liu, Pengjiang; Li, Shufang; Dou, Daolei; Wang, Yue; Yang, Rongcun; Xiang, Rong; Liu, Feifei

    2016-01-01

    The molecular defects which lead to multistep incidences of human T-cell leukemia have yet to be identified. The DNA-binding protein Helios (known as IKZF2), a member of the Ikaros family of Krüppel-like zinc-finger proteins, functions pivotally in T-cell differentiation and activation. In this study, we identify three novel short Helios splice variants which are T-cell leukemic specific, and demonstrate their dominant-negative function. We then test the cellular localization of distinct Helios isoforms, as well as their capability to form heterodimer with Ikaros, and the association with complexes comprising histone deacetylase (HDAC). In addition, the ectopic expression of T-cell leukemic Helios isoforms interferes with T-cell proliferation and apoptosis. The gene expression profiling and pathway analysis indicated the enrichment of signaling pathways essential for gene expression, translation, cell cycle checkpoint, and response to DNA damage stimulus. These data indicate the molecular function of Helios to be involved in the leukemogenesis and phenotype of T-cell leukemia, and also reveal Helios deregulation as a novel marker for T-cell leukemia. PMID:27681508

  1. A Dominant-Negative Isoform of IKAROS Expands Primitive Normal Human Hematopoietic Cells

    PubMed Central

    Beer, Philip A.; Knapp, David J.H.F.; Kannan, Nagarajan; Miller, Paul H.; Babovic, Sonja; Bulaeva, Elizabeth; Aghaeepour, Nima; Rabu, Gabrielle; Rostamirad, Shabnam; Shih, Kingsley; Wei, Lisa; Eaves, Connie J.

    2014-01-01

    Summary Disrupted IKAROS activity is a recurrent feature of some human leukemias, but effects on normal human hematopoietic cells are largely unknown. Here, we used lentivirally mediated expression of a dominant-negative isoform of IKAROS (IK6) to block normal IKAROS activity in primitive human cord blood cells and their progeny. This produced a marked (10-fold) increase in serially transplantable multipotent IK6+ cells as well as increased outputs of normally differentiating B cells and granulocytes in transplanted immunodeficient mice, without producing leukemia. Accompanying T/natural killer (NK) cell outputs were unaltered, and erythroid and platelet production was reduced. Mechanistically, IK6 specifically increased human granulopoietic progenitor sensitivity to two growth factors and activated CREB and its targets (c-FOS and Cyclin B1). In more primitive human cells, IK6 prematurely initiated a B cell transcriptional program without affecting the hematopoietic stem cell-associated gene expression profile. Some of these effects were species specific, thus identifying novel roles of IKAROS in regulating normal human hematopoietic cells. PMID:25418728

  2. A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51.

    PubMed

    Ameziane, Najim; May, Patrick; Haitjema, Anneke; van de Vrugt, Henri J; van Rossum-Fikkert, Sari E; Ristic, Dejan; Williams, Gareth J; Balk, Jesper; Rockx, Davy; Li, Hong; Rooimans, Martin A; Oostra, Anneke B; Velleuer, Eunike; Dietrich, Ralf; Bleijerveld, Onno B; Maarten Altelaar, A F; Meijers-Heijboer, Hanne; Joenje, Hans; Glusman, Gustavo; Roach, Jared; Hood, Leroy; Galas, David; Wyman, Claire; Balling, Rudi; den Dunnen, Johan; de Winter, Johan P; Kanaar, Roland; Gelinas, Richard; Dorsman, Josephine C

    2015-01-01

    Fanconi anaemia (FA) is a hereditary disease featuring hypersensitivity to DNA cross-linker-induced chromosomal instability in association with developmental abnormalities, bone marrow failure and a strong predisposition to cancer. A total of 17 FA disease genes have been reported, all of which act in a recessive mode of inheritance. Here we report on a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in one allele of the homologous recombination DNA repair gene RAD51 in an FA-like patient. This heterozygous mutation causes a novel FA subtype, 'FA-R', which appears to be the first subtype of FA caused by a dominant-negative mutation. The patient, who features microcephaly and mental retardation, has reached adulthood without the typical bone marrow failure and paediatric cancers. Together with the recent reports on RAD51-associated congenital mirror movement disorders, our results point to an important role for RAD51-mediated homologous recombination in neurodevelopment, in addition to DNA repair and cancer susceptibility. PMID:26681308

  3. A cancer-predisposing "hot spot" mutation of the fumarase gene creates a dominant negative protein.

    PubMed

    Lorenzato, Annalisa; Olivero, Martina; Perro, Mario; Brière, Jean Jacques; Rustin, Pierre; Di Renzo, Maria Flavia

    2008-02-15

    The Fumarase (Fumarate Hydratase, FH) is a tumor suppressor gene whose germline heterozygous mutations predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). The FH gene encodes an enzyme of the Krebs cycle, functioning as a homotetramer and catalyzing the hydration of fumarate to malate. Among the numerous FH mutations reported so far, the R190H missense mutation is the most frequent in HLRCC patients. Here we show the functional analyses of the R190H, in comparison to the better characterized E319Q mutation. We first expressed wild-type and mutated proteins in FH deficient human skin fibroblasts, using lentiviral vectors. The wild-type transgene was able to restore the FH enzymatic activity in cells, while the R190H- and E319Q-FH were not. More interestingly, when the same transgenes were expressed in normal, FH-proficient cells, only the R190H-FH reduced the endogenous FH enzymatic activity. By enforcing the expression of equal amount of wild-type and R190H-FH in the same cell, we showed that the mutated FH protein directly inhibited enzymatic activity by nearly abrogating the FH homotetramer formation. These data demonstrate the dominant negative effect of the R190H missense mutation in the FH gene and suggest that the FH tumor-suppressing activity might be impaired in cells carrying a heterozygous mutation. PMID:17960613

  4. A dominant negative mutation in the conserved RNA helicase motif 'SAT' causes splicing factor PRP2 to stall in spliceosomes.

    PubMed Central

    Plumpton, M; McGarvey, M; Beggs, J D

    1994-01-01

    To characterize sequences in the RNA helicase-like PRP2 protein of Saccharomyces cerevisiae that are essential for its function in pre-mRNA splicing, a pool of random PRP2 mutants was generated. A dominant negative allele was isolated which, when overexpressed in a wild-type yeast strain, inhibited cell growth by causing a defect in pre-mRNA splicing. This defect was partially alleviated by simultaneous co-overexpression of wild-type PRP2. The dominant negative PRP2 protein inhibited splicing in vitro and caused the accumulation of stalled splicing complexes. Immunoprecipitation with anti-PRP2 antibodies confirmed that dominant negative PRP2 protein competed with its wild-type counterpart for interaction with spliceosomes, with which the mutant protein remained associated. The PRP2-dn1 mutation led to a single amino acid change within the conserved SAT motif that in the prototype helicase eIF-4A is required for RNA unwinding. Purified dominant negative PRP2 protein had approximately 40% of the wild-type level of RNA-stimulated ATPase activity. As ATPase activity was reduced only slightly, but splicing activity was abolished, we propose that the dominant negative phenotype is due primarily to a defect in the putative RNA helicase activity of PRP2 protein. Images PMID:8112301

  5. Expression of a dominant negative PKA mutation in the kidney elicits a diabetes insipidus phenotype

    PubMed Central

    Gilbert, Merle L.; Yang, Linghai; Su, Thomas

    2015-01-01

    PKA plays a critical role in water excretion through regulation of the production and action of the antidiuretic hormone arginine vasopressin (AVP). The AVP prohormone is produced in the hypothalamus, where its transcription is regulated by cAMP. Once released into the circulation, AVP stimulates antidiuresis through activation of vasopressin 2 receptors in renal principal cells. Vasopressin 2 receptor activation increases cAMP and activates PKA, which, in turn, phosphorylates aquaporin (AQP)2, triggering apical membrane accumulation, increased collecting duct permeability, and water reabsorption. We used single-minded homolog 1 (Sim1)-Cre recombinase-mediated expression of a dominant negative PKA regulatory subunit (RIαB) to disrupt kinase activity in vivo and assess the role of PKA in fluid homeostasis. RIαB expression gave rise to marked polydipsia and polyuria; however, neither hypothalamic Avp mRNA expression nor urinary AVP levels were attenuated, indicating a primary physiological effect on the kidney. RIαB mice displayed a marked deficit in urinary concentrating ability and greatly reduced levels of AQP2 and phospho-AQP2. Dehydration induced Aqp2 mRNA in the kidney of both control and RIαB-expressing mice, but AQP2 protein levels were still reduced in RIαB-expressing mutants, and mice were unable to fully concentrate their urine and conserve water. We conclude that partial PKA inhibition in the kidney leads to posttranslational effects that reduce AQP2 protein levels and interfere with apical membrane localization. These findings demonstrate a distinct physiological role for PKA signaling in both short- and long-term regulation of AQP2 and characterize a novel mouse model of diabetes insipidus. PMID:25587115

  6. Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy

    PubMed Central

    Ramos-Kuri, Manuel; Rapti, Kleopatra; Mehel, Hind; Zhang, Shihong; Dhandapany, Perundurai S.; Liang, Lifan; García-Carrancá, Alejandro; Bobe, Regis; Fischmeister, Rodolphe; Adnot, Serge; Lebeche, Djamel; Hajjar, Roger J.; Lipskaia, Larissa; Chemaly, Elie R.

    2015-01-01

    The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats. Ras functions were modulated via adenovirus directed gene transfer of active mutant Ras-Val12 or dominant negative mutant N17-DN-Ras (DN-Ras). Ras-Val12 expression in vitro activates NFAT resulting in pro-hypertrophic and cardio-toxic effects on NRCM beating and Z-line organization. In contrast, the DN-Ras was antihypertrophic on NRCM, inhibited NFAT and exerted cardio-protective effects attested by preserved NRCM beating and Z line structure. Additional experiments with silencing H-Ras gene strategy corroborated the antihypertrophic effects of siRNA-H-Ras on NRCM. In vivo, with the POH model, both Ras mutants were associated with similar hypertrophy two weeks after simultaneous induction of POH and Ras-mutant gene transfer. However, LV diameters were higher and LV fractional shortening lower in the Ras-Val12 group compared to control and DN-Ras. Moreover, DN-Ras reduced the cross-sectional area of cardiomyocytes in vivo, and decreased the expression of markers of pathologic cardiac hypertrophy. In isolated adult cardiomyocytes after 2 weeks of POH and Ras-mutant gene transfer, DN-Ras improved sarcomere shortening and calcium transients compared to Ras-Val12. Overall, DN-Ras promotes a more physiological form of hypertrophy, suggesting an interesting therapeutic target for pathological cardiac hypertrophy. PMID:26260012

  7. Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy.

    PubMed

    Ramos-Kuri, Manuel; Rapti, Kleopatra; Mehel, Hind; Zhang, Shihong; Dhandapany, Perundurai S; Liang, Lifan; García-Carrancá, Alejandro; Bobe, Regis; Fischmeister, Rodolphe; Adnot, Serge; Lebeche, Djamel; Hajjar, Roger J; Lipskaia, Larissa; Chemaly, Elie R

    2015-11-01

    The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats. Ras functions were modulated via adenovirus directed gene transfer of active mutant Ras-Val12 or dominant negative mutant N17-DN-Ras (DN-Ras). Ras-Val12 expression in vitro activates NFAT resulting in pro-hypertrophic and cardio-toxic effects on NRCM beating and Z-line organization. In contrast, the DN-Ras was antihypertrophic on NRCM, inhibited NFAT and exerted cardio-protective effects attested by preserved NRCM beating and Z line structure. Additional experiments with silencing H-Ras gene strategy corroborated the antihypertrophic effects of siRNA-H-Ras on NRCM. In vivo, with the POH model, both Ras mutants were associated with similar hypertrophy two weeks after simultaneous induction of POH and Ras-mutant gene transfer. However, LV diameters were higher and LV fractional shortening lower in the Ras-Val12 group compared to control and DN-Ras. Moreover, DN-Ras reduced the cross-sectional area of cardiomyocytes in vivo, and decreased the expression of markers of pathologic cardiac hypertrophy. In isolated adult cardiomyocytes after 2 weeks of POH and Ras-mutant gene transfer, DN-Ras improved sarcomere shortening and calcium transients compared to Ras-Val12. Overall, DN-Ras promotes a more physiological form of hypertrophy, suggesting an interesting therapeutic target for pathological cardiac hypertrophy.

  8. Expression of a dominant negative PKA mutation in the kidney elicits a diabetes insipidus phenotype.

    PubMed

    Gilbert, Merle L; Yang, Linghai; Su, Thomas; McKnight, G Stanley

    2015-03-15

    PKA plays a critical role in water excretion through regulation of the production and action of the antidiuretic hormone arginine vasopressin (AVP). The AVP prohormone is produced in the hypothalamus, where its transcription is regulated by cAMP. Once released into the circulation, AVP stimulates antidiuresis through activation of vasopressin 2 receptors in renal principal cells. Vasopressin 2 receptor activation increases cAMP and activates PKA, which, in turn, phosphorylates aquaporin (AQP)2, triggering apical membrane accumulation, increased collecting duct permeability, and water reabsorption. We used single-minded homolog 1 (Sim1)-Cre recombinase-mediated expression of a dominant negative PKA regulatory subunit (RIαB) to disrupt kinase activity in vivo and assess the role of PKA in fluid homeostasis. RIαB expression gave rise to marked polydipsia and polyuria; however, neither hypothalamic Avp mRNA expression nor urinary AVP levels were attenuated, indicating a primary physiological effect on the kidney. RIαB mice displayed a marked deficit in urinary concentrating ability and greatly reduced levels of AQP2 and phospho-AQP2. Dehydration induced Aqp2 mRNA in the kidney of both control and RIαB-expressing mice, but AQP2 protein levels were still reduced in RIαB-expressing mutants, and mice were unable to fully concentrate their urine and conserve water. We conclude that partial PKA inhibition in the kidney leads to posttranslational effects that reduce AQP2 protein levels and interfere with apical membrane localization. These findings demonstrate a distinct physiological role for PKA signaling in both short- and long-term regulation of AQP2 and characterize a novel mouse model of diabetes insipidus.

  9. The mismatch negativity (MMN) in basic research of central auditory processing: a review.

    PubMed

    Näätänen, R; Paavilainen, P; Rinne, T; Alho, K

    2007-12-01

    In the present article, the basic research using the mismatch negativity (MMN) and analogous results obtained by using the magnetoencephalography (MEG) and other brain-imaging technologies is reviewed. This response is elicited by any discriminable change in auditory stimulation but recent studies extended the notion of the MMN even to higher-order cognitive processes such as those involving grammar and semantic meaning. Moreover, MMN data also show the presence of automatic intelligent processes such as stimulus anticipation at the level of auditory cortex. In addition, the MMN enables one to establish the brain processes underlying the initiation of attention switch to, conscious perception of, sound change in an unattended stimulus stream.

  10. Dominant region: a basic feature for group motion analysis and its application to teamwork evaluation in soccer games

    NASA Astrophysics Data System (ADS)

    Taki, Tsuyoshi; Hasegawa, Jun-ichi

    1998-12-01

    This paper proposes a basic feature for quantitative measurement and evaluation of group behavior of persons. This feature called 'dominant region' is a kind of sphere of influence for each person in the group. The dominant region is defined as a region in where the person can arrive earlier than any other persons and can be formulated as Voronoi region modified by replacing the distance function with a time function. This time function is calculated based on a computational model of moving ability of the person. As an application of the dominant region, we present a motion analysis system of soccer games. The purpose of this system is to evaluate the teamwork quantitatively based on movement of all the players in the game. From experiments using motion pictures of actual games, it is suggested that the proposed feature is useful for measurement and evaluation of group behavior in team sports. This basic feature may be applied to other team ball games, such as American football, basketball, handball and water polo.

  11. Effects of eye dominance (left vs. right) and cannabis use on intermanual coordination and negative symptoms in schizophrenia patients.

    PubMed

    Gorynia, Inge; Schwaiger, Markus; Heinz, Andreas

    2014-12-01

    Based on the previous findings, it has been assumed that in schizophrenia patients, eye dominance and cannabis use will affect negative symptoms and intermanual coordination (IMC), an index of interhemispheric communication. But eye dominance, specifically the clinical findings for it, has been neglected in schizophrenia research. We therefore investigated its effects in 52 right-handed (36 right-eyed and 16 left-eyed) and 51 left-handed (35 left-eyed and 16 right-eyed) schizophrenia in-patients without and with drug use. Eye dominance affected IMC in all schizophrenia patients. When comparing right- and left-handers, we found that this result was only significant in the right-handed patients and in the smaller subgroup without drug use. In the right-handers, left eye dominance-like left-handedness-was associated with higher values in IMC and less pronounced manifestation of negative symptoms, right eye dominance was not. Thus, left-eyed right-handers may be more closely related to left-handers than to right-handers. In accordance with the results from the literature, we suggest that these findings are due to better interhemispheric connections and less impairment of white matter structures, especially in right-hemispheric regions. Moreover, cannabis use was related to higher scores in IMC and less pronounced negative symptoms, but only in the right-eyed and not in the left-eyed right-handers or in the left-handers. Hence, differences in eye dominance and handedness may be partially responsible for different results in interhemispheric connections among cannabis users. In conclusion, both eye dominance and use of cannabis should be taken into account when assessing clinical symptoms in schizophrenia patients.

  12. A pilot study examining if satisfaction of basic needs can ameliorate negative effects of shift work

    PubMed Central

    SAKSVIK-LEHOUILLIER, Ingvild; HETLAND, Hilde

    2015-01-01

    The objective of the present study was to investigate if satisfaction of the basic needs of autonomy, competence, and relatedness is related to shift work tolerance, specifically physical and mental fatigue, insomnia, and digestive troubles in a sample of shift workers. This is a cross-sectional pilot questionnaire study, including 252 shift workers employed in a municipality in Norway. Autonomy was negatively related to physical fatigue and digestive troubles, while competence was negatively related to mental fatigue. Relatedness showed significant correlations with insomnia and mental fatigue, but did not reach significance in the regression model controlling for the two other basic needs as well as work scheduling, night work exposure, and sleep medication. Sleep medication was significant in the final regression model for insomnia, but unrelated to fatigue and digestive troubles. The demographic variables, work hours per week, work schedule, and night work exposure were unrelated to all four measures of shift work tolerance. Autonomy and competence may be more important for fatigue and digestive troubles among shift workers than work arrangement variables, night work exposure, and sleep medication use. PMID:26423327

  13. Negative Borrowing in an Indigenous-Language Shift to the Dominant National Language

    ERIC Educational Resources Information Center

    Dorian, Nancy C.

    2006-01-01

    Receding languages in contact with an expanding language are susceptible to various forms of transfer, including covert transfer or negative borrowing, the elimination of features not shared by the expanding language. Retention of two Scottish Gaelic grammatical features with English parallels and of two grammatical features without English…

  14. A dominant-negative pleiotrophin mutant introduced by homologous recombination leads to germ-cell apoptosis in male mice.

    PubMed

    Zhang, N; Yeh, H J; Zhong, R; Li, Y S; Deuel, T F

    1999-06-01

    Pleiotrophin (PTN) is an 18-kDa heparin-binding secretory growth/differentiation factor for different cell types. Its gene is differentially expressed in both mesenchyme and central nervous system during development and highly expressed in a number of different human tumors. Recently, a PTN mutant was found to act as a dominant-negative effector of PTN signaling. We have now used homologous recombination to introduce the dominant-negative PTN mutant into embryonic stem cells to generate chimeric mice. All highly chimeric male mice with germinal epithelium exclusively derived from embryonic stem cells with the heterologous PTN mutation were sterile. Their testes were uniformly atrophic, and the spermatocytes were strikingly apoptotic at all stages of development. The results support a central role of PTN signaling in normal spermatogenesis and suggest that interruption of PTN signaling may lead to sterility in males.

  15. Dominant negative mutants of the Cdc2 kinase uncouple cell division from iterative plant development.

    PubMed Central

    Hemerly, A; Engler, J de A; Bergounioux, C; Van Montagu, M; Engler, G; Inzé, D; Ferreira, P

    1995-01-01

    Because plant cells do not move and are surrounded by a rigid cell wall, cell division rates and patterns are believed to be directly responsible for generating new structures throughout development. To study the relationship between cell division and morphogenesis, transgenic tobacco and Arabidopsis plants were constructed expressing dominant mutations in a key regulator of the Arabidopsis cell cycle, the Cdc2a kinase. Plants constitutively overproducing the wild-type Cdc2a or the mutant form predicted to accelerate the cell cycle did not exhibit a significantly altered development. In contrast, a mutation expected to arrest the cell cycle abolished cell division when expressed in Arabidopsis, whereas some tobacco plants constitutively producing this mutant protein were recovered. These plants had a reduced histone H1 kinase activity and contained considerably fewer cells. These cells were, however, much larger and underwent normal differentiation. Morphogenesis, histogenesis and developmental timing were unaffected. The results indicate that, in plants, the developmental controls defining shape can act independently from cell division rates. Images PMID:7664733

  16. Molecular cloning of ID4, a novel dominant negative helix-loop-helix human gene on chromosome 6p21.3-p22

    SciTech Connect

    Pagliuca, A.; Bartoli, P.C.; Saccone, S.

    1995-05-01

    Transcription factors containing a basic helix-loop-helix (bHLH) motif regulate the expression of tissue-specific genes in a number of mammalian and insect systems. DNA-binding activity of the bHLH proteins is dependent upon formation of homo- and/or heterodimers. Dominant negative HLH proteins (Id-related genes) also contain the HLH-dimerization domain but lack the DNA-binding basic domain. Consequently, Id proteins inhibit binding to DNA and transcriptional transactivation by heterodimerization with bHLH proteins. The authors report here the cDNA sequence of a novel human HLH gene (HGMW-approved symbol ID4) that lacks the basic domain. ID4 is differentially expressed in adult organs in four mRNA molecules, which are presumably a result of differential splicing and/or alternative usage of the polyadenylation sites. Transfection experiments indicated that enforced expression of Id-4H protein inhibits the trans-activation of the muscle creatine kinase E-box enhancer by MyoD. Finally, the authors localized the ID4 gene to the chromosome 6p21-p22 region. 18 refs., 4 figs.

  17. An ABCA1 truncation shows no dominant negative effect in a familial hypoalphalipoproteinemia pedigree with three ABCA1 mutations

    SciTech Connect

    Sorrenson, Brie; Suetani, Rachel J.; Bickley, Vivienne M.; George, Peter M.; Williams, Michael J.A.; Scott, Russell S.; McCormick, Sally P.A.

    2011-06-10

    Highlights: {yields} Characterisation of an ABCA1 truncation mutant, C978fsX988, in a pedigree with three ABCA1 mutations. {yields} Functional analysis of C978fsX988 in patient fibroblasts and HEK 293 cells shows no cholesterol efflux function. {yields} Allele-specific quantification shows C978fsX988 not expressed at mRNA level in fibroblasts. {yields} Unlike other ABCA1 truncations, C978fsX988 mutant shows no dominant negative effect at mRNA or protein level. -- Abstract: The ATP binding cassette transporter (ABCA1) A1 is a key determinant of circulating high density lipoprotein cholesterol (HDL-C) levels. Mutations in ABCA1 are a major genetic contributor to low HDL-C levels within the general population. Following the finding of three different ABCA1 mutations, p.C978fsX988, p.T1512M and p.N1800H in a subject with hypoalphalipoproteinemia, we aimed to establish whether the p.C978fsX988 truncation exerted a dominant negative effect on the full-length ABCA1 alleles within family members as has been reported for other ABCA1 truncations. Characterisation of the p.C978fsX988 mutant in transfected HEK 293 cells showed it to be expressed as a GFP fusion protein but lacking in cholesterol efflux function. This was in keeping with results from cholesterol efflux assays in the fibroblasts of p.C978fsX988 carriers which also showed impaired efflux. Allele- specific quantification of p.C978fsX988 mRNA and analysis of ABCA1 protein levels in the fibroblasts of p.C978fsX988 heterozygotes showed negligible levels of mRNA and protein expression. There was no evidence of a dominant negative effect on wildtype or p.N1800H protein levels. We conclude that in the case of the p.C978fsX988 truncated mutant a lack of expression precludes it from having a dominant negative effect.

  18. A Dominant Negative Heterozygous G87R Mutation in the Zinc Transporter, ZnT-2 (SLC30A2), Results in Transient Neonatal Zinc Deficiency

    PubMed Central

    Lasry, Inbal; Seo, Young Ah; Ityel, Hadas; Shalva, Nechama; Pode-Shakked, Ben; Glaser, Fabian; Berman, Bluma; Berezovsky, Igor; Goncearenco, Alexander; Klar, Aharon; Levy, Jacob; Anikster, Yair; Kelleher, Shannon L.; Assaraf, Yehuda G.

    2012-01-01

    Zinc is an essential mineral, and infants are particularly vulnerable to zinc deficiency as they require large amounts of zinc for their normal growth and development. We have recently described the first loss-of-function mutation (H54R) in the zinc transporter ZnT-2 (SLC30A2) in mothers with infants harboring transient neonatal zinc deficiency (TNZD). Here we identified and characterized a novel heterozygous G87R ZnT-2 mutation in two unrelated Ashkenazi Jewish mothers with infants displaying TNZD. Transient transfection of G87R ZnT-2 resulted in endoplasmic reticulum-Golgi retention, whereas the WT transporter properly localized to intracellular secretory vesicles in HC11 and MCF-7 cells. Consequently, G87R ZnT-2 showed decreased stability compared with WT ZnT-2 as revealed by Western blot analysis. Three-dimensional homology modeling based on the crystal structure of YiiP, a close zinc transporter homologue from Escherichia coli, revealed that the basic arginine residue of the mutant G87R points toward the membrane lipid core, suggesting misfolding and possible loss-of-function. Indeed, functional assays including vesicular zinc accumulation, zinc secretion, and cytoplasmic zinc pool assessment revealed markedly impaired zinc transport in G87R ZnT-2 transfectants. Moreover, co-transfection experiments with both mutant and WT transporters revealed a dominant negative effect of G87R ZnT-2 over the WT ZnT-2; this was associated with mislocalization, decreased stability, and loss of zinc transport activity of the WT ZnT-2 due to homodimerization observed upon immunoprecipitation experiments. These findings establish that inactivating ZnT-2 mutations are an underlying basis of TNZD and provide the first evidence for the dominant inheritance of heterozygous ZnT-2 mutations via negative dominance due to homodimer formation. PMID:22733820

  19. Enhancement of NK Cell Cytotoxicity Induced by Long-Term Living in Negatively Charged-Particle Dominant Indoor Air-Conditions

    PubMed Central

    Nishimura, Yasumitsu; Takahashi, Kazuaki; Mase, Akinori; Kotani, Muneo; Ami, Kazuhisa; Maeda, Megumi; Shirahama, Takashi; Lee, Suni; Matsuzaki, Hidenori; Kumagai-Takei, Naoko; Yoshitome, Kei; Otsuki, Takemi

    2015-01-01

    Investigation of house conditions that promote health revealed that negatively charged-particle dominant indoor air-conditions (NCPDIAC) induced immune stimulation. Negatively charged air-conditions were established using a fine charcoal powder on walls and ceilings and utilizing forced negatively charged particles (approximate diameter: 20 nm) dominant in indoor air-conditions created by applying an electric voltage (72 V) between the backside of the walls and the ground. We reported previously that these conditions induced a slight and significant increase of interleukin-2 during a 2.5-h stay and an increase of NK cell cytotoxicity when examining human subjects after a two-week night stay under these conditions. In the present study, seven healthy volunteers had a device installed to create NCPDIAC in the living or sleeping rooms of their own homes. Every three months the volunteers then turned the NCPDIAC device on or off. A total of 16 ON and 13 OFF trials were conducted and their biological effects were analyzed. NK activity increased during ON trials and decreased during OFF trials, although no other adverse effects were found. In addition, there were slight increases of epidermal growth factor (EGF) during ON trials. Furthermore, a comparison of the cytokine status between ON and OFF trials showed that basic immune status was stimulated slightly during ON trials under NCPIADC. Our overall findings indicate that the NCPDIAC device caused activation of NK activity and stimulated immune status, particularly only on NK activity, and therefore could be set in the home or office buildings. PMID:26173062

  20. Non dominant-negative KCNJ2 gene mutations leading to Andersen-Tawil syndrome with an isolated cardiac phenotype.

    PubMed

    Limberg, Maren M; Zumhagen, Sven; Netter, Michael F; Coffey, Alison J; Grace, Andrew; Rogers, Jane; Böckelmann, Doris; Rinné, Susanne; Stallmeyer, Birgit; Decher, Niels; Schulze-Bahr, Eric

    2013-05-01

    Andersen-Tawil syndrome (ATS) is characterized by dysmorphic features, periodic paralyses and abnormal ventricular repolarization. After genotyping a large set of patients with congenital long-QT syndrome, we identified two novel, heterozygous KCNJ2 mutations (p.N318S, p.W322C) located in the C-terminus of the Kir2.1 subunit. These mutations have a different localization than classical ATS mutations which are mostly located at a potential interaction face with the slide helix or at the interface between the C-termini. Mutation carriers were without the key features of ATS, causing an isolated cardiac phenotype. While the N318S mutants regularly reached the plasma membrane, W322C mutants primarily resided in late endosomes. Co-expression of N318S or W322C with wild-type Kir2.1 reduced current amplitudes only by 20-25 %. This mild loss-of-function for the heteromeric channels resulted from defective channel trafficking (W322C) or gating (N318S). Strikingly, and in contrast to the majority of ATS mutations, neither mutant caused a dominant-negative suppression of wild-type Kir2.1, Kir2.2 and Kir2.3 currents. Thus, a mild reduction of native Kir2.x currents by non dominant-negative mutants may cause ATS with an isolated cardiac phenotype.

  1. Expanding the prion concept to cancer biology: dominant-negative effect of aggregates of mutant p53 tumour suppressor

    PubMed Central

    Silva, Jerson L.; Rangel, Luciana P.; Costa, Danielly C. F.; Cordeiro, Yraima; De Moura Gallo, Claudia V.

    2013-01-01

    p53 is a key protein that participates in cell-cycle control, and its malfunction can lead to cancer. This tumour suppressor protein has three main domains; the N-terminal transactivation domain, the CTD (C-terminal domain) and the core domain (p53C) that constitutes the sequence-specific DBD (DNA-binding region). Most p53 mutations related to cancer development are found in the DBD. Aggregation of p53 into amyloid oligomers and fibrils has been shown. Moreover, amyloid aggregates of both the mutant and WT (wild-type) forms of p53 were detected in tumour tissues. We propose that if p53 aggregation occurred, it would be a crucial aspect of cancer development, as p53 would lose its WT functions in an aggregated state. Mutant p53 can also exert a dominant-negative regulatory effect on WT p53. Herein, we discuss the dominant-negative effect in light of p53 aggregation and the fact that amyloid-like mutant p53 can convert WT p53 into more aggregated species, leading into gain of function in addition to the loss of tumour suppressor function. In summary, the results obtained in the last decade indicate that cancer may have characteristics in common with amyloidogenic and prion diseases. PMID:24003888

  2. The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit.

    PubMed

    Raffaello, Anna; De Stefani, Diego; Sabbadin, Davide; Teardo, Enrico; Merli, Giulia; Picard, Anne; Checchetto, Vanessa; Moro, Stefano; Szabò, Ildikò; Rizzuto, Rosario

    2013-08-28

    Mitochondrial calcium uniporter (MCU) channel is responsible for Ruthenium Red-sensitive mitochondrial calcium uptake. Here, we demonstrate MCU oligomerization by immunoprecipitation and Förster resonance energy transfer (FRET) and characterize a novel protein (MCUb) with two predicted transmembrane domains, 50% sequence similarity and a different expression profile from MCU. Based on computational modelling, MCUb includes critical amino-acid substitutions in the pore region and indeed MCUb does not form a calcium-permeable channel in planar lipid bilayers. In HeLa cells, MCUb is inserted into the oligomer and exerts a dominant-negative effect, reducing the [Ca(2+)]mt increases evoked by agonist stimulation. Accordingly, in vitro co-expression of MCUb with MCU drastically reduces the probability of observing channel activity in planar lipid bilayer experiments. These data unveil the structural complexity of MCU and demonstrate a novel regulatory mechanism, based on the inclusion of dominant-negative subunits in a multimeric channel, that underlies the fine control of the physiologically and pathologically relevant process of mitochondrial calcium homeostasis.

  3. Dominant-negative Gα subunits are a mechanism of dysregulated heterotrimeric G protein signaling in human disease

    PubMed Central

    Marivin, Arthur; Leyme, Anthony; Parag-Sharma, Kshitij; DiGiacomo, Vincent; Cheung, Anthony Y.; Nguyen, Lien T.; Dominguez, Isabel; Garcia-Marcos, Mikel

    2016-01-01

    Auriculo-Condylar Syndrome (ACS), a rare condition that impairs craniofacial development, is caused by mutations in a G protein-coupled receptor (GPCR) signaling pathway. In mice, disruption of signaling by the endothelin type A receptor (ETAR), which is mediated by the G protein subunit Gαq/11 and subsequently phospholipase C (PLC), impairs neural crest cell differentiation that is required for normal craniofacial development. Some ACS patients have mutations in GNAI3, which encodes Gαi3, but it is unknown whether this G protein has a role within the ETAR pathway. Here, we used a Xenopus model of vertebrate development, in vitro biochemistry, and biosensors of G protein activity in mammalian cells to systematically characterize the phenotype and function of all known ACS-associated Gαi3 mutants. We found that ACS-associated mutations in GNAI3 produce dominant-negative Gαi3 mutant proteins that couple to ETAR but cannot bind and hydrolyze guanosine triphosphate, resulting in the prevention of endothelin-mediated activation of Gαq/11 and PLC. Thus, ACS is caused by functionally dominant-negative mutations in a heterotrimeric G protein subunit. PMID:27072656

  4. A novel mutation in IFN-gamma receptor 2 with dominant negative activity: biological consequences of homozygous and heterozygous states.

    PubMed

    Rosenzweig, Sergio D; Dorman, Susan E; Uzel, Gulbu; Shaw, Stephen; Scurlock, Amy; Brown, Margaret R; Buckley, Rebecca H; Holland, Steven M

    2004-09-15

    We identified two siblings homozygous for a single base pair deletion in the IFN-gammaR2 transmembrane domain (791delG) who presented with multifocal Mycobacterium abscessus osteomyelitis (patient 1) and disseminated CMV and Mycobacterium avium complex infection (patient 2), respectively. Although the patients showed no IFN-gammaR activity, their healthy heterozygous parents showed only partial IFN-gammaR activity. An HLA-identical bone marrow transplant from the mother led patient 1 to complete hemopoietic reconstitution, but only partial IFN-gammaR function. We cloned and expressed fluorescent fusion proteins of the wild-type IFN-gammaR2, an IFN-gammaR2 mutant previously described to produce a complete autosomal recessive deficiency (278del2), and of 791delG to determine whether the intermediate phenotype in the 791delG heterozygous state was caused by haploinsufficiency or a dominant negative effect. When cotransfected together with the wild-type vector into IFN-gammaR2-deficient fibroblasts, the fusion protein with 791delG inhibited IFN-gammaR function by 48.7 +/- 5%, whereas fusion proteins with 278del2 had no inhibitory effect. Confocal microscopy of 791delG fusion proteins showed aberrant diffuse intracellular accumulation without plasma membrane localization. The fusion protein created by 791delG did not complete Golgi processing, and was neither expressed on the plasma membrane, nor shed extracellularly. The mutant construct 791delG exerts dominant negative effects on IFN-gamma signaling without cell surface display, suggesting that it is acting on pathways other than those involved in cell surface recognition of ligand.

  5. A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect.

    PubMed

    McEntagart, Meriel; Williamson, Kathleen A; Rainger, Jacqueline K; Wheeler, Ann; Seawright, Anne; De Baere, Elfride; Verdin, Hannah; Bergendahl, L Therese; Quigley, Alan; Rainger, Joe; Dixit, Abhijit; Sarkar, Ajoy; López Laso, Eduardo; Sanchez-Carpintero, Rocio; Barrio, Jesus; Bitoun, Pierre; Prescott, Trine; Riise, Ruth; McKee, Shane; Cook, Jackie; McKie, Lisa; Ceulemans, Berten; Meire, Françoise; Temple, I Karen; Prieur, Fabienne; Williams, Jonathan; Clouston, Penny; Németh, Andrea H; Banka, Siddharth; Bengani, Hemant; Handley, Mark; Freyer, Elisabeth; Ross, Allyson; van Heyningen, Veronica; Marsh, Joseph A; Elmslie, Frances; FitzPatrick, David R

    2016-05-01

    Gillespie syndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited to the Deciphering Developmental Disorders study. Whole-exome or targeted sequence analysis identified plausible disease-causing ITPR1 mutations in 10/10 additional GS-affected individuals. These ultra-rare protein-altering variants affected only three residues in ITPR1: Glu2094 missense (one de novo, one co-segregating), Gly2539 missense (five de novo, one inheritance uncertain), and Lys2596 in-frame deletion (four de novo). No clinical or radiological differences were evident between individuals with different mutations. ITPR1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. The homo-tetrameric structure has been solved by cryoelectron microscopy. Using estimations of the degree of structural change induced by known recessive- and dominant-negative mutations in other disease-associated multimeric channels, we developed a generalizable computational approach to indicate the likely mutational mechanism. This analysis supports a dominant-negative mechanism for GS variants in ITPR1. In GS-derived lymphoblastoid cell lines (LCLs), the proportion of ITPR1-positive cells using immunofluorescence was significantly higher in mutant than control LCLs, consistent with an abnormality of nuclear calcium signaling feedback control. Super-resolution imaging supports the existence of an ITPR1-lined nucleoplasmic reticulum. Mice with Itpr1 heterozygous null mutations showed no major iris defects. Purkinje cells of the cerebellum appear to be the most sensitive to impaired ITPR1 function in humans. Iris hypoplasia is likely to result from either complete loss of ITPR1 activity or structure-specific disruption of multimeric interactions. PMID:27108798

  6. Exposure to negatively charged-particle dominant air-conditions on human lymphocytes in vitro activates immunological responses.

    PubMed

    Nishimura, Yasumitsu; Takahashi, Kazuaki; Mase, Akinori; Kotani, Muneo; Ami, Kazuhisa; Maeda, Megumi; Shirahama, Takashi; Lee, Suni; Matsuzaki, Hidenori; Kumagai-Takei, Naoko; Yoshitome, Kei; Otsuki, Takemi

    2015-12-01

    Indoor air-conditions may play an important role in human health. Investigation of house conditions that promote health revealed that negatively charged-particle dominant indoor air-conditions (NAC) induced immune stimulation. NAC was established using fine charcoal powder on walls and ceilings and utilizing forced negatively charged particles (approximate diameter: 20 nm) dominant in indoor air-conditions created by applying an electric voltage (72 V) between the backside of the walls and the ground. We reported previously that these conditions induced a slight and significant increase of interleukin-2 during 2.5 h stay, and an increase of natural killer (NK) cell cytotoxicity, when examining human subjects after a two-week night stay under these conditions. In the present study, we investigated whether exposure to NAC in vitro affects immune conditions. Although the concentrations of particles were different, an incubator for cell culture with NAC was set and cellular compositions and functions of various freshly isolated human lymphocytes derived from healthy donors were assayed in the NAC incubator and compared with those of cultures in a standard (STD) incubator. Results showed that NAC cultivation caused an increase of CD25 and PD-1 expressing cells in the CD4 positive fraction, enhancement of NK cell cytotoxicity, production of interferon-y (IFNγ), and slight enhancement of regulatory T cell function. In addition, the formula designated as the "immune-index" clearly differed between STD and NAC culture conditions. Thus, NAC conditions may promote human health through slight activation of the immune system against cancer cells and virus infection as shown by this in vitro study and our previously reported human studies.

  7. Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis

    PubMed Central

    Bejaoui, Khemissa; Uchida, Yoshikazu; Yasuda, Satoshi; Ho, Mengfatt; Nishijima, Masahiro; Brown, Robert H.; Holleran, Walter M.; Hanada, Kentaro

    2002-01-01

    Hereditary sensory neuropathy type 1 (HSN1) is a dominantly inherited degenerative disorder of the peripheral nerves. HSN1 is clinically and genetically heterogeneous. One form arises from mutations in the gene SPTLC1 encoding long-chain base 1 (LCB1), one of two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the initial step of sphingolipid synthesis. We have examined the effects of the mutations C133Y and C133W, which we have identified in two HSN1 families, on the function of SPT. Although in HSN1 lymphoblasts, the C133Y and C133W mutations do not alter the steady-state levels of LCB1 and LCB2 subunits, they result in reduced SPT activity and sphingolipid synthesis. Moreover, in a mutant Chinese hamster ovary (CHO) cell strain with defective SPT activity due to a lack of the LCB1 subunit, these mutations impair the ability of the LCB1 subunit to complement the SPT deficiency. Furthermore, the overproduction of either the LCB1C133Y or LCB1C133W subunit inhibits SPT activity in CHO cells despite the presence of wild-type LCB1. In addition, we demonstrate that in CHO cells the mutant LCB1 proteins, similar to the normal LCB1, can interact with the wild-type LCB2 subunit. These results indicate that the HSN1-associated mutations in LCB1 confer dominant negative effects on the SPT enzyme. PMID:12417569

  8. Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis.

    PubMed

    Bejaoui, Khemissa; Uchida, Yoshikazu; Yasuda, Satoshi; Ho, Mengfatt; Nishijima, Masahiro; Brown, Robert H; Holleran, Walter M; Hanada, Kentaro

    2002-11-01

    Hereditary sensory neuropathy type 1 (HSN1) is a dominantly inherited degenerative disorder of the peripheral nerves. HSN1 is clinically and genetically heterogeneous. One form arises from mutations in the gene SPTLC1 encoding long-chain base 1 (LCB1), one of two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the initial step of sphingolipid synthesis. We have examined the effects of the mutations C133Y and C133W, which we have identified in two HSN1 families, on the function of SPT. Although in HSN1 lymphoblasts, the C133Y and C133W mutations do not alter the steady-state levels of LCB1 and LCB2 subunits, they result in reduced SPT activity and sphingolipid synthesis. Moreover, in a mutant Chinese hamster ovary (CHO) cell strain with defective SPT activity due to a lack of the LCB1 subunit, these mutations impair the ability of the LCB1 subunit to complement the SPT deficiency. Furthermore, the overproduction of either the LCB1C133Y or LCB1C133W subunit inhibits SPT activity in CHO cells despite the presence of wild-type LCB1. In addition, we demonstrate that in CHO cells the mutant LCB1 proteins, similar to the normal LCB1, can interact with the wild-type LCB2 subunit. These results indicate that the HSN1-associated mutations in LCB1 confer dominant negative effects on the SPT enzyme. PMID:12417569

  9. A novel genetic system to isolate a dominant negative effector on DNA-binding activity of Oct-2.

    PubMed Central

    Terunuma, A; Shiba, K; Noda, T

    1997-01-01

    Recent studies have revealed that interactions between transcription factors play an important role in regulation of gene expression in eukaryotic cells. To isolate cDNA clones that dominantly inhibit the DNA-binding activity of Oct-2, chosen as a representative factor, we have developed a novel screening system. This employs an Escherichia coli tester strain carrying a modified lac operon as a reporter gene, with the lac operator sequence replaced by an octamer sequence. Oct-2 expressed in this tester strain represses the expression of the reporter gene and changes the phenotype of the cell from Lac+to Lac-. Introduction of a cDNA expression library prepared from a human T-cell line into the Oct-2-harboring tester strain allowed selection of three Lac+clones out of 1 x 10(5) transformants. One of them, hT86, encoding a putative zinc finger protein was found to derepress beta-galactosidase activity in the Oct-2-harboring tester strain at the transcriptional level. In gel mobility shift assays, hT86 attenuated the intensity of the retarded band composed of the octamer probe and Oct-2, suggesting a dominant negative effect on the DNA-binding activity of Oct-2. The strategy described here provides a new approach for studying protein-protein interactions that govern the complex regulation of gene expression. PMID:9115366

  10. Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability.

    PubMed

    Campbell, Matthew D; Witcher, Marc; Gopal, Anoop; Michele, Daniel E

    2016-05-01

    Delta-sarcoglycan is a component of the sarcoglycan subcomplex within the dystrophin-glycoprotein complex located at the plasma membrane of muscle cells. While recessive mutations in δ-sarcoglycan cause limb girdle muscular dystrophy 2F, dominant mutations in δ-sarcoglycan have been linked to inherited dilated cardiomyopathy (DCM). The purpose of this study was to investigate functional cellular defects present in adult cardiac myocytes expressing mutant δ-sarcoglycans harboring the dominant inherited DCM mutations R71T or R97Q. This study demonstrates that DCM mutant δ-sarcoglycans can be stably expressed in adult rat cardiac myocytes and traffic similarly to wild-type δ-sarcoglycan to the plasma membrane, without perturbing assembly of the dystrophin-glycoprotein complex. However, expression of DCM mutant δ-sarcoglycan in adult rat cardiac myocytes is sufficient to alter cardiac myocyte plasma membrane stability in the presence of mechanical strain. Upon cyclical cell stretching, cardiac myocytes expressing mutant δ-sarcoglycan R97Q or R71T have increased cell-impermeant dye uptake and undergo contractures at greater frequencies than myocytes expressing normal δ-sarcoglycan. Additionally, the R71T mutation creates an ectopic N-linked glycosylation site that results in aberrant glycosylation of the extracellular domain of δ-sarcoglycan. Therefore, appropriate glycosylation of δ-sarcoglycan may also be necessary for proper δ-sarcoglycan function and overall dystrophin-glycoprotein complex function. These studies demonstrate that DCM mutations in δ-sarcoglycan can exert a dominant negative effect on dystrophin-glycoprotein complex function leading to myocardial mechanical instability that may underlie the pathogenesis of δ-sarcoglycan-associated DCM.

  11. Dominant-Negative Androgen Receptor Inhibition of Intracrine Androgen-Dependent Growth of Castration-Recurrent Prostate Cancer

    PubMed Central

    Kantor, Boris; Li, Xiangping; Haack, Karin; Moore, Dominic T.; Wilson, Elizabeth M.

    2012-01-01

    Background Prostate cancer (CaP) is the second leading cause of cancer death in American men. Androgen deprivation therapy is initially effective in CaP treatment, but CaP recurs despite castrate levels of circulating androgen. Continued expression of the androgen receptor (AR) and its ligands has been linked to castration-recurrent CaP growth. Principal Finding In this report, the ligand-dependent dominant-negative ARΔ142–337 (ARΔTR) was expressed in castration-recurrent CWR-R1 cell and tumor models to elucidate the role of AR signaling. Expression of ARΔTR decreased CWR-R1 tumor growth in the presence and absence of exogenous testosterone (T) and improved survival in the presence of exogenous T. There was evidence for negative selection of ARΔTR transgene in T-treated mice. Mass spectrometry revealed castration-recurrent CaP dihydrotestosterone (DHT) levels sufficient to activate AR and ARΔTR. In the absence of exogenous testosterone, CWR-R1-ARΔTR and control cells exhibited altered androgen profiles that implicated epithelial CaP cells as a source of intratumoral AR ligands. Conclusion The study provides in vivo evidence that activation of AR signaling by intratumoral AR ligands is required for castration-recurrent CaP growth and that epithelial CaP cells produce sufficient active androgens for CaP recurrence during androgen deprivation therapy. Targeting intracrine T and DHT synthesis should provide a mechanism to inhibit AR and growth of castration-recurrent CaP. PMID:22272301

  12. Dominant-Negative FADD Rescues the In Vivo Fitness of a Cytomegalovirus Lacking an Antiapoptotic Viral Gene▿

    PubMed Central

    Čičin-Šain, Luka; Ruzsics, Zsolt; Podlech, Juergen; Bubić, Ivan; Menard, Carine; Jonjić, Stipan; Reddehase, Matthias J.; Koszinowski, Ulrich H.

    2008-01-01

    Genes that inhibit apoptosis have been described for many DNA viruses. Herpesviruses often contain even more than one gene to control cell death. Apoptosis inhibition by viral genes is postulated to contribute to viral fitness, although a formal proof is pending. To address this question, we studied the mouse cytomegalovirus (MCMV) protein M36, which binds to caspase-8 and blocks death receptor-induced apoptosis. The growth of MCMV recombinants lacking M36 (ΔM36) was attenuated in vitro and in vivo. In vitro, caspase inhibition by zVAD-fmk blocked apoptosis in ΔM36-infected macrophages and rescued the growth of the mutant. In vivo, ΔM36 infection foci in liver tissue contained significantly more apoptotic hepatocytes and Kupffer cells than did revertant virus foci, and apoptosis occurred during the early phase of virus replication prior to virion assembly. To further delineate the mode of M36 function, we replaced the M36 gene with a dominant-negative FADD (FADDDN) in an MCMV recombinant. FADDDN was expressed in cells infected with the recombinant and blocked the death-receptor pathway, replacing the antiapoptotic function of M36. Most importantly, FADDDN rescued ΔM36 virus replication, both in vitro and in vivo. These findings have identified the biological role of M36 and define apoptosis inhibition as a key determinant of viral fitness. PMID:18094168

  13. Glassy-state stabilization of a dominant negative inhibitor anthrax vaccine containing aluminum hydroxide and glycopyranoside lipid A adjuvants.

    PubMed

    Hassett, Kimberly J; Vance, David J; Jain, Nishant K; Sahni, Neha; Rabia, Lilia A; Cousins, Megan C; Joshi, Sangeeta; Volkin, David B; Middaugh, C Russell; Mantis, Nicholas J; Carpenter, John F; Randolph, Theodore W

    2015-02-01

    During transport and storage, vaccines may be exposed to temperatures outside of the range recommended for storage, potentially causing efficacy losses. To better understand and prevent such losses, dominant negative inhibitor (DNI), a recombinant protein antigen for a candidate vaccine against anthrax, was formulated as a liquid and as a glassy lyophilized powder with the adjuvants aluminum hydroxide and glycopyranoside lipid A (GLA). Freeze-thawing of the liquid vaccine caused the adjuvants to aggregate and decreased its immunogenicity in mice. Immunogenicity of liquid vaccines also decreased when stored at 40°C for 8 weeks, as measured by decreases in neutralizing antibody titers in vaccinated mice. Concomitant with efficacy losses at elevated temperatures, changes in DNI structure were detected by fluorescence spectroscopy and increased deamidation was observed by capillary isoelectric focusing (cIEF) after only 1 week of storage of the liquid formulation at 40°C. In contrast, upon lyophilization, no additional deamidation after 4 weeks at 40°C and no detectable changes in DNI structure or reduction in immunogenicity after 16 weeks at 40°C were observed. Vaccines containing aluminum hydroxide and GLA elicited higher immune responses than vaccines adjuvanted with only aluminum hydroxide, with more mice responding to a single dose. PMID:25581103

  14. Overexpression of the Dominant-Negative Form of Interferon Regulatory Factor 1 in Oligodendrocytes Protects against Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Ren, Zhihua; Wang, Yan; Tao, Duan; Liebenson, David; Liggett, Thomas; Goswami, Rajendra; Clarke, Robert; Stefoski, Dusan

    2011-01-01

    Interferon regulatory factor 1 (IRF-1) is a transcription factor that has been implicated in the pathogenesis of the human autoimmune demyelinating disease multiple sclerosis (MS) and in its animal model, experimental autoimmune encephalomyelitis (EAE). The goal of the present study was to directly examine the role of IRF-1 in oligodendrocyte injury and inflammatory demyelination. For the purpose of this study, we generated a transgenic mouse line (CNP/dnIRF-1) that overexpresses the dominant-negative form of IRF-1 (dnIRF1) specifically in oligodendrocytes. CNP/dnIRF-1 mice exhibited no phenotypic abnormalities but displayed suppressed IRF-1 signaling in oligodendrocytes. The major finding of our study was that the CNP/dnIRF-1 mice, compared with the wild-type mice, were protected against EAE, a phenomenon associated with significant reduction of inflammatory demyelination and with oligodendrocyte and axonal preservation. The observed protection was related to suppressed IRF-1 signaling and impaired expression of immune and proapoptotic genes in oligodendrocytes. No significant differences in the peripheral immune responses between the wild-type and the CNP/dnIRF-1 mice were identified throughout the experiments. This study indicates that IRF-1 plays a critical role in the pathogenesis of EAE by mediating oligodendrocyte response to inflammation and injury. It also suggests that oligodendrocytes are actively involved in the neuroimmune network, and that exploring oligodendrocyte-related pathogenic mechanisms, in addition to the conventional immune-based ones, may have important therapeutic implications in MS. PMID:21653838

  15. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans.

    PubMed

    Hikida, Takatoshi; Jaaro-Peled, Hanna; Seshadri, Saurav; Oishi, Kenichi; Hookway, Caroline; Kong, Stephanie; Wu, Di; Xue, Rong; Andradé, Manuella; Tankou, Stephanie; Mori, Susumu; Gallagher, Michela; Ishizuka, Koko; Pletnikov, Mikhail; Kida, Satoshi; Sawa, Akira

    2007-09-01

    Here, we report generation and characterization of Disrupted-In-Schizophrenia-1 (DISC1) genetically engineered mice as a potential model for major mental illnesses, such as schizophrenia. DISC1 is a promising genetic risk factor for major mental illnesses. In this transgenic model, a dominant-negative form of DISC1 (DN-DISC1) is expressed under the alphaCaMKII promoter. In vivo MRI of the DN-DISC1 mice detected enlarged lateral ventricles particularly on the left side, suggesting a link to the asymmetrical change in anatomy found in brains of patients with schizophrenia. Furthermore, selective reduction in the immunoreactivity of parvalbumin in the cortex, a marker for an interneuron deficit that may underlie cortical asynchrony, is observed in the DN-DISC1 mice. These results suggest that these transgenic mice may be used as a model for schizophrenia. DN-DISC1 mice also display several behavioral abnormalities, including hyperactivity, disturbance in sensorimotor gating and olfactory-associated behavior, and an anhedonia/depression-like deficit.

  16. A novel human aquaporin-4 splice variant exhibits a dominant-negative activity: a new mechanism to regulate water permeability

    PubMed Central

    De Bellis, Manuela; Pisani, Francesco; Mola, Maria Grazia; Basco, Davide; Catalano, Francesco; Nicchia, Grazia Paola; Svelto, Maria; Frigeri, Antonio

    2014-01-01

    Two major isoforms of aquaporin-4 (AQP4) have been described in human tissue. Here we report the identification and functional analysis of an alternatively spliced transcript of human AQP4, AQP4-Δ4, that lacks exon 4. In transfected cells AQP4-Δ4 is mainly retained in the endoplasmic reticulum and shows no water transport properties. When AQP4-Δ4 is transfected into cells stably expressing functional AQP4, the surface expression of the full-length protein is reduced. Furthermore, the water transport activity of the cotransfectants is diminished in comparison to transfectants expressing only AQP4. The observed down-regulation of both the expression and water channel activity of AQP4 is likely to originate from a dominant-negative effect caused by heterodimerization between AQP4 and AQP4-Δ4, which was detected in coimmunoprecipitation studies. In skeletal muscles, AQP4-Δ4 mRNA expression inversely correlates with the level of AQP4 protein and is physiologically associated with different types of skeletal muscles. The expression of AQP4-Δ4 may represent a new regulatory mechanism through which the cell-surface expression and therefore the activity of AQP4 can be physiologically modulated. PMID:24356448

  17. Allele-specific silencing of mutant p53 attenuates dominant-negative and gain-of-function activities

    PubMed Central

    Iyer, Swathi V.; Parrales, Alejandro; Begani, Priya; Narkar, Akshay; Adhikari, Amit S.; Martinez, Luis A.; Iwakuma, Tomoo

    2016-01-01

    Many p53 hotspot mutants not only lose the transcriptional activity, but also show dominant-negative (DN) and oncogenic gain-of-function (GOF) activities. Increasing evidence indicates that knockdown of mutant p53 (mutp53) in cancer cells reduces their aggressive properties, suggesting that survival and proliferation of cancer cells are, at least partially, dependent on the presence of mutp53. However, these p53 siRNAs can downregulate both wild-type p53 (wtp53) and mutp53, which limits their therapeutic applications. In order to specifically deplete mutp53, we have developed allele-specific siRNAs against p53 hotspot mutants and validated their biological effects in the absence or presence of wtp53. First, the mutp53-specific siRNAs selectively reduced protein levels of matched p53 mutants with minimal reduction in wtp53 levels. Second, downregulation of mutp53 in cancer cells expressing a mutp53 alone (p53mut) resulted in significantly decreased cell proliferation and migration. Third, transfection of mutp53-specific siRNAs in cancer cells expressing both wtp53 and mutp53 also reduced cell proliferation and migration with increased transcripts of p53 downstream target genes, which became further profound when cells were treated with an MDM2 inhibitor Nutlin-3a or a chemotherapeutic agent doxorubicin. These results indicate that depletion of mutp53 by its specific siRNA restored endogenous wtp53 activity in cells expressing both wtp53 and mutp53. This is the first study demonstrating biological effects and therapeutic potential of allele-specific silencing of mutp53 by mutp53-specific siRNAs in cancer cells expressing both wtp53 and mutp53, thus providing a novel strategy towards targeted cancer therapies. PMID:26700961

  18. Elevating CLIC4 in Multiple Cell Types Reveals a TGF- Dependent Induction of a Dominant Negative Smad7 Splice Variant

    PubMed Central

    Shukla, Anjali; Yang, Yihan; Madanikia, Sara; Ho, Yan; Li, Mangmang; Sanchez, Vanesa; Cataisson, Christophe; Huang, Jing; Yuspa, Stuart H.

    2016-01-01

    CLIC4 (Chloride intracellular channel 4) belongs to a family of putative intracellular chloride channel proteins expressed ubiquitously in multiple tissues. CLIC4 is predominantly soluble and traffics between the cytoplasm and nucleus and participates in cell cycle control and differentiation. Transforming growth factor beta (TGF-β) elevates CLIC4, which enhances TGF-β signaling through CLIC4 mediated stabilization of phospho-Smad2/3. CLIC4 is essential for TGF-β induced conversion of fibroblasts to myofibroblasts and expression of matrix proteins, signaling via the p38MAPK pathway. Therefore, regulation of TGF-β signaling is a major mechanism by which CLIC4 modifies normal growth and differentiation. We now report that elevated CLIC4 alters Smad7 function, a feedback inhibitor of the TGF-β pathway. Overexpression of CLIC4 in keratinocytes, mouse embryonic fibroblasts and other mouse and human cell types increases the expression of Smad7Δ, a novel truncated form of Smad7. The alternatively spliced Smad7Δ variant is missing 94bp in exon 4 of Smad 7 and is conserved between mouse and human cells. The deletion is predicted to lack the TGF-β signaling inhibitory MH2 domain of Smad7. Treatment with exogenous TGF-β1 also enhances expression of Smad7Δ that is amplified in the presence of CLIC4. While Smad7 expression inhibits TGF-β signaling, exogenously expressed Smad7Δ does not inhibit TGF-β signaling as determined by TGF-β dependent proliferation, reporter assays and phosphorylation of Smad proteins. Instead, exogenous Smad7Δ acts as a dominant negative inhibitor of Smad7, thus increasing TGF-β signaling. This discovery adds another dimension to the myriad ways by which CLIC4 modifies TGF-β signaling. PMID:27536941

  19. Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance.

    PubMed

    Stump, Madeliene; Guo, Deng-Fu; Lu, Ko-Ting; Mukohda, Masashi; Liu, Xuebo; Rahmouni, Kamal; Sigmund, Curt D

    2016-07-01

    Peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPARγ in mouse brain, and specifically in the pro-opiomelanocortin (POMC) neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPARγ in POMC neurons controls energy balance, we constructed a Cre-recombinase-dependent conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ and the tdTomato reporter. Inducible expression of both forms of PPARγ was validated in cells in culture, in liver of mice infected with an adenovirus expressing Cre-recombinase (AdCre), and in the brain of mice expressing Cre-recombinase either in all neurons (NES(Cre)/PPARγ-P467L) or selectively in POMC neurons (POMC(Cre)/PPARγ-P467L). Whereas POMC(Cre)/PPARγ-P467L mice exhibited a normal pattern of weight gain when fed 60% high-fat diet, they exhibited increased weight gain and fat mass accumulation in response to a 10% fat isocaloric-matched control diet. POMC(Cre)/PPARγ-P467L mice were leptin sensitive on control diet but became leptin resistant when fed 60% high-fat diet. There was no difference in body weight between POMC(Cre)/PPARγ-WT mice and controls in response to 60% high-fat diet. However, POMC(Cre)/PPARγ-WT, but not POMC(Cre)/PPARγ-P467L, mice increased body weight in response to rosiglitazone, a PPARγ agonist. These observations support the concept that alterations in PPARγ-driven mechanisms in POMC neurons can play a role in the regulation of metabolic homeostasis under certain dietary conditions. PMID:27199455

  20. Expression of a dominant-negative Ras mutant does not affect stimulation of glucose uptake and glycogen synthesis by insulin.

    PubMed

    Dorrestijn, J; Ouwens, D M; Van den Berghe, N; Bos, J L; Maassen, J A

    1996-05-01

    It has previously been shown that insulin-induced stimulation of glucose uptake and glycogen synthesis requires activation of phosphatidylinositol-3-kinase (PI3kinase). Insulin also induces formation of RasGTP in cells and various studies have yielded inconsistent data with respect to the contribution of signalling pathways activated by RasGTP, to insulin-stimulated glucose uptake and glycogen synthesis. We have examined the requirement of RasGTP-mediated signalling for these insulin responses by expression of a dominant negative mutant of Ras (RasN17) in cells by vaccinia virus mediated gene transfer. This Ras-mutant abrogates the signalling pathways mediated by endogenous RasGTP. Subsequently, the ability of insulin to stimulate 2-deoxyglucose uptake and glycogen was examined. We observed that expression of RasN17 in 3T3L1 adipocytes did not affect the stimulation of hexose uptake by insulin. Similarly, expression of RasN17 in A14 cells, an NIH 3T3-derived cell line with high expression of insulin receptors, did not affect insulin-induced stimulation of glycogen synthesis. In both cell lines, insulin-induced phosphorylation of Mapkinase (Erk1,2) was abrogated after expression of RasN17, demonstrating the functional interference by RasN17 with signalling mediated by endogenous RasGTP. Wortmannin, an inhibitor of PI3kinase, abolished dose-dependently the insulin-induced stimulation of hexose uptake and glycogen synthesis without an effect on RasGTP levels in both cell types. We conclude that stimulation of glucose transport and glycogen synthesis by insulin occurs independently of RasGTP-mediated signalling.

  1. A Dominant Negative ERβ Splice Variant Determines the Effectiveness of Early or Late Estrogen Therapy after Ovariectomy in Rats

    PubMed Central

    Wang, Jun Ming; Hou, Xu; Adeosun, Samuel; Hill, Rosanne; Henry, Sherry; Paul, Ian; Irwin, Ronald W.; Ou, Xiao-Ming; Bigler, Steven; Stockmeier, Craig; Brinton, Roberta Diaz; Gomez-Sanchez, Elise

    2012-01-01

    The molecular mechanisms for the discrepancy in outcome of initiating estrogen therapy (ET) around peri-menopause or several years after menopause in women are unknown. We hypothesize that the level of expression of a dominant negative estrogen receptor (ER) β variant, ERβ2, may be a key factor determining the effectiveness of ET in post-menopausal women. We tested this hypothesis in ovariectomized nine month-old (an age when irregular estrous cycles occur) female Sprague Dawley rats. Estradiol treatment was initiated either 6 days (Early ET, analogous to 4 months post-menopause in humans), or 180 days (Late ET, analogous to 11 years post-menopause in humans) after ovariectomy. Although ERβ2 expression increased in all OVX rats, neurogenic and neuroprotective responses to estradiol differed in Early and Late ET. Early ET reduced ERβ2 expression in both hippocampus and white blood cells, increased the hippocampal cell proliferation as assessed by Ki-67 expression, and improved mobility in the forced swim test. Late ET resulted in either no or modest effects on these parameters. There was a close correlation between the degree of ERβ2 expression and the preservation of neural effects by ET after OVX in rats, supporting the hypothesis that persistent elevated levels of ERβ2 are a molecular basis for the diminished effectiveness of ET in late post-menopausal women. The correlation between the expression of ERβ2 in circulating white blood cells and brain cells suggests that ERβ2 expression in peripheral blood cells may be an easily accessible marker to predict the effective window for ET in the brain. PMID:22428062

  2. An alternative splicing product of the murine trpv1 gene dominant negatively modulates the activity of TRPV1 channels.

    PubMed

    Wang, Chunbo; Hu, Hong-Zhen; Colton, Craig K; Wood, Jackie D; Zhu, Michael X

    2004-09-01

    Transient receptor potential vanilloid 1 (TRPV1), or vanilloid receptor 1, is the founding member of the vanilloid type of TRP superfamily of nonselective cation channels. TRPV1 is activated by noxious heat, acid, and alkaloid irritants as well as several endogenous ligands and is sensitized by inflammatory factors, thereby serving important functions in detecting noxious stimuli in the sensory system and pathological states in different parts of the body. Whereas numerous studies have been carried out using the rat and human TRPV1 cDNA, the mouse TRPV1 cDNA has not been characterized. Here, we report molecular cloning of two TRPV1 cDNA variants from dorsal root ganglia of C57BL/6 mice. The deduced proteins are designated TRPV1alpha and TRPV1beta and contain 839 and 829 amino acids, respectively. TRPV1beta arises from an alternative intron recognition signal within exon 7 of the trpv1 gene. We found a predominant expression of TRPV1alpha in many tissues and significant expression of TRPV1beta in dorsal root ganglia, skin, stomach, and tongue. When expressed in HEK 293 cells or Xenopus oocytes, TRPV1alpha formed a Ca(2+)-permeable channel activated by ligands known to stimulate TRPV1. TRPV1beta was not functional by itself but its co-expression inhibited the function of TRPV1alpha. Furthermore, although both isoforms were synthesized at a similar rate, less TRPV1beta than TRPV1alpha protein was found in cells and on the cell surface, indicating that the beta isoform is highly unstable. Our data suggest that TRPV1beta is a naturally occurring dominant-negative regulator of the responses of sensory neurons to noxious stimuli. PMID:15234965

  3. In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.

    PubMed

    Anderson, Blair R; Howell, David N; Soldano, Karen; Garrett, Melanie E; Katsanis, Nicholas; Telen, Marilyn J; Davis, Erica E; Ashley-Koch, Allison E

    2015-07-01

    African Americans have a disproportionate risk for developing nephropathy. This disparity has been attributed to coding variants (G1 and G2) in apolipoprotein L1 (APOL1); however, there is little functional evidence supporting the role of this protein in renal function. Here, we combined genetics and in vivo modeling to examine the role of apol1 in glomerular development and pronephric filtration and to test the pathogenic potential of APOL1 G1 and G2. Translational suppression or CRISPR/Cas9 genome editing of apol1 in zebrafish embryos results in podocyte loss and glomerular filtration defects. Complementation of apol1 morphants with wild-type human APOL1 mRNA rescues these defects. However, the APOL1 G1 risk allele does not ameliorate defects caused by apol1 suppression and the pathogenicity is conferred by the cis effect of both individual variants of the G1 risk haplotype (I384M/S342G). In vivo complementation studies of the G2 risk allele also indicate that the variant is deleterious to protein function. Moreover, APOL1 G2, but not G1, expression alone promotes developmental kidney defects, suggesting a possible dominant-negative effect of the altered protein. In sickle cell disease (SCD) patients, we reported previously a genetic interaction between APOL1 and MYH9. Testing this interaction in vivo by co-suppressing both transcripts yielded no additive effects. However, upon genetic or chemical induction of anemia, we observed a significantly exacerbated nephropathy phenotype. Furthermore, concordant with the genetic interaction observed in SCD patients, APOL1 G2 reduces myh9 expression in vivo, suggesting a possible interaction between the altered APOL1 and myh9. Our data indicate a critical role for APOL1 in renal function that is compromised by nephropathy-risk encoding variants. Moreover, our interaction studies indicate that the MYH9 locus is also relevant to the phenotype in a stressed microenvironment and suggest that consideration of the context

  4. A Dominant-negative Gα Mutant That Traps a Stable Rhodopsin-Gα-GTP-βγ Complex*

    PubMed Central

    Ramachandran, Sekar; Cerione, Richard A.

    2011-01-01

    Residues comprising the guanine nucleotide-binding sites of the α subunits of heterotrimeric (large) G-proteins (Gα subunits), as well as the Ras-related (small) G-proteins, are highly conserved. This is especially the case for the phosphate-binding loop (P-loop) where both Gα subunits and Ras-related G-proteins have a conserved serine or threonine residue. Substitutions for this residue in Ras and related (small) G-proteins yield nucleotide-depleted, dominant-negative mutants. Here we have examined the consequences of changing the conserved serine residue in the P-loop to asparagine, within a chimeric Gα subunit (designated αT*) that is mainly comprised of the α subunit of the retinal G-protein transducin and a limited region from the α subunit of Gi1. The αT*(S43N) mutant exhibits a significantly higher rate of intrinsic GDP-GTP exchange compared with wild-type αT*, with light-activated rhodopsin (R*) causing only a moderate increase in the kinetics of nucleotide exchange on αT*(S43N). The αT*(S43N) mutant, when bound to either GDP or GTP, was able to significantly slow the rate of R*-catalyzed GDP-GTP exchange on wild-type αT*. Thus, GTP-bound αT*(S43N), as well as the GDP-bound mutant, is capable of forming a stable complex with R*. αT*(S43N) activated the cGMP phosphodiesterase (PDE) with a dose-response similar to wild-type αT*. Activation of the PDE by αT*(S43N) was unaffected if either R* or β1γ1 alone was present, whereas it was inhibited when R* and the β1γ1 subunit were added together. Overall, our studies suggest that the S43N substitution on αT* stabilizes an intermediate on the G-protein activation pathway consisting of an activated G-protein-coupled receptor, a GTP-bound Gα subunit, and the β1γ1 complex. PMID:21285355

  5. Improved wound management by regulated negative pressure-assisted wound therapy and regulated, oxygen- enriched negative pressure-assisted wound therapy through basic science research and clinical assessment.

    PubMed

    Topaz, Moris

    2012-05-01

    Regulated negative pressure-assisted wound therapy (RNPT) should be regarded as a state-of-the-art technology in wound treatment and the most important physical, nonpharmaceutical, platform technology developed and applied for wound healing in the last two decades. RNPT systems maintain the treated wound's environment as a semi-closed, semi-isolated system applying external physical stimulations to the wound, leading to biological and biochemical effects, with the potential to substantially influence wound-host interactions, and when properly applied may enhance wound healing. RNPT is a simple, safe, and affordable tool that can be utilized in a wide range of acute and chronic conditions, with reduced need for complicated surgical procedures, and antibiotic treatment. This technology has been shown to be effective and safe, saving limbs and lives on a global scale. Regulated, oxygen-enriched negative pressure-assisted wound therapy (RO-NPT) is an innovative technology, whereby supplemental oxygen is concurrently administered with RNPT for their synergistic effect on treatment and prophylaxis of anaerobic wound infection and promotion of wound healing. Understanding the basic science, modes of operation and the associated risks of these technologies through their fundamental clinical mechanisms is the main objective of this review.

  6. Improved wound management by regulated negative pressure-assisted wound therapy and regulated, oxygen- enriched negative pressure-assisted wound therapy through basic science research and clinical assessment.

    PubMed

    Topaz, Moris

    2012-05-01

    Regulated negative pressure-assisted wound therapy (RNPT) should be regarded as a state-of-the-art technology in wound treatment and the most important physical, nonpharmaceutical, platform technology developed and applied for wound healing in the last two decades. RNPT systems maintain the treated wound's environment as a semi-closed, semi-isolated system applying external physical stimulations to the wound, leading to biological and biochemical effects, with the potential to substantially influence wound-host interactions, and when properly applied may enhance wound healing. RNPT is a simple, safe, and affordable tool that can be utilized in a wide range of acute and chronic conditions, with reduced need for complicated surgical procedures, and antibiotic treatment. This technology has been shown to be effective and safe, saving limbs and lives on a global scale. Regulated, oxygen-enriched negative pressure-assisted wound therapy (RO-NPT) is an innovative technology, whereby supplemental oxygen is concurrently administered with RNPT for their synergistic effect on treatment and prophylaxis of anaerobic wound infection and promotion of wound healing. Understanding the basic science, modes of operation and the associated risks of these technologies through their fundamental clinical mechanisms is the main objective of this review. PMID:23162229

  7. Improved wound management by regulated negative pressure-assisted wound therapy and regulated, oxygen- enriched negative pressure-assisted wound therapy through basic science research and clinical assessment

    PubMed Central

    Topaz, Moris

    2012-01-01

    Regulated negative pressure-assisted wound therapy (RNPT) should be regarded as a state-of-the-art technology in wound treatment and the most important physical, nonpharmaceutical, platform technology developed and applied for wound healing in the last two decades. RNPT systems maintain the treated wound's environment as a semi-closed, semi-isolated system applying external physical stimulations to the wound, leading to biological and biochemical effects, with the potential to substantially influence wound-host interactions, and when properly applied may enhance wound healing. RNPT is a simple, safe, and affordable tool that can be utilized in a wide range of acute and chronic conditions, with reduced need for complicated surgical procedures, and antibiotic treatment. This technology has been shown to be effective and safe, saving limbs and lives on a global scale. Regulated, oxygen-enriched negative pressure-assisted wound therapy (RO-NPT) is an innovative technology, whereby supplemental oxygen is concurrently administered with RNPT for their synergistic effect on treatment and prophylaxis of anaerobic wound infection and promotion of wound healing. Understanding the basic science, modes of operation and the associated risks of these technologies through their fundamental clinical mechanisms is the main objective of this review. PMID:23162229

  8. Probing the structure, function, and interactions of the Escherichia coli H-NS and StpA proteins by using dominant negative derivatives.

    PubMed

    Williams, R M; Rimsky, S; Buc, H

    1996-08-01

    Twelve different dominant negative mutants of the Escherichia coli nucleoid-associated protein, H-NS, have been selected and characterized in vivo. The mutants are all severely defective in promoter repression activity in a strain lacking H-NS, and they all disrupt the repression normally exerted by H-NS at two of its target promoters. From the locations of the alterations in these mutants, which result in both large truncations and amino acid substitutions, we propose that H-NAS contains at least two distinct domains. The in vitro protein-protein cross-linking data presented in this report indicate that the proposed N-terminal domain of H-NS has a role in H-NS multimerization. StpA is a protein with known structural and functional homologies to H-NS. We have analyzed the extent of these homologies by constructing and studying StpA mutants predicted to be dominant negative. Our data indicate that the substitutions and deletions found in dominant negative H-NS have similar effects in the context of StpA. We conclude that the domain organizations and functions in StpA and H-NS are closely related. Furthermore, dominant negative H-NS can disrupt the activity of native StpA, and reciprocally, dominant negative StpA can disrupt the activity of native H-NS. We demonstrate that the N-terminal domain of H-NS can be chemically cross-linked to both full-length H-NS and StpA. We account for these observations by proposing that H-NS and StpA have the ability to form hybrid species.

  9. Altered promoter recycling rates contribute to dominant-negative activity of human peroxisome proliferator-activated receptor-gamma mutations associated with diabetes.

    PubMed

    Li, Gang; Leff, Todd

    2007-04-01

    The transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma) plays an important role in regulating lipid and glucose metabolism and improves insulin sensitivity in diabetic patients when activated by thiazolidinedione drugs. Several loss-of-function mutations in PPARgamma have been identified that cause lipodystrophy and diabetes in humans. Because affected individuals are heterozygotes and have one normal PPARgamma allele, it is of interest to know whether these mutations act in a dominant-negative fashion to inhibit the activity of the wild-type (WT) receptor. Here we compare the molecular phenotypes of two previously identified PPARgamma mutations: P467L, reported to be dominant negative; and F388L, reported to be devoid of dominant-negative activity. We developed a competitive chromatin immunoprecipitation assay to measure the relative ability of mutant PPARgamma to compete with WT receptor for binding to a PPAR regulatory element (PPRE)-containing promoter. By determining the ratio of mutant and WT receptors bound to a PPRE over time, we estimated the relative promoter turnover rate of each receptor. This assay demonstrated that PPARgamma bearing the P467L had a reduced promoter turnover rate compared with the F388L receptor, and over time out-competed the WT receptor for promoter binding sites. We propose that the P467L receptor is dominant negative because in a cell containing both WT and mutant receptors, the majority of the PPAR-regulated promoters will be occupied by the transcriptionally defective mutant receptor. In contrast, the F388L mutation lacks dominant-negative activity because its more rapid promoter turnover rate prevented it from out-competing the WT receptor for promoter binding sites.

  10. The structural basis of the dominant negative phenotype of the Gαi1β1γ2 G203A/A326S heterotrimer

    PubMed Central

    Liu, Ping; Jia, Ming-zhu; Zhou, X Edward; De Waal, Parker W; Dickson, Bradley M; Liu, Bo; Hou, Li; Yin, Yan-ting; Kang, Yan-yong; Shi, Yi; Melcher, Karsten; Xu, H Eric; Jiang, Yi

    2016-01-01

    Aim: Dominant negative mutant G proteins have provided critical insight into the mechanisms of G protein-coupled receptor (GPCR) signaling, but the mechanisms underlying the dominant negative characteristics are not completely understood. The aim of this study was to determine the structure of the dominant negative Gαi1β1γ2 G203A/A326S complex (Gi-DN) and to reveal the structural basis of the mutation-induced phenotype of Gαi1β1γ2. Methods: The three subunits of the Gi-DN complex were co-expressed with a baculovirus expression system. The Gi-DN heterotrimer was purified, and the structure of its complex with GDP was determined through X-ray crystallography. Results: The Gi-DN heterotrimer structure revealed a dual mechanism underlying the dominant negative characteristics. The mutations weakened the hydrogen bonding network between GDP/GTP and the binding pocket residues, and increased the interactions in the Gα-Gβγ interface. Concomitantly, the Gi-DN heterotrimer adopted a conformation, in which the C-terminus of Gαi and the N-termini of both the Gβ and Gγ subunits were more similar to the GPCR-bound state compared with the wild type complex. From these structural observations, two additional mutations (T48F and D272F) were designed that completely abolish the GDP binding of the Gi-DN heterotrimer. Conclusion: Overall, the results suggest that the mutations impede guanine nucleotide binding and Gα-Gβγ protein dissociation and favor the formation of the G protein/GPCR complex, thus blocking signal propagation. In addition, the structure provides a rationale for the design of other mutations that cause dominant negative effects in the G protein, as exemplified by the T48F and D272F mutations. PMID:27498775

  11. Effect of basic physical parameters to control plasma meniscus and beam halo formation in negative ion sources

    SciTech Connect

    Miyamoto, K.; Okuda, S.; Nishioka, S.; Hatayama, A.

    2013-09-14

    Our previous study shows that the curvature of the plasma meniscus causes the beam halo in the negative ion sources: the negative ions extracted from the periphery of the meniscus are over-focused in the extractor due to the electrostatic lens effect, and consequently become the beam halo. In this article, the detail physics of the plasma meniscus and beam halo formation is investigated with two-dimensional particle-in-cell simulation. It is shown that the basic physical parameters such as the H{sup −} extraction voltage and the effective electron confinement time significantly affect the formation of the plasma meniscus and the resultant beam halo since the penetration of electric field for negative ion extraction depends on these physical parameters. Especially, the electron confinement time depends on the characteristic time of electron escape along the magnetic field as well as the characteristic time of electron diffusion across the magnetic field. The plasma meniscus penetrates deeply into the source plasma region when the effective electron confinement time is short. In this case, the curvature of the plasma meniscus becomes large, and consequently the fraction of the beam halo increases.

  12. Dominant Negative Mutants of Bacillus thuringiensis Cry1Ab Toxin Function as Anti-Toxins: Demonstration of the Role of Oligomerization in Toxicity

    PubMed Central

    Rodríguez-Almazán, Claudia; Zavala, Luis Enrique; Muñoz-Garay, Carlos; Jiménez-Juárez, Nuria; Pacheco, Sabino; Masson, Luke; Soberón, Mario; Bravo, Alejandra

    2009-01-01

    Background Bacillus thuringiensis Cry toxins, that are used worldwide in insect control, kill insects by a mechanism that depends on their ability to form oligomeric pores that insert into the insect-midgut cells. These toxins are being used worldwide in transgenic plants or spray to control insect pests in agriculture. However, a major concern has been the possible effects of these insecticidal proteins on non-target organisms mainly in ecosystems adjacent to agricultural fields. Methodology/Principal Findings We isolated and characterized 11 non-toxic mutants of Cry1Ab toxin affected in different steps of the mechanism of action namely binding to receptors, oligomerization and pore-formation. These mutant toxins were analyzed for their capacity to block wild type toxin activity, presenting a dominant negative phenotype. The dominant negative phenotype was analyzed at two levels, in vivo by toxicity bioassays against susceptible Manduca sexta larvae and in vitro by pore formation activity in black lipid bilayers. We demonstrate that some mutations located in helix α-4 completely block the wild type toxin activity at sub-stoichiometric level confirming a dominant negative phenotype, thereby functioning as potent antitoxins. Conclusions/Significance This is the first reported case of a Cry toxin dominant inhibitor. These data demonstrate that oligomerization is a fundamental step in Cry toxin action and represent a potential mechanism to protect special ecosystems from the possible effect of Cry toxins on non-target organisms. PMID:19440244

  13. Hair penalties: the negative influence of Afrocentric hair on ratings of Black women’s dominance and professionalism

    PubMed Central

    Opie, Tina R.; Phillips, Katherine W.

    2015-01-01

    Purpose: Women are penalized if they do not behave in a stereotype-congruent manner (Heilman, 1983, 2001; Eagly and Carli, 2007). For example, because women are not expected to be agentic they incur an “agency penalty” for expressing anger, dominance or assertiveness (Rudman, 1998; Rudman and Glick, 1999, 2001; Eagly and Karau, 2002; Rudman and Fairchild, 2004; Brescoll and Uhlmann, 2008; Livingston et al., 2012). Yet, all women are not equally penalized (Livingston et al., 2012). We make a novel contribution by examining how both White and Black evaluators respond to displays of Black women’s dominance, in this case, whether Black women choose to wear Afrocentric or Eurocentric hairstyles. Design/methodology/approach: We conducted three experimental studies to examine the influence of target hairstyle and participant race on ratings of the target’s professionalism (Studies 1, 2, and 3) and dominance (Study 2). Study 1 was an online experimental study with 200 participants (112 females, 87 males, 1 missing gender; 160 Whites, 19 Blacks, 11 Latinos, 7 Asian Americans and 3 who identify as “other”; Mage = 35.5, SD = 11.4). Study 2 was an online experimental study with 510 participants (276 women, 234 males; 256 Blacks, 254 Whites; Mage = 41.25 years, SD = 12.21). Study 3 was an online experimental study with 291 participants (141 Blacks, 150 Whites, Mage = 47.5 years, SD = 11.66). Findings: Black, as compared to White, evaluators gave higher agency penalties to Black employment candidates when they donned Afrocentric versus Eurocentric hair, rating them as more dominant and less professional. Implications: The present research illustrates the significance of considering both target and evaluator race when examining the influence of agency, and specifically dominance, on ratings of professionalism. PMID:26379612

  14. A poor start in life negatively affects dominance status in adulthood independent of body size in green swordtails Xiphophorus helleri.

    PubMed

    Royle, Nick J; Lindström, Jan; Metcalfe, Neil B

    2005-09-22

    Whilst there is an abundance of studies revealing how dominance interactions affect access to resources critical for survival and reproductive success, very little is known about how dominance status is influenced by early life experiences. However, there is increasing evidence that early developmental trajectories can shape the physiology and behaviour of the adult. In particular, compensatory growth following a period of poor nutrition can have long-term effects on the phenotype. Since catch-up growth increases daily energy requirements and hence the motivation to acquire sufficient resources, it might either increase or decrease competitive ability and aggression. Here we test whether growth compensation early in life subsequently affects the dominance status of adult male swordtail fishes Xiphophorus helleri, a species with strong sexual dimorphism and male-male competition. Males that experienced a period of restricted food early in life subsequently caught up and achieved the same adult body and ornament size as control males that had been raised on ad libitum food throughout development, but were subordinate to size-matched controls, suggesting a trade-off between sexual attractiveness and competitive ability. This indicates that early life history and/or growth trajectory can be an important determinant of competitive ability independent of current body size. PMID:16191597

  15. Fearless Dominance and reduced feedback-related negativity amplitudes in a time-estimation task – Further neuroscientific evidence for dual-process models of psychopathy☆

    PubMed Central

    Schulreich, Stefan; Pfabigan, Daniela M.; Derntl, Birgit; Sailer, Uta

    2013-01-01

    Dual-process models of psychopathy postulate two etiologically relevant processes. Their involvement in feedback processing and its neural correlates has not been investigated so far. Multi-channel EEG was collected while healthy female volunteers performed a time-estimation task and received negative or positive feedback in form of signs or emotional faces. The affective-interpersonal factor Fearless Dominance, but not Self-Centered Impulsivity, was associated with reduced feedback-related negativity (FRN) amplitudes. This neural dissociation extends previous findings on the impact of psychopathy on feedback processing and further highlights the importance of distinguishing psychopathic traits and extending previous (neuroscientific) models of psychopathy. PMID:23607997

  16. Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism

    SciTech Connect

    Spritz, R.A.; Giebel, L.B.; Holmes, S.A. )

    1992-02-01

    Piebaldism is an autosomal dominant disorder of melanocyte development and is characterized by congenital white parches of skin and hair from which melanocytes are completely absent. A similar disorder of the mouse, 'dominant white spotting' (W), results from mutations of the c-kit proto-oncogene, which encodes the cellular tyrosine kinases receptor for the mast/stem cell growth factor. The authors have identified c-kit gene mutations in three patients with piebaldism. A missense substitution (Phe[r arrow]Leu) at codon 584, within the tyrosine kinases domain, is associated with a severe piebald phenotype, whereas two different frameshifts, within codons 561 and 642, are both associated with a variable and relatively mild piebald phenotype. This is consistent with a possible 'dominant negative' effect of missense c-kit polypeptides on the function of the dimeric receptor.

  17. Simulated leakage of high pCO2 water negatively impacts bivalve dominated infaunal communities from the Western Baltic Sea.

    PubMed

    Schade, Hanna; Mevenkamp, Lisa; Guilini, Katja; Meyer, Stefanie; Gorb, Stanislav N; Abele, Doris; Vanreusel, Ann; Melzner, Frank

    2016-01-01

    Carbon capture and storage is promoted as a mitigation method counteracting the increase of atmospheric CO2 levels. However, at this stage, environmental consequences of potential CO2 leakage from sub-seabed storage sites are still largely unknown. In a 3-month-long mesocosm experiment, this study assessed the impact of elevated pCO2 levels (1,500 to 24,400 μatm) on Cerastoderma edule dominated benthic communities from the Baltic Sea. Mortality of C. edule was significantly increased in the highest treatment (24,400 μatm) and exceeded 50%. Furthermore, mortality of small size classes (0-1 cm) was significantly increased in treatment levels ≥6,600 μatm. First signs of external shell dissolution became visible at ≥1,500 μatm, holes were observed at >6,600 μatm. C. edule body condition decreased significantly at all treatment levels (1,500-24,400 μatm). Dominant meiofauna taxa remained unaffected in abundance. Densities of calcifying meiofauna taxa (i.e. Gastropoda and Ostracoda) decreased in high CO2 treatments (>6,600 μatm), while the non - calcifying Gastrotricha significantly increased in abundance at 24,400 μatm. In addition, microbial community composition was altered at the highest pCO2 level. We conclude that strong CO2 leakage can alter benthic infauna community composition at multiple trophic levels, likely due to high mortality of the dominant macrofauna species C. edule. PMID:27538361

  18. Simulated leakage of high pCO2 water negatively impacts bivalve dominated infaunal communities from the Western Baltic Sea

    PubMed Central

    Schade, Hanna; Mevenkamp, Lisa; Guilini, Katja; Meyer, Stefanie; Gorb, Stanislav N.; Abele, Doris; Vanreusel, Ann; Melzner, Frank

    2016-01-01

    Carbon capture and storage is promoted as a mitigation method counteracting the increase of atmospheric CO2 levels. However, at this stage, environmental consequences of potential CO2 leakage from sub-seabed storage sites are still largely unknown. In a 3-month-long mesocosm experiment, this study assessed the impact of elevated pCO2 levels (1,500 to 24,400 μatm) on Cerastoderma edule dominated benthic communities from the Baltic Sea. Mortality of C. edule was significantly increased in the highest treatment (24,400 μatm) and exceeded 50%. Furthermore, mortality of small size classes (0–1 cm) was significantly increased in treatment levels ≥6,600 μatm. First signs of external shell dissolution became visible at ≥1,500 μatm, holes were observed at >6,600 μatm. C. edule body condition decreased significantly at all treatment levels (1,500–24,400 μatm). Dominant meiofauna taxa remained unaffected in abundance. Densities of calcifying meiofauna taxa (i.e. Gastropoda and Ostracoda) decreased in high CO2 treatments (>6,600 μatm), while the non - calcifying Gastrotricha significantly increased in abundance at 24,400 μatm. In addition, microbial community composition was altered at the highest pCO2 level. We conclude that strong CO2 leakage can alter benthic infauna community composition at multiple trophic levels, likely due to high mortality of the dominant macrofauna species C. edule. PMID:27538361

  19. Simulated leakage of high pCO2 water negatively impacts bivalve dominated infaunal communities from the Western Baltic Sea

    NASA Astrophysics Data System (ADS)

    Schade, Hanna; Mevenkamp, Lisa; Guilini, Katja; Meyer, Stefanie; Gorb, Stanislav N.; Abele, Doris; Vanreusel, Ann; Melzner, Frank

    2016-08-01

    Carbon capture and storage is promoted as a mitigation method counteracting the increase of atmospheric CO2 levels. However, at this stage, environmental consequences of potential CO2 leakage from sub-seabed storage sites are still largely unknown. In a 3-month-long mesocosm experiment, this study assessed the impact of elevated pCO2 levels (1,500 to 24,400 μatm) on Cerastoderma edule dominated benthic communities from the Baltic Sea. Mortality of C. edule was significantly increased in the highest treatment (24,400 μatm) and exceeded 50%. Furthermore, mortality of small size classes (0–1 cm) was significantly increased in treatment levels ≥6,600 μatm. First signs of external shell dissolution became visible at ≥1,500 μatm, holes were observed at >6,600 μatm. C. edule body condition decreased significantly at all treatment levels (1,500–24,400 μatm). Dominant meiofauna taxa remained unaffected in abundance. Densities of calcifying meiofauna taxa (i.e. Gastropoda and Ostracoda) decreased in high CO2 treatments (>6,600 μatm), while the non - calcifying Gastrotricha significantly increased in abundance at 24,400 μatm. In addition, microbial community composition was altered at the highest pCO2 level. We conclude that strong CO2 leakage can alter benthic infauna community composition at multiple trophic levels, likely due to high mortality of the dominant macrofauna species C. edule.

  20. Simulated leakage of high pCO2 water negatively impacts bivalve dominated infaunal communities from the Western Baltic Sea.

    PubMed

    Schade, Hanna; Mevenkamp, Lisa; Guilini, Katja; Meyer, Stefanie; Gorb, Stanislav N; Abele, Doris; Vanreusel, Ann; Melzner, Frank

    2016-08-19

    Carbon capture and storage is promoted as a mitigation method counteracting the increase of atmospheric CO2 levels. However, at this stage, environmental consequences of potential CO2 leakage from sub-seabed storage sites are still largely unknown. In a 3-month-long mesocosm experiment, this study assessed the impact of elevated pCO2 levels (1,500 to 24,400 μatm) on Cerastoderma edule dominated benthic communities from the Baltic Sea. Mortality of C. edule was significantly increased in the highest treatment (24,400 μatm) and exceeded 50%. Furthermore, mortality of small size classes (0-1 cm) was significantly increased in treatment levels ≥6,600 μatm. First signs of external shell dissolution became visible at ≥1,500 μatm, holes were observed at >6,600 μatm. C. edule body condition decreased significantly at all treatment levels (1,500-24,400 μatm). Dominant meiofauna taxa remained unaffected in abundance. Densities of calcifying meiofauna taxa (i.e. Gastropoda and Ostracoda) decreased in high CO2 treatments (>6,600 μatm), while the non - calcifying Gastrotricha significantly increased in abundance at 24,400 μatm. In addition, microbial community composition was altered at the highest pCO2 level. We conclude that strong CO2 leakage can alter benthic infauna community composition at multiple trophic levels, likely due to high mortality of the dominant macrofauna species C. edule.

  1. Negative phototropism is seen in Arabidopsis inflorescences when auxin signaling is reduced to a minimal level by an Aux/IAA dominant mutation, axr2.

    PubMed

    Sato, Atsuko; Sasaki, Shu; Matsuzaki, Jun; Yamamoto, Kotaro T

    2015-01-01

    Inflorescences of a dominant mutant of Arabidopsis Aux/IAA7, axr2, showed negative phototropism with a similar fluence response curve to the positive phototropism of wild-type stems. Application of a synthetic auxin, NAA, and an inhibitor of polar auxin transport, NPA, increased and decreased respectively the magnitude of the phototropic response in the wild type, while in axr2 application of NAA reduced the negative phototropic response and NPA had no effect. Decapitation of the apex induced a small negative phototropism in wild-type stems, and had no effect in axr2 plants. Inflorescences of the double mutants of auxin transporters, pgp1 pgp19, showed no phototropic response, while decapitation resulted in a negative phototropic response. These results suggest that negative phototropism can occur when the level of auxin or of auxin signaling is reduced to a minimal level, and that in plant axial organs the default phototropic response to unilateral blue light may be negative. Expression of axr2 protein by an endodermis-specific promoter resulted in agravitropism of inflorescences in a similar way to that of axr2, but phototropism was normal, confirming that the endodermis does not play a critical role in phototropism.

  2. Dominant negative selection of vaccinia virus using a thymidine kinase/thymidylate kinase fusion gene and the prodrug azidothymidine

    SciTech Connect

    Holzer, Georg W. . E-mail: falknef@baxter.com

    2005-07-05

    The Escherichia coli thymidine kinase/thymidylate kinase (tk/tmk) fusion gene encodes an enzyme that efficiently converts the prodrug 3'-azido-2',3'-dideoxythymidine (AZT) into its toxic triphosphate derivative, a substance which stops DNA chain elongation. Integration of this marker gene into vaccinia virus that normally is not inhibited by AZT allowed the establishment of a powerful selection procedure for recombinant viruses. In contrast to the conventional vaccinia thymidine kinase (tk) selection that is performed in tk-negative cell lines, AZT selection can be performed in normal (tk-positive) cell lines. The technique is especially useful for the generation of replication-deficient vaccinia viruses and may also be used for gene knock-out studies of essential vaccinia genes.

  3. A comparative analysis of perturbations caused by a gene knock-out, a dominant negative allele, and a set of peptide aptamers.

    PubMed

    Abed, Nadia; Bickle, Marc; Mari, Bernard; Schapira, Matthieu; Sanjuan-España, Raquel; Robbe Sermesant, Karine; Moncorgé, Olivier; Mouradian-Garcia, Sandrine; Barbry, Pascal; Rudkin, Brian B; Fauvarque, Marie-Odile; Michaud-Soret, Isabelle; Colas, Pierre

    2007-12-01

    The study of protein function mostly relies on perturbing regulatory networks by acting upon protein expression levels or using transdominant negative agents. Here we used the Escherichia coli global transcription regulator Fur (ferric uptake regulator) as a case study to compare the perturbations exerted by a gene knock-out, the expression of a dominant negative allele of a gene, and the expression of peptide aptamers that bind a gene product. These three perturbations caused phenotypes that differed quantitatively and qualitatively from one another. The Fur peptide aptamers inhibited the activity of their target to various extents and reduced the virulence of a pathogenic E. coli strain in Drosophila. A genome-wide transcriptome analysis revealed that the "penetrance" of a peptide aptamer was comparable to that of a dominant negative allele but lower than the penetrance of the gene knock-out. Our work shows that comparative analysis of phenotypic and transcriptome responses to different types of perturbation can help decipher complex regulatory networks that control various biological processes.

  4. Response to Multiple Radiation Doses of Human Colorectal Carcinoma Cells Infected With Recombinant Adenovirus Containing Dominant-Negative Ku70 Fragment

    SciTech Connect

    Urano, Muneyasu; He Fuqiu; Minami, Akiko; Ling, C. Clifton; Li, Gloria C.

    2010-07-01

    Purpose: To investigate the effect of recombinant replication-defective adenovirus containing dominant-negative Ku70 fragment on the response of tumor cells to multiple small radiation doses. Our ultimate goal is to demonstrate the feasibility of using this virus in gene-radiotherapy to enhance the radiation response of tumor cells. Methods and Materials: Human colorectal HCT8 and HT29 carcinoma cells were plated in glass tubes, infected with virus (25 multiplicity of infection), and irradiated with a single dose or zero to five doses of 3 Gy each at 6-h intervals. Hypoxia was induced by flushing with 100% nitrogen gas. The cells were trypsinized 0 or 6 h after the final irradiation, and cell survival was determined by colony formation. The survival data were fitted to linear-quadratic model or exponential line. Results: Virus infection enhanced the radiation response of the HCT8 and HT29 cells. The virus enhancement ratio for single-dose irradiation at a surviving fraction of 0.1 was {approx}1.3 for oxic and hypoxic HCT8 and 1.4 and 1.1 for oxic and hypoxic HT29, respectively. A similar virus enhancement ratio of 1.2-1.3 was observed for both oxic and hypoxic cells irradiated with multiple doses; however, these values were smaller than the values found for dominant-negative Ku70-transfected Rat-1 cells. This difference has been discussed. The oxygen enhancement ratio for HCT8 and HT29 receiving fractionated doses was 1.2 and 2.0, respectively, and virus infection altered them slightly. Conclusion: Infection of recombinant replication-defective adenovirus containing dominant-negative Ku70 fragment enhanced the response of human colorectal cancer cells to single and multiple radiation doses.

  5. A Screen for Dominant Negative Mutants of SEC18 Reveals a Role for the AAA Protein Consensus Sequence in ATP Hydrolysis

    PubMed Central

    Steel, Gregor J.; Harley, Carol; Boyd, Alan; Morgan, Alan

    2000-01-01

    An evolutionarily ancient mechanism is used for intracellular membrane fusion events ranging from endoplasmic reticulum–Golgi traffic in yeast to synaptic vesicle exocytosis in the human brain. At the heart of this mechanism is the core complex of N-ethylmaleimide-sensitive fusion protein (NSF), soluble NSF attachment proteins (SNAPs), and SNAP receptors (SNAREs). Although these proteins are accepted as key players in vesicular traffic, their molecular mechanisms of action remain unclear. To illuminate important structure–function relationships in NSF, a screen for dominant negative mutants of yeast NSF (Sec18p) was undertaken. This involved random mutagenesis of a GAL1-regulated SEC18 yeast expression plasmid. Several dominant negative alleles were identified on the basis of galactose-inducible growth arrest, of which one, sec18-109, was characterized in detail. The sec18-109 phenotype (abnormal membrane trafficking through the biosynthetic pathway, accumulation of a membranous tubular network, growth suppression, increased cell density) is due to a single A-G substitution in SEC18 resulting in a missense mutation in Sec18p (Thr394→Pro). Thr394 is conserved in most AAA proteins and indeed forms part of the minimal AAA consensus sequence that serves as a signature of this large protein family. Analysis of recombinant Sec18-109p indicates that the mutation does not prevent hexamerization or interaction with yeast α-SNAP (Sec17p), but instead results in undetectable ATPase activity that cannot be stimulated by Sec17p. This suggests a role for the AAA protein consensus sequence in regulating ATP hydrolysis. Furthermore, this approach of screening for dominant negative mutants in yeast can be applied to other conserved proteins so as to highlight important functional domains in their mammalian counterparts. PMID:10749934

  6. Negative Regulation of the Pseudomonas aeruginosa Outer Membrane Porin OprD Selective for Imipenem and Basic Amino Acids

    PubMed Central

    Ochs, Martina M.; McCusker, Matthew P.; Bains, Manjeet; Hancock, Robert E. W.

    1999-01-01

    Pseudomonas aeruginosa OprD is a specific porin which facilitates the uptake of basic amino acids and imipenem, a carbapenem antibiotic. Resistance to imipenem due to the loss of OprD is an important mechanism for the loss of clinical effectiveness. To investigate the negative regulatory mechanisms influencing oprD expression, a gene upstream of the coregulated mexEF-oprN efflux operon, designated mexT, was cloned. The predicted 304-amino-acid mature MexT protein showed strong homology to LysR-type regulators. When overexpressed it induced the expression of the mexEF-oprN efflux operon while decreasing the level of expression of OprD. The use of an oprD::xylE transcriptional fusion indicated that it acted by repressing the transcription of oprD. Salicylate, a weak aromatic acid known to reduce porin expression and induce low levels of multiple antibiotic resistance in Escherichia coli, was able to induce imipenem resistance and reduce the expression of OprD but not multiple antibiotic resistance or OprN expression in P. aeruginosa. This was also demonstrated to occur at the level of transcription. Acetyl salicylate and benzoate, but not catechol, were also able to reduce the levels of OprD in the P. aeruginosa outer membranes. These OprD-suppressing compounds increased imipenem resistance even in a mexT-overexpressing and nfxC mutant backgrounds, suggesting that such resistance is independent of the MexT repressor and that oprD is influenced by more than a single mechanism of repression. PMID:10223918

  7. Selective expression of a dominant-negative type Iα PKA regulatory subunit in striatal medium spiny neurons impairs gene expression and leads to reduced feeding and locomotor activity.

    PubMed

    Yang, Linghai; Gilbert, Merle L; Zheng, Ruimao; McKnight, G Stanley

    2014-04-01

    Striatal medium spiny neurons (MSNs) mediate many of the physiological effects of dopamine, including the regulation of feeding and motor behaviors. Dopaminergic inputs from the midbrain modulate MSN excitability through pathways that involve cAMP and protein kinase A (PKA), but the physiological role of specific PKA isoforms in MSN neurons remains poorly understood. One of the major PKA regulatory (R) subunit isoforms expressed in MSNs is RIIβ, which localizes the PKA holoenzyme primarily to dendrites by interaction with AKAP5 and other scaffolding proteins. However, RI (RIα and RIβ) subunits are also expressed in MSNs and the RI holoenzyme has a weaker affinity for most scaffolding proteins and tends to localize in the cell body. We generated mice with selective expression of a dominant-negative RI subunit (RIαB) in striatal MSNs and show that this dominant-negative RIαB localizes to the cytoplasm and specifically inhibits type I PKA activity in the striatum. These mice are normal at birth; however, soon after weaning they exhibit growth retardation and the adult mice are hypophagic, lean, and resistant to high-fat diet-induced hyperphagia and obesity. The RIαB-expressing mice also exhibit decreased locomotor activity and decreased dopamine-regulated CREB phosphorylation and c-fos gene expression in the striatum. Our results demonstrate a critical role for cytoplasmic RI-PKA holoenzyme in gene regulation and the overall physiological function of MSNs. PMID:24695708

  8. A transgenic mouse model demonstrates a dominant negative effect of a point mutation in the RPS19 gene associated with Diamond-Blackfan anemia.

    PubMed

    Devlin, Emily E; Dacosta, Lydie; Mohandas, Narla; Elliott, Gene; Bodine, David M

    2010-10-14

    Diamond Blackfan anemia (DBA) is an inherited erythroblastopenia associated with mutations in at least 8 different ribosomal protein genes. Mutations in the gene encoding ribosomal protein S19 (RPS19) have been identified in approximately 25% of DBA families. Most of these mutations disrupt either the translation or stability of the RPS19 protein and are predicted to cause DBA by haploinsufficiency. However, approximately 30% of RPS19 mutations are missense mutations that do not alter the stability of the RPS19 protein and are hypothesized to act by a dominant negative mechanism. To formally test this hypothesis, we generated a transgenic mouse model expressing an RPS19 mutation in which an arginine residue is replaced with a tryptophan residue at codon 62 (RPS19R62W). Constitutive expression of RPS19R62W in developing mice was lethal. Conditional expression of RPS19R62W resulted in growth retardation, a mild anemia with reduced numbers of erythroid progenitors, and significant inhibition of terminal erythroid maturation, similar to DBA. RNA profiling demonstrated more than 700 dysregulated genes belonging to the same pathways that are disrupted in RNA profiles of DBA patient cells. We conclude that RPS19R62W is a dominant negative DBA mutation.

  9. Genetic study of the loss and restoration of Mutator transposon activity in maize: evidence against dominant-negative regulator associated with loss of activity.

    PubMed

    Brown, J; Sundaresan, V

    1992-04-01

    The Mutator system of transposable elements is characterized by a family of transposons called Mu transposons that share common termini and are actively transposing in Robertson's Mutator (Mu) lines of maize. Mu lines lose transposition activity during propagation by either outcrossing or inbreeding. This loss of transposition activity, which can occur at non-Mendelian frequencies, is in the form of loss of forward transposition activity resulting in a decrease in the generation of new mutations, as well as the loss of mutability of Mu transposon induced mutations, and it has been correlated with hypermethylation of the Mu elements. Previous studies have concluded that restoration of Mutator transposon activity by crossing inactive lines back to active lines is incomplete or transient, and depends upon the sex of the inactive parent. Further, it has been proposed that the inactive system is dominant to the active system, with the dominance possibly mediated through a negative regulatory factor that is preferentially transmitted through the female. In this study, we have examined the frequencies of loss and restoration of Mu transposon activity using a Mu line carrying an insertion in the bronze 1 locus. We find that transmission of Mu transposon activity to non-Mu plants can occur at high rates through males and females, but individual cases of decreased transmission through the male were observed. We also find that in crosses between inactive-Mu and active-Mu plants, reactivation was efficient as well as heritable, regardless of the sex of the inactive parent. Similar results were obtained whether the inactivation occurred in an outcross or a self. In all cases examined, loss of Mu transposon activity was correlated with hypermethylation of Mu elements, and reactivation was correlated with their demethylation. Our results indicate that an inactive Mu system does not exhibit dominance over an active Mu system. We conclude that contrary to current models

  10. Dominant negative mutant of retinoic acid receptor alpha inhibits retinoic acid-induced P19 cell differentiation by binding to DNA.

    PubMed

    Costa, S L; McBurney, M W

    1996-05-25

    Retinoic acid (RA) is a potent inducer of P19 cell differentiation. RA activity is thought to be mediated by nuclear RA receptors (RARs), transcription factors whose activity is dependent on RA. There are three RARs called alpha, beta, and gamma. We created truncated versions of the three RARs and compared their activities as inhibitors of RA-mediated gene transcription and of P19 cell differentiation. Only mutants of the RAR alpha were inhibitory in these assays. A mutant of RAR alpha carrying a 10-amino-acid insert was able to heterodimerize with RXRbeta or with the normal RAR alpha and the inhibitory activity of this mutant was dependent on an intact DNA binding domain. We conclude that dominant negative mutants of RAR alpha act by heterodimerizing with RXRs or RARs and binding to RA response elements on DNA, thereby preventing binding of the normal receptors to those sites. PMID:8635515

  11. Caveolin-1 mutants P132L and Y14F are dominant negative regulators of invasion, migration and aggregation in H1299 lung cancer cells

    SciTech Connect

    Shatz, Maria; Lustig, Gila; Reich, Reuven; Liscovitch, Mordechai

    2010-06-10

    Caveolin-1 is an essential protein constituent of caveolae. Accumulating evidence indicates that caveolin-1 may act as a positive regulator of cancer progression. In this study, we investigated the function of caveolin-1 in human lung cancer cells. Caveolin-1 knockdown inhibited cell proliferation and reduced focal adhesion kinase (Fak) phosphorylation. Matrix invasion and cell migration as well as expression and activity of matrix metalloproteases were attenuated following caveolin-1 RNAi-mediated knockdown or overexpression of Y14F and P132L mutants, demonstrating dominant-negative activity of these mutants. Time-lapse fluorescence microscopy revealed that caveolin-1 and its mutants P132L and Y14F are localized to the trailing edge of migrating cells during both random and directed cell movement, implying an active role of caveolin-1 in the migration process. Suppression of caveolin-1 function greatly elevated the percentage of H1299 cells exhibiting focal adhesions. In addition, cell aggregation was increased by wild type caveolin-1 and attenuated by both P132L and Y14F mutants. Overexpression of wild type caveolin-1 increased caveolae density, however, P132L and Y14F mutants did not affect caveolae formation, suggesting that in this respect that the mutants do not act in a dominant negative manner, and that effects of caveolin-1 on caveolae and cell invasion, migration, focal adhesion and aggregation, are separable. Our data provide novel mechanistic insights into the role of caveolin-1 in cell motility, invasiveness and aggregation, therefore, expanding our understanding of the tumor-promoting activities of caveolin-1 in advanced-stage cancer.

  12. Demonstration of differential quantitative requirements for NSF among multiple vesicle fusion pathways of GLUT4 using a dominant-negative ATPase-deficient NSF

    SciTech Connect

    Chen Xiaoli; Matsumoto, Hideko; Hinck, Cynthia S.; Al-Hasani, Hadi; St-Denis, Jean-Francois; Whiteheart, Sidney W.; Cushman, Samuel W. . E-mail: sam_cushman@nih.gov

    2005-07-22

    In this study, we investigated the relative participation of N-ethylmaleimide-sensitive factor (NSF) in vivo in a complex multistep vesicle trafficking system, the translocation response of GLUT4 to insulin in rat adipose cells. Transfections of rat adipose cells demonstrate that over-expression of wild-type NSF has no effect on total, or basal and insulin-stimulated cell-surface expression of HA-tagged GLUT4. In contrast, a dominant-negative NSF (NSF-D1EQ) can be expressed at a low enough level that it has little effect on total HA-GLUT4, but does reduce both basal and insulin-stimulated cell-surface HA-GLUT4 by {approx}50% without affecting the GLUT4 fold-translocation response to insulin. However, high expression levels of NSF-D1EQ decrease total HA-GLUT4. The inhibitory effect of NSF-D1EQ on cell-surface HA-GLUT4 is reversed when endocytosis is inhibited by co-expression of a dominant-negative dynamin (dynamin-K44A). Moreover, NSF-D1EQ does not affect cell-surface levels of constitutively recycling GLUT1 and TfR, suggesting a predominant effect of low-level NSF-D1EQ on the trafficking of GLUT4 from the endocytic recycling compared to the intracellular GLUT4-specific compartment. Thus, our data demonstrate that the multiple fusion steps in GLUT4 trafficking have differential quantitative requirements for NSF activity. This indicates that the rates of plasma and intracellular membrane fusion reactions vary, leading to differential needs for the turnover of the SNARE proteins.

  13. Mdm2 ligase dead mutants did not act in a dominant negative manner to re-activate p53, but promoted tumor cell growth.

    PubMed

    Swaroop, Manju; Sun, Yi

    2003-01-01

    Mdm2 (murine double minute 2) is an oncogene, first identified in BALB/c 3T3 cells. Over-expression and gene amplification of Mdm2 were found in a variety of human cancers. Recently, Mdm2 was found to be an E3 ubiquitin ligase that promotes degradation of p53, which contributes significantly to its oncogenic activity. In this study, we test a hypothesis that Mdm2 ligase dead mutants, which retained p53 binding activity but lost degradation activity, would act in a dominant negative manner to re-activate p53, especially upon stressed conditions. Five Mdm2 constructs expressing wild-type and E3 ligase-dead Mdm2 proteins were generated in a Tet-Off system and transfected into MCF-7 breast cancer cells (p53+/+ with Mdm2 overexpression) as well as MCF10A immortalized breast cells (p53+/+ without Mdm2 overexpression) as a normal control. We found that expression of Mdm2 mutants were tightly regulated by doxycycline. Withdrawal of doxycycline in culture medium triggered overexpression of Mdm2 mutants. However, expression of ligase dead mutants in MCF7 and MCF10A cells did not reactivate p53 as shown by a luciferase-reporter transcription assay and Western blot of p53 and its downstream target p21 under either unstressed condition or after exposure to DNA damaging agents. Biologically, over-expression of Mdm2 mutants had no effect on p53-induced apoptosis following DNA damage. Interestingly, over-expression of Mdm2 mutants promoted growth of MCF7 tumor cells probably via a p53-independent mechanism. Over-expression of Mdm2 mutants, however, had no effect on the growth of normal MCF10A cells and did not cause their transformation. Thus, ligase dead mutants of Mdm2 did not act in a dominant negative manner to reactivate p53 and they are not oncogenes in MCF10A cells.

  14. The thanatos mutation in Arabidopsis thaliana cellulose synthase 3 (AtCesA3) has a dominant-negative effect on cellulose synthesis and plant growth.

    PubMed

    Daras, Gerasimos; Rigas, Stamatis; Penning, Bryan; Milioni, Dimitra; McCann, Maureen C; Carpita, Nicholas C; Fasseas, Constantinos; Hatzopoulos, Polydefkis

    2009-01-01

    Genetic functional analyses of mutants in plant genes encoding cellulose synthases (CesAs) have suggested that cellulose deposition requires the activity of multiple CesA proteins. Here, a genetic screen has led to the identification of thanatos (than), a semi-dominant mutant of Arabidopsis thaliana with impaired growth of seedlings. Homozygous seedlings of than germinate and grow but do not survive. In contrast to other CesA mutants, heterozygous plants are dwarfed and display a radially swollen root phenotype. Cellulose content is reduced by approximately one-fifth in heterozygous and by two-fifths in homozygous plants, showing gene-dosage dependence. Map-based cloning revealed an amino acid substitution (P578S) in the catalytic domain of the AtCesA3 gene, indicating a critical role for this residue in the structure and function of the cellulose synthase complex. Ab initio analysis of the AtCesA3 subdomain flanking the conserved proline residue predicted that the amino acid substitution to serine alters protein secondary structure in the catalytic domain. Gene dosage-dependent expression of the AtCesA3 mutant gene in wild-type A. thaliana plants resulted in a than dominant-negative phenotype. We propose that the incorporation of a mis-folded CesA3 subunit into the cellulose synthase complex may stall or prevent the formation of functional rosette complexes. PMID:19645738

  15. A CaV2.1 N-terminal fragment relieves the dominant-negative inhibition by an Episodic ataxia 2 mutant.

    PubMed

    Dahimene, Shehrazade; Page, Karen M; Nieto-Rostro, Manuela; Pratt, Wendy S; D'Arco, Marianna; Dolphin, Annette C

    2016-09-01

    Episodic ataxia 2 (EA2) is an autosomal dominant disorder caused by mutations in the gene CACNA1A that encodes the pore-forming CaV2.1 calcium channel subunit. The majority of EA2 mutations reported so far are nonsense or deletion/insertion mutations predicted to form truncated proteins. Heterologous expression of wild-type CaV2.1, together with truncated constructs that mimic EA2 mutants, significantly suppressed wild-type calcium channel function, indicating that the truncated protein produces a dominant-negative effect (Jouvenceau et al., 2001; Page et al., 2004). A similar finding has been shown for CaV2.2 (Raghib et al., 2001). We show here that a highly conserved sequence in the cytoplasmic N-terminus is involved in this process, for both CaV2.1 and CaV2.2 channels. Additionally, we were able to interfere with the suppressive effect of an EA2 construct by mutating key N-terminal residues within it. We postulate that the N-terminus of the truncated channel plays an essential part in its interaction with the full-length CaV2.1, which prevents the correct folding of the wild-type channel. In agreement with this, we were able to disrupt the interaction between EA2 and the full length channel by co-expressing a free N-terminal peptide. PMID:27260834

  16. A CaV2.1 N-terminal fragment relieves the dominant-negative inhibition by an Episodic ataxia 2 mutant.

    PubMed

    Dahimene, Shehrazade; Page, Karen M; Nieto-Rostro, Manuela; Pratt, Wendy S; D'Arco, Marianna; Dolphin, Annette C

    2016-09-01

    Episodic ataxia 2 (EA2) is an autosomal dominant disorder caused by mutations in the gene CACNA1A that encodes the pore-forming CaV2.1 calcium channel subunit. The majority of EA2 mutations reported so far are nonsense or deletion/insertion mutations predicted to form truncated proteins. Heterologous expression of wild-type CaV2.1, together with truncated constructs that mimic EA2 mutants, significantly suppressed wild-type calcium channel function, indicating that the truncated protein produces a dominant-negative effect (Jouvenceau et al., 2001; Page et al., 2004). A similar finding has been shown for CaV2.2 (Raghib et al., 2001). We show here that a highly conserved sequence in the cytoplasmic N-terminus is involved in this process, for both CaV2.1 and CaV2.2 channels. Additionally, we were able to interfere with the suppressive effect of an EA2 construct by mutating key N-terminal residues within it. We postulate that the N-terminus of the truncated channel plays an essential part in its interaction with the full-length CaV2.1, which prevents the correct folding of the wild-type channel. In agreement with this, we were able to disrupt the interaction between EA2 and the full length channel by co-expressing a free N-terminal peptide.

  17. Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.

    PubMed

    Hannan, Fadil M; Howles, Sarah A; Rogers, Angela; Cranston, Treena; Gorvin, Caroline M; Babinsky, Valerie N; Reed, Anita A; Thakker, Clare E; Bockenhauer, Detlef; Brown, Rosalind S; Connell, John M; Cook, Jacqueline; Darzy, Ken; Ehtisham, Sarah; Graham, Una; Hulse, Tony; Hunter, Steven J; Izatt, Louise; Kumar, Dhavendra; McKenna, Malachi J; McKnight, John A; Morrison, Patrick J; Mughal, M Zulf; O'Halloran, Domhnall; Pearce, Simon H; Porteous, Mary E; Rahman, Mushtaqur; Richardson, Tristan; Robinson, Robert; Scheers, Isabelle; Siddique, Haroon; Van't Hoff, William G; Wang, Timothy; Whyte, Michael P; Nesbit, M Andrew; Thakker, Rajesh V

    2015-09-15

    The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue. PMID:26082470

  18. Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.

    PubMed

    Hannan, Fadil M; Howles, Sarah A; Rogers, Angela; Cranston, Treena; Gorvin, Caroline M; Babinsky, Valerie N; Reed, Anita A; Thakker, Clare E; Bockenhauer, Detlef; Brown, Rosalind S; Connell, John M; Cook, Jacqueline; Darzy, Ken; Ehtisham, Sarah; Graham, Una; Hulse, Tony; Hunter, Steven J; Izatt, Louise; Kumar, Dhavendra; McKenna, Malachi J; McKnight, John A; Morrison, Patrick J; Mughal, M Zulf; O'Halloran, Domhnall; Pearce, Simon H; Porteous, Mary E; Rahman, Mushtaqur; Richardson, Tristan; Robinson, Robert; Scheers, Isabelle; Siddique, Haroon; Van't Hoff, William G; Wang, Timothy; Whyte, Michael P; Nesbit, M Andrew; Thakker, Rajesh V

    2015-09-15

    The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

  19. A conserved domain of the large subunit of replication factor C binds PCNA and acts like a dominant negative inhibitor of DNA replication in mammalian cells.

    PubMed

    Fotedar, R; Mossi, R; Fitzgerald, P; Rousselle, T; Maga, G; Brickner, H; Messier, H; Kasibhatla, S; Hübscher, U; Fotedar, A

    1996-08-15

    Replication factor C (RF-C), a complex of five polypeptides, is essential for cell-free SV40 origin-dependent DNA replication and viability in yeast. The cDNA encoding the large subunit of human RF-C (RF-Cp145) was cloned in a Southwestern screen. Using deletion mutants of RF-Cp145 we have mapped the DNA binding domain of RF-Cp145 to amino acid residues 369-480. This domain is conserved among both prokaryotic DNA ligases and eukaryotic poly(ADP-ribose) polymerases and is absent in other subunits of RF-C. The PCNA binding domain maps to amino acid residues 481-728 and is conserved in all five subunits of RF-C. The PCNA binding domain of RF-Cp145 inhibits several functions of RF-C, such as: (i) in vitro DNA replication of SV40 origin-containing DNA; (ii) RF-C-dependent loading of PCNA onto DNA; and (iii) RF-C-dependent DNA elongation. The PCNA binding domain of RF-Cp145 localizes to the nucleus and inhibits DNA synthesis in transfected mammalian cells. In contrast, the DNA binding domain of RF-Cp145 does not inhibit DNA synthesis in vitro or in vivo. We therefore conclude that amino acid residues 481-728 of human RF-Cp145 are critical and act as a dominant negative mutant of RF-C function in DNA replication in vivo.

  20. Dominant-negative cyclin-selective ubiquitin carrier protein E2-C/UbcH10 blocks cells in metaphase

    PubMed Central

    Townsley, Fiona M.; Aristarkhov, Alexander; Beck, Sharon; Hershko, Avram; Ruderman, Joan V.

    1997-01-01

    Destruction of mitotic cyclins by ubiquitin-dependent proteolysis is required for cells to complete mitosis and enter interphase of the next cell cycle. In clam eggs, this process is catalyzed by a cyclin-selective ubiquitin carrier protein, E2-C, and the cyclosome/anaphase promoting complex (APC), a 20S particle containing cyclin-selective ubiquitin ligase activity. Here we report cloning a human homolog of E2-C, UbcH10, which shares 61% amino acid identity with clam E2-C and can substitute for clam E2-C in vitro. Dominant-negative clam E2-C and human UbcH10 proteins, created by altering the catalytic cysteine to serine, inhibit the in vitro ubiquitination and destruction of cyclin B in clam oocyte extracts. When transfected into mammalian cells, mutant UbcH10 inhibits the destruction of both cyclin A and B, arrests cells in M phase, and inhibits the onset of anaphase, presumably by blocking the ubiquitin-dependent proteolysis of proteins responsible for sister chromatid separation. Thus, E2-C/UbcH10-mediated ubiquitination is involved in both cdc2 inactivation and sister chromatid separation, processes that are normally coordinated during exit from mitosis. PMID:9122200

  1. Transformation by Raf and other oncogenes renders cells differentially sensitive to growth inhibition by a dominant negative c-jun mutant.

    PubMed

    Rapp, U R; Troppmair, J; Beck, T; Birrer, M J

    1994-12-01

    In NIH3T3 cells expressing active Raf-1 protein serine/threonine kinase (PSK) c-jun expression is constitutive while c-fos expression is attenuated. This alteration prompted us to determine whether oncogene transformation would render cells differentially sensitive to growth inhibition by a dominant negative mutant of c-jun, TAM 67. Growth inhibition was observed in three types of assays: (1) transfection of TAM 67 into cells stably transformed by a variety of oncogenes, (2) cotransfection of TAM 67 with oncogene expression plasmids into NIH3T3 cells and (3) titration of oncogene-expressing retroviruses on cells stably expressing TAM 67. The results clearly demonstrate that Raf-1 dependent oncogenes, which include receptor protein tyrosine kinases (PTKs)-, intracellular PTKs- and Ras-derived genes share the Raf phenotype of constitutive c-jun expression, attenuated c-fos induction, and high sensitivity to growth suppression by TAM 67. Additionally, the intracellular PSK oncogene, mos and the nuclear oncogenes c-myc, c-fos, and SV40 T antigen were TAM 67-sensitive for transformation. This universal pattern of altered growth regulation in oncogene transformed fibroblast cell lines highlights the potential usefulness of c-jun based inhibitors for control of tumor cell growth.

  2. Ultraviolet B-induced activated protein-1 activation does not require epidermal growth factor receptor but is blocked by a dominant negative PKClambda/iota.

    PubMed

    Huang, C; Ma, W y; Bowden, G T; Dong, Z

    1996-12-01

    The exposure of mammalian cells to UV irradiation leads to the activation of transcription factors such as activated protein-1 (AP-1) and NFkappaB. It is postulated that epidermal growth factor (EGF) receptor, but not protein kinase C (PKC), is the major membrane mediator in UV-induced signal transduction. Since UVB is responsible for most of the carcinogenic effects of sun exposure, we investigated the role of EGF receptors and PKC in UVB-induced AP-1 activation. Our results indicated that while the down-regulation of novel PKC (nPKC) and conventional PKC (cPKC) by pretreatment of cells with 12-O-tetradecanoyl phorbol-13-acetate cannot block UVB-induced AP-1 activity, it can block 12-O-tetradecanoyl phorbol-13-acetate-induced AP-1 activity. Further, the dominant negative mutant PKClambda/iota blocked UVB-induced AP-1 activity in all doses and time courses studied. In contrast, UVB-induced AP-1 activity from cells devoid of EGF receptor (B82) was not significantly different from that of the stable transfectants with a kinase-deficient EGF receptor (B82M721) or those with a wild-type EGF receptor (B82L) at all UVB irradiation doses and time courses studied. All of this evidence indicated that aPKC, but not EGF receptor, is involved in UVB-induced AP-1 activation. PMID:8940130

  3. Ectopic Expression of the Petunia MADS Box Gene UNSHAVEN Accelerates Flowering and Confers Leaf-Like Characteristics to Floral Organs in a Dominant-Negative MannerW⃞

    PubMed Central

    Ferrario, Silvia; Busscher, Jacqueline; Franken, John; Gerats, Tom; Vandenbussche, Michiel; Angenent, Gerco C.; Immink, Richard G.H.

    2004-01-01

    Several genes belonging to the MADS box transcription factor family have been shown to be involved in the transition from vegetative to reproductive growth. The Petunia hybrida MADS box gene UNSHAVEN (UNS) shares sequence similarity with the Arabidopsis thaliana flowering gene SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1, is expressed in vegetative tissues, and is downregulated upon floral initiation and the formation of floral meristems. To understand the role of UNS in the flowering process, knockout mutants were identified and UNS was expressed ectopically in petunia and Arabidopsis. No phenotype was observed in petunia plants in which UNS was disrupted by transposon insertion, indicating that its function is redundant. Constitutive expression of UNS leads to an acceleration of flowering and to the unshaven floral phenotype, which is characterized by ectopic trichome formation on floral organs and conversion of petals into organs with leaf-like features. The same floral phenotype, accompanied by a delay in flowering, was obtained when a truncated version of UNS, lacking the MADS box domain, was introduced. We demonstrated that the truncated protein is not translocated to the nucleus. Using the overexpression approach with both the full-length and the nonfunctional truncated UNS protein, we could distinguish between phenotypic alterations because of a dominant-negative action of the protein and because of its native function in promoting floral transition. PMID:15155884

  4. Dominant Negative Effect of Mutated Thyroid Stimulating Hormone Receptor (P556L) Causes Hypothyroidism in C.RF-Tshrhyt/wild Mice

    PubMed Central

    Endo, Toyoshi; Kobayashi, Tetsuro

    2012-01-01

    C.RF-Tshrhyt/hyt mice have a mutated thyroid stimulating hormone receptor (P556L-TSHR) and these mice develop severe hypothyroidism. We found that C.RF-Tshrhyt/wild heterozygous mice are also in a hypothyroid state. Thyroid glands from C.RF-Tshrhyt/wild mice are smaller than those from wild-type mice, and 125I uptake activities of the former are significantly lower than those in the latter. When TSHR (TSHR(W)) and P556L-TSHR (TSHR(M)) cDNAs were cloned and co-transfected into HEK 293 cells, the cells retained 125I-TSH binding activity, but cAMP response to TSH was decreased to about 20% of HEK 293 cells transfected with TSHR(W) cDNA. When TSHR(W) and TSHR(M) were tagged with eCFP or eYFP, we observed fluorescence resonance energy transfer (FRET) in HEK 293 cells expressing TSHR(W)-eCFP and TSHR(W)-eYFP in the absence of TSH, but not in the presence of TSH. In contrast, we obtained FRET in HEK 293 cells expressing TSHR(W)-eCFP and TSHR (M)-eYFP, regardless of the presence or absence of TSH. These results suggest that P556L TSHR has a dominant negative effect on TSHR(W) by impairing polymer to monomer dissociation, which decreases TSH responsiveness and induces hypothyroidism in C.RF-Tshrhyt/wild mice. PMID:22916127

  5. Human dominant-negative class II transactivator transgenic pigs - effect on the human anti-pig T-cell immune response and immune status.

    PubMed

    Hara, Hidetaka; Witt, William; Crossley, Tanner; Long, Cassandra; Isse, Kumiko; Fan, Liming; Phelps, Carol J; Ayares, David; Cooper, David K C; Dai, Yifan; Starzl, Thomas E

    2013-09-01

    Swine leucocyte antigen (SLA) class II molecules on porcine (p) cells play a crucial role in xenotransplantation as activators of recipient human CD4(+) T cells. A human dominant-negative mutant class II transactivator (CIITA-DN) transgene under a CAG promoter with an endothelium-specific Tie2 enhancer was constructed. CIITA-DN transgenic pigs were produced by nuclear transfer/embryo transfer. CIITA-DN pig cells were evaluated for expression of SLA class II with/without activation, and the human CD4(+) T-cell response to cells from CIITA-DN and wild-type (WT) pigs was compared. Lymphocyte subset numbers and T-cell function in CIITA-DN pigs were compared with those in WT pigs. The expression of SLA class II on antigen-presenting cells from CIITA-DN pigs was significantly reduced (40-50% reduction compared with WT; P < 0·01), and was completely suppressed on aortic endothelial cells (AECs) even after activation (100% suppression; P < 0·01). The human CD4(+) T-cell response to CIITA-DN pAECs was significantly weaker than to WT pAECs (60-80% suppression; P < 0·01). Although there was a significantly lower frequency of CD4(+) cells in the PBMCs from CIITA-DN (20%) than from WT (30%) pigs (P < 0·01), T-cell proliferation was similar, suggesting no significant immunological compromise. Organs and cells from CIITA-DN pigs should be partially protected from the human cellular immune response.

  6. Expression of Dominant-Negative Thyroid Hormone Receptor Alpha1 in Leydig and Sertoli Cells Demonstrates No Additional Defect Compared with Expression in Sertoli Cells Only

    PubMed Central

    Fumel, Betty; Froment, Pascal; Holzenberger, Martin; Livera, Gabriel; Monget, Philippe; Fouchécourt, Sophie

    2015-01-01

    Background In the testis, thyroid hormone (T3) regulates the number of gametes produced through its action on Sertoli cell proliferation. However, the role of T3 in the regulation of steroidogenesis is still controversial. Methods The TRαAMI knock-in allele allows the generation of transgenic mice expressing a dominant-negative TRα1 (thyroid receptor α1) isoform restricted to specific target cells after Cre-loxP recombination. Here, we introduced this mutant allele in both Sertoli and Leydig cells using a novel aromatase-iCre (ARO-iCre) line that expresses Cre recombinase under control of the human Cyp19(IIa)/aromatase promoter. Findings We showed that loxP recombination induced by this ARO-iCre is restricted to male and female gonads, and is effective in Sertoli and Leydig cells, but not in germ cells. We compared this model with the previous introduction of TRαAMI specifically in Sertoli cells in order to investigate T3 regulation of steroidogenesis. We demonstrated that TRαAMI-ARO males exhibited increased testis weight, increased sperm reserve in adulthood correlated to an increased proliferative index at P3 in vivo, and a loss of T3-response in vitro. Nevertheless, TRαAMI-ARO males showed normal fertility. This phenotype is similar to TRαAMI-SC males. Importantly, plasma testosterone and luteinizing hormone levels, as well as mRNA levels of steroidogenesis enzymes StAR, Cyp11a1 and Cyp17a1 were not affected in TRαAMI-ARO. Conclusions/Significance We concluded that the presence of a mutant TRαAMI allele in both Leydig and Sertoli cells does not accentuate the phenotype in comparison with its presence in Sertoli cells only. This suggests that direct T3 regulation of steroidogenesis through TRα1 is moderate in Leydig cells, and that Sertoli cells are the main target of T3 action in the testis. PMID:25793522

  7. Venus fly trap domain of mGluR1 functions as a dominant negative against group I mGluR signaling.

    PubMed

    Beqollari, Donald; Kammermeier, Paul J

    2010-07-01

    Metabotropic glutamate receptors (mGluRs) form covalently linked homodimers and contain large, N-terminal extracellular ligand binding, "venus fly trap" (VFT) domains. These domains, when expressed separately, are secreted as disulfide linked dimers and can dimerize with full-length receptors. mGluR splice variants have been described that contain only this domain, but the consequences of their interaction on receptor signaling have not been explored. Here it is shown that an mGluR1 mutant containing only the VFT is retained on the cell surface when a full-length receptor is co-expressed. Further, when expressed in rat superior cervical ganglion (SCG) neurons and modulation of native calcium currents is used as an assay for receptor activity, the VFT acts as a dominant negative with respect to mGluR1 signaling. Although full-length mGluR1 and mGluR5 are not known to heterodimerize, the mGluR5 VFT partially occludes mGluR1 signaling and the mGluR1 VFT potently occludes mGluR5 signaling in SCG neurons. In addition, an mGluR1 point mutant, mGluR1 C140G, which cannot covalently dimerize, functions like the wild-type receptor when expressed alone. The C140G mutant is inhibited by the mGluR1 VFT construct but does not retain the mGluR1 VFT on the cell surface, suggesting that the loss of C140 renders the interaction reversible. Finally, a peptide designed to disrupt mGluR1 dimerization reduced signaling through the C140G mutant receptor, but only when applied intracellularly for several hours, indicating that loss of signaling requires disruption of dimerization prior to plasma membrane insertion.

  8. Conditional inactivation of p53 in mouse ovarian surface epithelium does not alter MIS driven Smad2-dominant negative epithelium-lined inclusion cysts or teratomas.

    PubMed

    Quartuccio, Suzanne M; Lantvit, Daniel D; Bosland, Maarten C; Burdette, Joanna E

    2013-01-01

    Epithelial ovarian cancer is the most lethal gynecological malignancy among US women. The etiology of this disease, although poorly understood, may involve the ovarian surface epithelium or the epithelium of the fallopian tube fimbriae as the progenitor cell. Disruptions in the transforming growth factor beta (TGFβ) pathway and p53 are frequently found in chemotherapy-resistant serous ovarian tumors. Transgenic mice expressing a dominant negative form of Smad2 (Smad2DN), a downstream transcription factor of the TGFβ signaling pathway, targeted to tissues of the reproductive tract were created on a FVB background. These mice developed epithelium-lined inclusion cysts, a potential precursor lesion to ovarian cancer, which morphologically resembled oviductal epithelium but exhibited protein expression more closely resembling the ovarian surface epithelium. An additional genetic "hit" of p53 deletion was predicted to result in ovarian tumors. Tissue specific deletion of p53 in the ovaries and oviducts alone was attempted through intrabursal or intraoviductal injection of Cre-recombinase expressing adenovirus (AdCreGFP) into p53 (flox/flox) mice. Ovarian bursal cysts were detected in some mice 6 months after intrabursal injection. No pathological abnormalities were detected in mice with intraoviductal injections, which may be related to decreased infectivity of the oviductal epithelium with adenovirus as compared to the ovarian surface epithelium. Bitransgenic mice, expressing both the Smad2DN transgene and p53 (flox/flox), were then exposed to AdCreGFP in the bursa and oviductal lumen. These mice did not develop any additional phenotypes. Exposure to AdCreGFP is not an effective methodology for conditional deletion of floxed genes in oviductal epithelium and tissue specific promoters should be employed in future mouse models of the disease. In addition, a novel phenotype was observed in mice with high expression of the Smad2DN transgene as validated through q

  9. Dominant-Negative Effects of Adult-Onset Huntingtin Mutations Alter the Division of Human Embryonic Stem Cells-Derived Neural Cells

    PubMed Central

    Lopes, Carla; Aubert, Sophie; Bourgois-Rocha, Fany; Barnat, Monia; Rego, Ana Cristina; Déglon, Nicole

    2016-01-01

    Mutations of the huntingtin protein (HTT) gene underlie both adult-onset and juvenile forms of Huntington’s disease (HD). HTT modulates mitotic spindle orientation and cell fate in mouse cortical progenitors from the ventricular zone. Using human embryonic stem cells (hESC) characterized as carrying mutations associated with adult-onset disease during pre-implantation genetic diagnosis, we investigated the influence of human HTT and of an adult-onset HD mutation on mitotic spindle orientation in human neural stem cells (NSCs) derived from hESCs. The RNAi-mediated silencing of both HTT alleles in neural stem cells derived from hESCs disrupted spindle orientation and led to the mislocalization of dynein, the p150Glued subunit of dynactin and the large nuclear mitotic apparatus (NuMA) protein. We also investigated the effect of the adult-onset HD mutation on the role of HTT during spindle orientation in NSCs derived from HD-hESCs. By combining SNP-targeting allele-specific silencing and gain-of-function approaches, we showed that a 46-glutamine expansion in human HTT was sufficient for a dominant-negative effect on spindle orientation and changes in the distribution within the spindle pole and the cell cortex of dynein, p150Glued and NuMA in neural cells. Thus, neural derivatives of disease-specific human pluripotent stem cells constitute a relevant biological resource for exploring the impact of adult-onset HD mutations of the HTT gene on the division of neural progenitors, with potential applications in HD drug discovery targeting HTT-dynein-p150Glued complex interactions. PMID:26863614

  10. Suppression of Erk activation and in vivo growth in esophageal cancer cells by the dominant negative Ras mutant, N116Y.

    PubMed

    Senmaru, N; Shichinohe, T; Takeuchi, M; Miyamoto, M; Sazawa, A; Ogiso, Y; Takahashi, T; Okushiba, S; Takimoto, M; Kato, H; Kuzumaki, N

    1998-10-29

    Our previous studies demonstrated that introduction of a dominant negative H-ras mutant, N116Y, inhibits the growth of various types of cancer cells in vitro. In this study, we tested the efficacy of N116Y in blocking the growth of esophageal cancer cells using an adenoviral vector. Infection with N116Y adenovirus, (AdCMV-N116Y), in which N116Y expression is driven by the cytomegalovirus promoter, significantly reduced the in vitro growth of all esophageal cancer cell lines studied. Esophageal cancer cells that contained wild-type K-ras and H-ras (TE8, SGF3, SGF7) were more sensitive to AdCMV-N116Y than HEC46 cells that expressed mutant K-ras protein. Most importantly, direct injection of AdCMV-N116Y into TE8- or SGF3-induced tumors in nude mice suppressed their growth significantly. To examine the suppressive mechanism of N116Y, cell cycle profile and the activation of extracellular signal-regulated kinase 2 (Erk2) were examined by flow cytometry and Western blot analysis, respectively. In TE8 cells, progression into S phase was clearly blocked after infection with AdCMV-N116Y. Infection with AdCMV-N116Y did not strongly suppress the activation of Erk2 after EGF stimulation in serum-starved HEC46 cells, whereas it completely suppressed activation in TE8, SGF3 and SGF7 cells. Our observations suggest that N116Y reduces growth of human esophageal cancer cells and suppresses the activation of Erk2; they also indicate that N116Y is a potential candidate gene for human esophageal cancer gene therapy.

  11. Isolated 3-methylcrotonyl-CoA carboxylase deficiency: evidence for an allele-specific dominant negative effect and responsiveness to biotin therapy.

    PubMed

    Baumgartner, Matthias R; Dantas, M Fernanda; Suormala, Terttu; Almashanu, Shlomo; Giunta, Cecilia; Friebel, Dolores; Gebhardt, Boris; Fowler, Brian; Hoffmann, Georg F; Baumgartner, E Regula; Valle, David

    2004-11-01

    Deficiency of 3-methylcrotonyl-CoA carboxylase (MCC) results in elevated excretion of 3-methylcrotonylglycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA). MCC is a heteromeric mitochondrial enzyme comprising biotin-containing alpha subunits and smaller beta subunits, encoded by MCCA and MCCB, respectively. Mutations in these genes cause isolated MCC deficiency, an autosomal recessive disorder with a variable phenotype that ranges from severe neonatal to asymptomatic adult forms. No reported patients have responded to biotin therapy. Here, we describe two patients with a biochemical and, in one case, clinical phenotype of MCC deficiency, both of whom were responsive to biotin. The first patient presented at 3 months with seizures and progressive psychomotor retardation. Metabolic investigation at 2 years revealed elevated excretion of 3-MCG and 3-HIVA, suggesting MCC deficiency. High-dose biotin therapy was associated with a dramatic reduction in seizures, normalization of the electroencephalogram, and correction of the organic aciduria, within 4 weeks. MCC activity in fibroblasts was 25% of normal levels. The second patient, a newborn detected by tandem-mass-spectrometry newborn screening, displayed the same biochemical phenotype and remained asymptomatic with biotin up to the age of 18 months. In both patients, sequence analysis of the complete open reading frames of MCCA and MCCB revealed heterozygosity for MCCA-R385S and for the known polymorphic variant MCCA-P464H but revealed no other coding alterations. MCCA-R385S is unusual, in that it has a normal amount of MCC alpha protein but confers no MCC activity. We show that MCCA-R385S, but not other MCCA missense alleles, reduces the MCC activity of cotransfected MCCA-wild-type allele. Our results suggest that MCCA-R385S is a dominant negative allele and is biotin responsive in vivo.

  12. Aberrant cell cycle progression contributes to the early-stage accelerated carcinogenesis in transgenic epidermis expressing the dominant negative TGFbetaRII.

    PubMed

    Go, C; He, W; Zhong, L; Li, P; Huang, J; Brinkley, B R; Wang, X J

    2000-07-27

    Mutations in the transforming growth factor beta type II receptor (TGFbetaRII) have been found in various malignant tumors, suggesting that loss of TGFbeta signaling plays a causal role in late-stage cancer development. To test whether loss of TGFbetaRII is involved in early-stage carcinogenesis, we have generated transgenic mice expressing a dominant negative TGFbetaRII (deltabetaRII) in the epidermis. These mice exhibited an increased susceptibility to chemical carcinogenesis protocols at both early and late stages. In the current study, parameters for cell cycle progression and chromosome instability were analysed in deltabetaRII tumors. DeltabetaRII papillomas showed an increased S phase in flow cytometry. Bromodeoxyuridine (BrdU) labeling and mitotic indices in deltabetaRII papillomas also showed a threefold increase compared to papillomas developing in non-transgenic mice. When papillomas further progressed to squamous cell carcinomas (SCC), both control and deltabetaRII SCC showed similar BrdU labeling indices and percentages of S phase cells. However, deltabetaRII SCC cells showed a sixfold increase in the G2/M population. Mitotic indices in deltabetaRII SCC also showed a threefold increase compared to non-transgenic SCC. Consistent with a perturbed cell cycle, deltabetaRII papillomas and SCC showed reduced expression of the TGFbeta target genes p15 (INK4b), p21 (WAF-1) and p27 (Kip1), inhibitors of cyclin-dependent kinases (cdks). However, most deltabetaRII papilloma cells exhibited normal centrosome numbers, and deltabetaRII SCC exhibited a similar extent of centrosome abnormalities compared to control SCC (35-40% cells). Most of deltabetaRII SCC exhibited diploid chromosome profiles. These data indicate that inactivation of TGFbetaRII accelerates skin tumorigenesis at early stages by the acceleration of loss of cell cycle control, but not by increased chromosome instability.

  13. Dominant-Negative Effects of Adult-Onset Huntingtin Mutations Alter the Division of Human Embryonic Stem Cells-Derived Neural Cells.

    PubMed

    Lopes, Carla; Aubert, Sophie; Bourgois-Rocha, Fany; Barnat, Monia; Rego, Ana Cristina; Déglon, Nicole; Perrier, Anselme L; Humbert, Sandrine

    2016-01-01

    Mutations of the huntingtin protein (HTT) gene underlie both adult-onset and juvenile forms of Huntington's disease (HD). HTT modulates mitotic spindle orientation and cell fate in mouse cortical progenitors from the ventricular zone. Using human embryonic stem cells (hESC) characterized as carrying mutations associated with adult-onset disease during pre-implantation genetic diagnosis, we investigated the influence of human HTT and of an adult-onset HD mutation on mitotic spindle orientation in human neural stem cells (NSCs) derived from hESCs. The RNAi-mediated silencing of both HTT alleles in neural stem cells derived from hESCs disrupted spindle orientation and led to the mislocalization of dynein, the p150Glued subunit of dynactin and the large nuclear mitotic apparatus (NuMA) protein. We also investigated the effect of the adult-onset HD mutation on the role of HTT during spindle orientation in NSCs derived from HD-hESCs. By combining SNP-targeting allele-specific silencing and gain-of-function approaches, we showed that a 46-glutamine expansion in human HTT was sufficient for a dominant-negative effect on spindle orientation and changes in the distribution within the spindle pole and the cell cortex of dynein, p150Glued and NuMA in neural cells. Thus, neural derivatives of disease-specific human pluripotent stem cells constitute a relevant biological resource for exploring the impact of adult-onset HD mutations of the HTT gene on the division of neural progenitors, with potential applications in HD drug discovery targeting HTT-dynein-p150Glued complex interactions.

  14. A Mutant S3 RNase of Petunia inflata Lacking RNase Activity Has an Allele-Specific Dominant Negative Effect on Self-Incompatibility Interactions.

    PubMed Central

    McCubbin, A. G.; Chung, Y. Y.; Kao, Th.

    1997-01-01

    Gametophytic self-incompatibility in the Solanaceae is controlled by a multiallelic locus called the S locus. Growth of pollen tubes in the pistil is inhibited when the pollen has one of the two S alleles carried by the pistil. The products of a number of pistil S alleles[mdash]S proteins or S RNases[mdash]have been identified, and their role in controlling the pistil's ability to reject self-pollen has been positively established. In contrast, the existence of pollen S allele products has so far been inferred entirely from genetic evidence. Here, we introduced a modified S3 gene of Petunia inflata encoding an S3 RNase lacking RNase activity into P. inflata plants of the S2S3 genotype to determine whether the production of the mutant protein, designated S3(H93R), would have any effect on the ability of the transgenic plants to reject S2 and S3 pollen. Analysis of the self-incompatibility behavior of 49 primary transgenic plants and the progeny of three plants (H30, H37, and H40) that produced S3(H93R) in addition to producing wild-type levels of endogenous S2 and S3 RNases revealed that S3(H93R) had a dominant negative effect on the function of the S3 RNase in rejecting self-pollen; however, it had no effect on the function of the S2 RNase. One likely explanation of the results is that S3(H93R) competes with the S3 RNase for binding to a common molecule, which is presumably the product of the pollen S3 allele. PMID:12237345

  15. Dominant negative effect of mutated thyroid stimulating hormone receptor (P556L) causes hypothyroidism in C.RF-Tshr(hyt/wild) mice.

    PubMed

    Endo, Toyoshi; Kobayashi, Tetsuro

    2012-01-01

    C.RF-Tshr(hyt/hyt) mice have a mutated thyroid stimulating hormone receptor (P556L-TSHR) and these mice develop severe hypothyroidism. We found that C.RF-Tshr(hyt/wild) heterozygous mice are also in a hypothyroid state. Thyroid glands from C.RF-Tshr(hyt/wild) mice are smaller than those from wild-type mice, and (125)I uptake activities of the former are significantly lower than those in the latter. When TSHR (TSHR(W)) and P556L-TSHR (TSHR(M)) cDNAs were cloned and co-transfected into HEK 293 cells, the cells retained (125)I-TSH binding activity, but cAMP response to TSH was decreased to about 20% of HEK 293 cells transfected with TSHR(W) cDNA. When TSHR(W) and TSHR(M) were tagged with eCFP or eYFP, we observed fluorescence resonance energy transfer (FRET) in HEK 293 cells expressing TSHR(W)-eCFP and TSHR(W)-eYFP in the absence of TSH, but not in the presence of TSH. In contrast, we obtained FRET in HEK 293 cells expressing TSHR(W)-eCFP and TSHR (M)-eYFP, regardless of the presence or absence of TSH. These results suggest that P556L TSHR has a dominant negative effect on TSHR(W) by impairing polymer to monomer dissociation, which decreases TSH responsiveness and induces hypothyroidism in C.RF-Tshr(hyt/wild) mice. PMID:22916127

  16. Progression of mouse skin carcinogenesis is associated with increased ERα levels and is repressed by a dominant negative form of ERα.

    PubMed

    Logotheti, Stella; Papaevangeliou, Dimitra; Michalopoulos, Ioannis; Sideridou, Maria; Tsimaratou, Katerina; Christodoulou, Ioannis; Pyrillou, Katerina; Gorgoulis, Vassilis; Vlahopoulos, Spiros; Zoumpourlis, Vassilis

    2012-01-01

    Estrogen receptors (ER), namely ERα and ERβ, are hormone-activated transcription factors with an important role in carcinogenesis. In the present study, we aimed at elucidating the implication of ERα in skin cancer, using chemically-induced mouse skin tumours, as well as cell lines representing distinct stages of mouse skin oncogenesis. First, using immunohistochemical staining we showed that ERα is markedly increased in aggressive mouse skin tumours in vivo as compared to the papilloma tumours, whereas ERβ levels are low and become even lower in the aggressive spindle tumours of carcinogen-treated mice. Then, using the multistage mouse skin carcinogenesis model, we showed that ERα gradually increases during promotion and progression stages of mouse skin carcinogenesis, peaking at the most aggressive stage, whereas ERβ levels only slightly change throughout skin carcinogenesis. Stable transfection of the aggressive, spindle CarB cells with a dominant negative form of ERα (dnERα) resulted in reduced ERα levels and reduced binding to estrogen responsive elements (ERE)-containing sequences. We characterized two highly conserved EREs on the mouse ERα promoter through which dnERα decreased endogenous ERα levels. The dnERα-transfected CarB cells presented altered protein levels of cytoskeletal and cell adhesion molecules, slower growth rate and impaired anchorage-independent growth in vitro, whereas they gave smaller tumours with extended latency period of tumour onset in vivo. Our findings suggest an implication of ERα in the aggressiveness of spindle mouse skin cancer cells, possibly through regulation of genes affecting cell shape and adhesion, and they also provide hints for the effective targeting of spindle cancer cells by dnERα. PMID:22870269

  17. Alternative Splicing Generates a Diacylglycerol Kinase α Transcript That Acts as a Dominant-Negative Modulator of Superoxide Production in Localized Aggressive Periodontitis

    PubMed Central

    Batista, Eraldo L.; Kantarci, Alpdogan I.; Hasturk, Hatice; Van Dyke, Thomas E.

    2015-01-01

    Background Diacylglycerol (DAG), levels of which are tightly regulated by diacylglycerol kinases (DGKs), is a lipid mediator linked to key biologic functions. Members of the DGK family undergo alternative splicing, generating the protein diversity necessary to control different intracellular DAG pools. DGKα function is altered in polymorphonuclear neutrophils (PMNs) of patients with localized aggressive periodontitis (LAgP), suggesting a genetic basis. Here, the authors assess DGKα spliced transcripts in human LAgP neutrophils. Methods In an expression library of a patient with LAgP, PMNs were screened for different DGKα transcripts. Real-time polymerase chain reaction and in vitro expression assays were performed to assess the fate of different transcripts on protein translocation and superoxide production in human leukemia cells (HL-60) and COS-7 cells. Results A DGKα transcript that lacks exon 10 (DGKαΔ10) and generates a premature stop codon and a truncated protein was identified as being upregulated in LAgP neutrophils. In vitro assays revealed that DGKαΔ10 translocation occurred even in the absence of important regulatory motifs. Transfection of HL-60 neutrophil-like cells with the DGKαΔ10 spliced variant induced an increase in the stimulated production of su-peroxide anion replicating the phenotype of LAgP PMNs. Conclusion DGKαΔ10 can act as a dominant-negative transcript that can modulate superoxide production and provides an example of genetic regulation of the inflammatory response that may be relevant to human inflammatory diseases such as LAgP. J Periodontol 2014;85:934-943. PMID:24171497

  18. A dominant-negative form of the major human abasic endonuclease enhances cellular sensitivity to laboratory and clinical DNA-damaging agents.

    PubMed

    McNeill, Daniel R; Wilson, David M

    2007-01-01

    Apurinic/apyrimidinic (AP) endonuclease 1 (APE1) is the primary enzyme in mammals for the repair of abasic sites in DNA, as well as a variety of 3' damages that arise upon oxidation or as products of enzymatic processing. If left unrepaired, APE1 substrates can promote mutagenic and cytotoxic outcomes. We describe herein a dominant-negative form of APE1 that lacks detectable nuclease activity and binds substrate DNA with a 13-fold higher affinity than the wild-type protein. This mutant form of APE1, termed ED, possesses two amino acid substitutions at active site residues Glu(96) (changed to Gln) and Asp(210) (changed to Asn). In vitro biochemical assays reveal that ED impedes wild-type APE1 AP site incision function, presumably by binding AP-DNA and blocking normal lesion processing. Moreover, tetracycline-regulated (tet-on) expression of ED in Chinese hamster ovary cells enhances the cytotoxic effects of the laboratory DNA-damaging agents, methyl methanesulfonate (MMS; 5.4-fold) and hydrogen peroxide (1.5-fold). This MMS-induced, ED-dependent cell killing coincides with a hyperaccumulation of AP sites, implying that excessive DNA damage is the cause of cell death. Because an objective of the study was to identify a protein reagent that could be used in targeted gene therapy protocols, the effects of ED on cellular sensitivity to a number of chemotherapeutic compounds was tested. We show herein that ED expression sensitizes Chinese hamster ovary cells to the killing effects of the alkylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (also known as carmustine) and the chain terminating nucleoside analogue dideoxycytidine (also known as zalcitabine), but not to the radiomimetic bleomycin, the nucleoside analogue beta-D-arabinofuranosylcytosine (also known as cytarabine), the topoisomerase inhibitors camptothecin and etoposide, or the cross-linking agents mitomycin C and cisplatin. Transient expression of ED in the human cancer cell line NCI-H1299 enhanced cellular

  19. Rough endoplasmic reticulum trafficking errors by different classes of mutant dentin sialophosphoprotein (DSPP) cause dominant negative effects in both dentinogenesis imperfecta and dentin dysplasia by entrapping normal DSPP.

    PubMed

    von Marschall, Zofia; Mok, Seeun; Phillips, Matthew D; McKnight, Dianalee A; Fisher, Larry W

    2012-06-01

    Families with nonsyndromic dentinogenesis imperfecta (DGI) and the milder, dentin dysplasia (DD), have mutations in one allele of the dentin sialophosphoprotein (DSPP) gene. Because loss of a single Dspp allele in mice (and likely, humans) causes no dental phenotype, the mechanism(s) underling the dominant negative effects were investigated. DSPP mutations occur in three classes. (The first class, the mid-leader missense mutation, Y6D, was not investigated in this report.) All other 5′ mutations of DSPP result in changes/loss in the first three amino acids (isoleucine-proline-valine [IPV]) of mature DSPP or, for the A15V missense mutation, some retention of the hydrophobic leader sequence. All of this second class of mutations caused mutant DSPP to be retained in the rough endoplasmic reticulum (rER) of transfected HEK293 cells. Trafficking out of the rER by coexpressed normal DSPP was reduced in a dose-responsive manner, probably due to formation of Ca2+-dependent complexes with the retained mutant DSPP. IPV-like sequences begin many secreted Ca2+-binding proteins, and changing the third amino acid to the charged aspartate (D) in three other acidic proteins also caused increased rER accumulation. Both the leader-retaining A15V and the long string of hydrophobic amino acids resulting from all known frameshift mutations within the 3′-encoded Ca2+-binding repeat domain (third class of mutations) caused retention by association of the mutant proteins with rER membranes. More 5′ frameshift mutations result in longer mutant hydrophobic domains, but the milder phenotype, DD, probably due to lower effectiveness of the remaining, shorter Ca2+-binding domain in capturing normal DSPP protein within the rER. This study presents evidence of a shared underlying mechanism of capturing of normal DSPP by two different classes of DSPP mutations and offers an explanation for the mild (DD-II) versus severe (DGI-II and III) nonsyndromic dentin phenotypes. Evidence is also

  20. Mutations in the ubiquitin-binding domain of OPTN/optineurin interfere with autophagy-mediated degradation of misfolded proteins by a dominant-negative mechanism.

    PubMed

    Shen, Wen-Chuan; Li, Huei-Ying; Chen, Guang-Chao; Chern, Yijuang; Tu, Pang-Hsien

    2015-04-01

    OPTN (optineurin) is an autophagy receptor and mutations in the OPTN gene result in familial glaucoma (E50K) and amyotrophic lateral sclerosis (ALS) (E478G). However, the mechanisms through which mutant OPTN leads to human diseases remain to be characterized. Here, we demonstrated that OPTN colocalized with inclusion bodies (IBs) formed by mutant HTT/huntingtin protein (mHTT) in R6/2 transgenic mice and IBs formed by 81QNmHTT (nuclear form), 109QmHTT (cytoplasmic form) or the truncated form of TARDBP/TDP-43 (TARDBP(ND251)) in Neuro2A cells. This colocalization required the ubiquitin (Ub)-binding domain (UbBD, amino acids 424 to 511) of OPTN. Overexpression of wild-type (WT) OPTN decreased IBs through K63-linked polyubiquitin-mediated autophagy. E50K or 210 to 410Δ (with amino acids 210 to 410 deleted) whose mutation or deletion was outside the UbBD decreased the IBs formed by 109QmHTT or TARDBP(ND251), as was the case with WT OPTN. In contrast, UbBD mutants, including E478G, D474N, UbBDΔ, 411 to 520Δ and 210 to 520Δ, increased accumulation of IBs. UbBD mutants (E478G, UbBDΔ) retained a substantial ability to interact with WT OPTN, and were found to colocalize with polyubiquitinated IBs, which might occur indirectly through their WT partner in a WT-mutant complex. They decreased autophagic flux evidenced by alteration in LC3 level and turnover and in the number of LC3-positive puncta under stresses like starvation or formation of IBs. UbBD mutants exhibited a weakened interaction with MYO6 (myosin VI) and TOM1 (target of myb1 homolog [chicken]), important for autophagosome maturation, in cells or sorted 109QmHtt IBs. Taken together, our data indicated that UbBD mutants acted as dominant-negative traps through the formation of WT-mutant hybrid complexes to compromise the maturation of autophagosomes, which in turn interfered with OPTN-mediated autophagy and clearance of IBs. PMID:25484089

  1. Dominant Negative Phenotype of Bacillus thuringiensis Cry1Ab, Cry11Aa and Cry4Ba Mutants Suggest Hetero-Oligomer Formation among Different Cry Toxins

    PubMed Central

    Carmona, Daniela; Rodríguez-Almazán, Claudia; Muñoz-Garay, Carlos; Portugal, Leivi; Pérez, Claudia; de Maagd, Ruud A.; Bakker, Petra; Soberón, Mario; Bravo, Alejandra

    2011-01-01

    Background Bacillus thuringiensis Cry toxins are used worldwide in the control of different insect pests important in agriculture or in human health. The Cry proteins are pore-forming toxins that affect the midgut cell of target insects. It was shown that non-toxic Cry1Ab helix α-4 mutants had a dominant negative (DN) phenotype inhibiting the toxicity of wildtype Cry1Ab when used in equimolar or sub-stoichiometric ratios (1∶1, 0.5∶1, mutant∶wt) indicating that oligomer formation is a key step in toxicity of Cry toxins. Methodology/Principal Findings The DN Cry1Ab-D136N/T143D mutant that is able to block toxicity of Cry1Ab toxin, was used to analyze its capacity to block the activity against Manduca sexta larvae of other Cry1 toxins, such as Cry1Aa, Cry1Ac, Cry1Ca, Cry1Da, Cry1Ea and Cry1Fa. Cry1Ab-DN mutant inhibited toxicity of Cry1Aa, Cry1Ac and Cry1Fa. In addition, we isolated mutants in helix α-4 of Cry4Ba and Cry11Aa, and demonstrate that Cry4Ba-E159K and Cry11Aa-V142D are inactive and completely block the toxicity against Aedes aegypti of both wildtype toxins, when used at sub-stoichiometric ratios, confirming a DN phenotype. As controls we analyzed Cry1Ab-R99A or Cry11Aa-E97A mutants that are located in helix α-3 and are affected in toxin oligomerization. These mutants do not show a DN phenotype but were able to block toxicity when used in 10∶1 or 100∶1 ratios (mutant∶wt) probably by competition of binding with toxin receptors. Conclusions/Significance We show that DN phenotype can be observed among different Cry toxins suggesting that may interact in vivo forming hetero-oligomers. The DN phenotype cannot be observed in mutants affected in oligomerization, suggesting that this step is important to inhibit toxicity of other toxins. PMID:21603577

  2. PIL5, a Phytochrome-Interacting Basic Helix-Loop-Helix Protein, Is a Key Negative Regulator of Seed Germination in Arabidopsis thalianaW⃞

    PubMed Central

    Oh, Eunkyoo; Kim, Jonghyun; Park, Eunae; Kim, Jeong-Il; Kang, Changwon; Choi, Giltsu

    2004-01-01

    The first decision made by an angiosperm seed, whether to germinate or not, is based on integration of various environmental signals such as water and light. The phytochromes (Phys) act as red and far-red light (Pfr) photoreceptors to mediate light signaling through yet uncharacterized pathways. We report here that the PIF3-like 5 (PIL5) protein, a basic helix-loop-helix transcription factor, is a key negative regulator of phytochrome-mediated seed germination. PIL5 preferentially interacts with the Pfr forms of Phytochrome A (PhyA) and Phytochrome B (PhyB). Analyses of a pil5 mutant in conjunction with phyA and phyB mutants, a pif3 pil5 double mutant, and PIL5 overexpression lines indicate that PIL5 is a negative factor in Phy-mediated promotion of seed germination, inhibition of hypocotyl negative gravitropism, and inhibition of hypocotyl elongation. Our data identify PIL5 as the first Phy-interacting protein that regulates seed germination. PMID:15486102

  3. Myelin basic protein-specific T lymphocyte repertoire in multiple sclerosis. Complexity of the response and dominance of nested epitopes due to recruitment of multiple T cell clones.

    PubMed Central

    Meinl, E; Weber, F; Drexler, K; Morelle, C; Ott, M; Saruhan-Direskeneli, G; Goebels, N; Ertl, B; Jechart, G; Giegerich, G

    1993-01-01

    The human T cell response to the myelin basic protein (MBP) has been studied with respect to T cell receptor (TCR) usage, HLA class II restriction elements, and epitope specificity using a total of 215 long-term MBP-specific T cell lines (TCL) isolated from the peripheral blood of 13 patients with multiple sclerosis (MS) and 10 healthy donors. In most donors, the anti-MBP response was exceedingly heterogeneous. Using a panel of overlapping synthetic peptides spanning the entire length of human MBP, at least 26 epitopes recognized by human TCL could be distinguished. The MBP domain most commonly recognized was sequence 80-105 (31% of MS TCL, and 24% of control TCL). Sequence 29-48 was recognized more frequently by control-derived TCL (24%) than by TCL from MS patients (5%). The MBP epitopes were recognized in the context of DRB1 *0101, DRB5*0101, DRB1*1501, DRB1*0301, DRB1*0401, DRB1*1402, and DRB3*0102, as demonstrated using a panel of DR gene-transfected L cells. The TCR gene usage was also heterogeneous. V beta 5.2, a peptide of which is currently being used in a clinical trial for treatment of MS patients, was expressed by only one of our TCL. However, within this complex pattern of MBP-specific T cell responses, a minority of MS patients were found to exhibit a more restricted response with respect to their TCL epitope specificity. In these patients 75-87% of the TCL responded to a single, patient-specific cluster of immunodominant T cell epitopes located within a small (20-amino acid) domain of MBP. These nested clusters of immunodominant epitopes were noted within the amino acids 80-105, 108-131, and 131-153. The T cell response to the immunodominant epitopes was not monoclonal, but heterogeneous, with respect to fine specificity, TCR usage, and even HLA restriction. In one patient (H.K.), this restricted epitope profile remained stable for > 2 yr. The TCR beta chain sequences of TCL specific for the immunodominant region of HK are consistent with an

  4. Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W37, Wv, W41 and W.

    PubMed Central

    Nocka, K; Tan, J C; Chiu, E; Chu, T Y; Ray, P; Traktman, P; Besmer, P

    1990-01-01

    The proto-oncogene c-kit encodes a transmembrane tyrosine protein kinase receptor for an unknown ligand and is allelic with the murine white-spotting locus (W). Mutations at the W locus affect various aspects of hematopoiesis, the proliferation and migration of primordial germ cells and melanoblasts during development. The original W mutation and W37 are severe lethal mutations when homozygous. In the heterozygous state the W mutation has a weak phenotype while W37 has dominant characteristics. Wv and W41 are weak W mutations with dominant characteristics. We have characterized the molecular basis of these four W mutations and determined their effects on mast cell differentiation by using a fibroblast/mast cell co-culture assay. We show that W37, Wv and W41 are the result of missense mutations in the kinase domain of the c-kit coding sequence (W37 E----K at position 582; Wv T----M position 660 and W41 V----M position 831), which affect the c-kit associated tyrosine kinase to varying degrees. The c-kit protein products in homozygous mutant mast cells are expressed normally, although the 160 kd cell membrane form of the c-kitW37 protein displays accelerated turnover characteristics. The W mutation is the result of a 78 amino acid deletion which includes the transmembrane domain of the c-kit protein. A 125 kd c-kit protein was detected in homozygous W/W mast cells which lacks kinase activity and is not expressed on the cell surface.(ABSTRACT TRUNCATED AT 250 WORDS) Images Fig. 2. Fig. 3. Fig. 5. PMID:1693331

  5. Activation of PI3K/Akt signaling has a dominant negative effect on IL-12 production by macrophages infected with Leishmania amazonensis promastigotes

    PubMed Central

    Ruhland, Aaron; Kima, Peter E.

    2009-01-01

    Infection of macrophages with Leishmania parasites does not result in the production of IL-12. In addition, infection with Leishmania suppresses IL-12 production elicited by otherwise potent activators of IL-12. We provide evidence that engagement of phosphatidyl inositol-3 kinase (PI3K) signaling during Leishmania amazonensis infection leads to the prevention of IL-12 p70 production at the level of transcription of its p40 subunit in bone marrow derived macrophages (BMDMϕ). Inhibition of PI3K signaling with specific inhibitors of PI3K or the downstream kinase Akt, reverses the IL-12 blockade. Although the MAP kinase ERK (p44 and p42) was transiently activated by infection with L. amazonensis, inhibition of MEK, the kinase upstream of ERK, with PD98059, did not reverse the blockade of IL-12. Furthermore, inhibition of the other MAP kinases JNK and p38 as well as treatment of cells with pertussis toxin that blocks G protein mediated signaling, did not reverse the prevention of IL-12 production by Leishmania infection. Interestingly, activation of PI3K/Akt signaling had differential effects on ERK and p38 activation. Taken together we propose that infection of BMDMϕ with Leishmania promastigotes activates both positive and negative signaling pathways that control IL-12 production. PI3K signaling activated by the infection is the negative signaling pathway that prevents IL-12 production. PMID:19186178

  6. Activation of PI3K/Akt signaling has a dominant negative effect on IL-12 production by macrophages infected with Leishmania amazonensis promastigotes.

    PubMed

    Ruhland, Aaron; Kima, Peter E

    2009-05-01

    Infection of macrophages with Leishmania parasites does not result in the production of IL-12. In addition, infection with Leishmania suppresses IL-12 production elicited by otherwise potent activators of IL-12. We provide evidence that engagement of phosphatidyl inositol-3 kinase (PI3K) signaling during Leishmania amazonensis infection leads to the prevention of IL-12 p70 production at the level of transcription of its p40 subunit in bone marrow derived macrophages (BMDMPhi). Inhibition of PI3K signaling with specific inhibitors of PI3K or the downstream kinase Akt, reverses the IL-12 blockade. Although the MAP kinase ERK (p44 and p42) was transiently activated by infection with L. amazonensis, inhibition of MEK, the kinase upstream of ERK, with PD98059, did not reverse the blockade of IL-12. Furthermore, inhibition of the other MAP kinases JNK and p38 as well as treatment of cells with pertussis toxin that blocks G protein mediated signaling, did not reverse the prevention of IL-12 production by Leishmania infection. Interestingly, activation of PI3K/Akt signaling had differential effects on ERK and p38 activation. Taken together we propose that infection of BMDMPhi with Leishmania promastigotes activates both positive and negative signaling pathways that control IL-12 production. PI3K signaling activated by the infection is the negative signaling pathway that prevents IL-12 production.

  7. Dominating expression of negative regulatory factors downmodulates major histocompatibility complex Class-II expression on dendritic cells in chronic hepatitis C infection

    PubMed Central

    Tomer, Shallu; Chawla, Yogesh K; Duseja, Ajay; Arora, Sunil K

    2016-01-01

    AIM: To elucidate the molecular mechanisms leading to development of functionally impaired dendritic cells (DCs) in chronic hepatitis C (CHC) patients infected with genotype 3 virus. METHODS: This prospective study was conducted on the cohorts of CHC individuals identified as responders or non-responders to antiviral therapy. Myeloid DCs were isolated from the peripheral blood of each subject using CD1c (BDCA1)+ DC isolation Kit. Monocytes from healthy donor were cultured with DC growth factors such as IL-4 and GM-CSF either in the presence or absence of hepatitis C virus (HCV) viral proteins followed by LPS stimulation. Phenotyping was done by flowcytometry and gene expression profiling was evaluated by real-time PCR. RESULTS: Non-responders [sustained virological response (SVR)-ve] to conventional antiviral therapy had significantly higher expression of genes associated with interferon responsive element such as IDO1 and PD-L1 (6-fold) and negative regulators of JAK-STAT pathway such as SOCS (6-fold) as compared to responders (SVR+ve) to antiviral therapy. The down-regulated genes in non-responders included factors involved in antigen processing and presentation mainly belonging to major histocompatibility complex (MHC) Class-II family as HLA-DP, HLA-DQ (2-fold) and superoxide dismutase (2-fold). Cells grown in the presence of HCV viral proteins had genes down-regulated for factors involved in innate response, interferon signaling, DC maturation and co-stimulatory signaling to T-cells, while the genes for cytokine signaling and Toll-like receptors (4-fold) were up-regulated as compared to cells grown in absence of viral proteins. CONCLUSION: Underexpressed MHC class-II genes and upregulated negative regulators in non-responders indicate diminished capacity to present antigen and may constitute mechanism of functionally defective state of DCs. PMID:27298560

  8. Dominant-Negative Effect of a Missense Variant in the TASK-2 (KCNK5) K+ Channel Associated with Balkan Endemic Nephropathy

    PubMed Central

    Abd-Wahab, Firdaus; Tucker, Stephen J.

    2016-01-01

    TASK-2, a member of the Two-Pore Domain (K2P) subfamily of K+ channels, is encoded by the KCNK5 gene. The channel is expressed primarily in renal epithelial tissues and a potentially deleterious missense variant in KCNK5 has recently been shown to be prevalent amongst patients predisposed to the development of Balkan Endemic Nephropathy (BEN), a chronic tubulointerstitial renal disease of unknown etiology. In this study we show that this variant (T108P) results in a complete loss of channel function and is associated with a major reduction in TASK-2 channel subunits at the cell surface. Furthermore, these mutant subunits have a suppressive or ‘dominant-negative’ effect on channel function when coexpressed with wild-type subunits. This missense variant is located at the extracellular surface of the M2 transmembrane helix and by using a combination of structural modelling and further functional analysis we also show that this highly-conserved threonine residue is critical for the correct function of other K2P channels. These results therefore provide further structural and functional insights into the possible pathophysiological effects of this missense variant in TASK-2. PMID:27228168

  9. Heteromeric p97/p97R155C complexes induce dominant negative changes in wild-type and autophagy 9-deficient Dictyostelium strains.

    PubMed

    Arhzaouy, Khalid; Strucksberg, Karl-Heinz; Tung, Sze Man; Tangavelou, Karthikeyan; Stumpf, Maria; Faix, Jan; Schröder, Rolf; Clemen, Christoph S; Eichinger, Ludwig

    2012-01-01

    Heterozygous mutations in the human VCP (p97) gene cause autosomal-dominant IBMPFD (inclusion body myopathy with early onset Paget's disease of bone and frontotemporal dementia), ALS14 (amyotrophic lateral sclerosis with or without frontotemporal dementia) and HSP (hereditary spastic paraplegia). Most prevalent is the R155C point mutation. We studied the function of p97 in the social amoeba Dictyostelium discoideum and have generated strains that ectopically express wild-type (p97) or mutant p97 (p97(R155C)) fused to RFP in AX2 wild-type and autophagy 9 knock-out (ATG9(KO)) cells. Native gel electrophoresis showed that both p97 and p97(R155C) assemble into hexamers. Co-immunoprecipitation studies revealed that endogenous p97 and p97(R155C)-RFP form heteromers. The mutant strains displayed changes in cell growth, phototaxis, development, proteasomal activity, ubiquitinylated proteins, and ATG8(LC3) indicating mis-regulation of multiple essential cellular processes. Additionally, immunofluorescence analysis revealed an increase of protein aggregates in ATG9(KO)/p97(R155C)-RFP and ATG9(KO) cells. They were positive for ubiquitin in both strains, however, solely immunoreactive for p97 in the ATG9(KO) mutant. A major finding is that the expression of p97(R155C)-RFP in the ATG9(KO) strain partially or fully rescued the pleiotropic phenotype. We also observed dose-dependent effects of p97 on several cellular processes. Based on findings in the single versus the double mutants we propose a novel mode of p97 interaction with the core autophagy protein ATG9 which is based on mutual inhibition. PMID:23056506

  10. Too Many Is Too Bad: Long-Term Net Negative Effects of High Density Ungulate Populations on a Dominant Mediterranean Shrub

    PubMed Central

    Lecomte, Xavier; Fedriani, José M.; Caldeira, Maria C.; Clemente, Adelaide S.; Olmi, Alessandro; Bugalho, Miguel N.

    2016-01-01

    Plant–animal interactions imply costs and benefits with net balance depending on interacting species and ecological context. Ungulates, in particular, confer costs (e.g., plant leaf consumption, flower bud predation) and benefits (e.g., plant overcompensation, seed dispersal) to plants. Magnitude of costs and benefits may be altered by habitat management or ecological conditions favoring high density ungulate populations. Little is known however on whether plant costs or benefits predominate over the years, or the long-term outcomes of plant-animal interactions in habitat types sustaining high density ungulate populations. We investigated how high density ungulate populations alter plant costs and benefits by quantifying ungulate long-term effects on the shrub Cistus ladanifer (Cistaceae) individual size, seed weight and number, seed bank, and population density, through a 12-year ungulate exclusion experiment in a Mediterranean scrubland. We monitored plant size and flower buds in plants exposed or protected from ungulates and number of developed capsules and seeds consumed (potential seed dispersal) by ungulates during three reproductive seasons. We found that ungulates negatively affected shrub size and led to a dramatically decline of shrub reproductive structures and seed production, affecting the plant reproductive cycle. Number of buds was 27 times higher and number of developed seed 5 times higher in ungulate-excluded as compared to ungulate-exposed plots. After 9 years of ungulate exclusion, the C. ladanifer seed bank was 2.6 times higher in ungulate-excluded plots. The population density of C. ladanifer was 4 times higher in ungulate-excluded plots. Our long-term experiment showed that high density ungulate populations can alter plant-animal interactions by reducing plant benefits and increasing plant costs. PMID:27387134

  11. Too Many Is Too Bad: Long-Term Net Negative Effects of High Density Ungulate Populations on a Dominant Mediterranean Shrub.

    PubMed

    Lecomte, Xavier; Fedriani, José M; Caldeira, Maria C; Clemente, Adelaide S; Olmi, Alessandro; Bugalho, Miguel N

    2016-01-01

    Plant-animal interactions imply costs and benefits with net balance depending on interacting species and ecological context. Ungulates, in particular, confer costs (e.g., plant leaf consumption, flower bud predation) and benefits (e.g., plant overcompensation, seed dispersal) to plants. Magnitude of costs and benefits may be altered by habitat management or ecological conditions favoring high density ungulate populations. Little is known however on whether plant costs or benefits predominate over the years, or the long-term outcomes of plant-animal interactions in habitat types sustaining high density ungulate populations. We investigated how high density ungulate populations alter plant costs and benefits by quantifying ungulate long-term effects on the shrub Cistus ladanifer (Cistaceae) individual size, seed weight and number, seed bank, and population density, through a 12-year ungulate exclusion experiment in a Mediterranean scrubland. We monitored plant size and flower buds in plants exposed or protected from ungulates and number of developed capsules and seeds consumed (potential seed dispersal) by ungulates during three reproductive seasons. We found that ungulates negatively affected shrub size and led to a dramatically decline of shrub reproductive structures and seed production, affecting the plant reproductive cycle. Number of buds was 27 times higher and number of developed seed 5 times higher in ungulate-excluded as compared to ungulate-exposed plots. After 9 years of ungulate exclusion, the C. ladanifer seed bank was 2.6 times higher in ungulate-excluded plots. The population density of C. ladanifer was 4 times higher in ungulate-excluded plots. Our long-term experiment showed that high density ungulate populations can alter plant-animal interactions by reducing plant benefits and increasing plant costs. PMID:27387134

  12. AAV-Dominant Negative Tumor Necrosis Factor (DN-TNF) Gene Transfer to the Striatum Does Not Rescue Medium Spiny Neurons in the YAC128 Mouse Model of Huntington's Disease

    PubMed Central

    Alto, Laura Taylor; Chen, Xi; Ruhn, Kelly A.; Treviño, Isaac; Tansey, Malú G.

    2014-01-01

    CNS inflammation is a hallmark of neurodegenerative disease, and recent studies suggest that the inflammatory response may contribute to neuronal demise. In particular, increased tumor necrosis factor (TNF) signaling is implicated in the pathology of both Parkinson's disease (PD) and Alzheimer's disease (AD). We have previously shown that localized gene delivery of dominant negative TNF to the degenerating brain region can limit pathology in animal models of PD and AD. TNF is upregulated in Huntington's disease (HD), like in PD and AD, but it is unknown whether TNF signaling contributes to neuronal degeneration in HD. We used in vivo gene delivery to test whether selective reduction of soluble TNF signaling could attenuate medium spiny neuron (MSN) degeneration in the YAC128 transgenic (TG) mouse model of Huntington's disease (HD). AAV vectors encoding cDNA for dominant-negative tumor necrosis factor (DN-TNF) or GFP (control) were injected into the striatum of young adult wild type WT and YAC128 TG mice and achieved 30–50% target coverage. Expression of dominant negative TNF protein was confirmed immunohistologically and biochemically and was maintained as mice aged to one year, but declined significantly over time. However, the extent of striatal DN-TNF gene transfer achieved in our studies was not sufficient to achieve robust effects on neuroinflammation, rescue degenerating MSNs or improve motor function in treated mice. Our findings suggest that alternative drug delivery strategies should be explored to determine whether greater target coverage by DN-TNF protein might afford some level of neuroprotection against HD-like pathology and/or that soluble TNF signaling may not be the primary driver of striatal neuroinflammation and MSN loss in YAC128 TG mice. PMID:24824433

  13. Production of a Dominant-Negative Fragment Due to G3BP1 Cleavage Contributes to the Disruption of Mitochondria-Associated Protective Stress Granules during CVB3 Infection

    PubMed Central

    Fung, Gabriel; Ng, Chen Seng; Zhang, Jingchun; Shi, Junyan; Wong, Jerry; Piesik, Paulina; Han, Lillian; Chu, Fanny; Jagdeo, Julienne; Jan, Eric; Fujita, Takashi; Luo, Honglin

    2013-01-01

    Stress granules (SGs) are dynamic cytosolic aggregates containing messenger ribonucleoproteins and target poly-adenylated (A)-mRNA. A key component of SGs is Ras-GAP SH3 domain binding protein-1 (G3BP1), which in part mediates protein-protein and protein-RNA interactions. SGs are modulated during infection by several viruses, however, the function and significance of this process remains poorly understood. In this study, we investigated the interplay between SGs and Coxsackievirus type B3 (CVB3), a member of the Picornaviridae family. Our studies demonstrated that SGs were formed early during CVB3 infection; however, G3BP1-positive SGs were actively disassembled at 5 hrs post-infection, while poly(A)-positive RNA granules persisted. Furthermore, we confirmed G3BP1 cleavage by 3Cpro at Q325. We also demonstrated that overexpression of G3BP1-SGs negatively impacted viral replication at the RNA, protein, and viral progeny levels. Using electron microscopy techniques, we showed that G3BP1-positive SGs localized near mitochondrial surfaces. Finally, we provided evidence that the C-terminal cleavage product of G3BP1 inhibited SG formation and promoted CVB3 replication. Taken together, we conclude that CVB3 infection selectively targets G3BP1-SGs by cleaving G3BP1 to produce a dominant-negative fragment that further inhibits G3BP1-SG formation and facilitates viral replication. PMID:24260247

  14. Manipulation of cellular GSH biosynthetic capacity via TAT-mediated protein transduction of wild-type or a dominant-negative mutant of glutamate cysteine ligase alters cell sensitivity to oxidant-induced cytotoxicity

    SciTech Connect

    Backos, Donald S.; Brocker, Chad N.; Franklin, Christopher C.

    2010-02-15

    The glutathione (GSH) antioxidant defense system plays a central role in protecting mammalian cells against oxidative injury. Glutamate cysteine ligase (GCL) is the rate-limiting enzyme in GSH biosynthesis and is a heterodimeric holoenzyme composed of catalytic (GCLC) and modifier (GCLM) subunits. As a means of assessing the cytoprotective effects of enhanced GSH biosynthetic capacity, we have developed a protein transduction approach whereby recombinant GCL protein can be rapidly and directly transferred into cells when coupled to the HIV TAT protein transduction domain. Bacterial expression vectors encoding TAT fusion proteins of both GCL subunits were generated and recombinant fusion proteins were synthesized and purified to near homogeneity. The TAT-GCL fusion proteins were capable of heterodimerization and formation of functional GCL holoenzyme in vitro. Exposure of Hepa-1c1c7 cells to the TAT-GCL fusion proteins resulted in the time- and dose-dependent transduction of both GCL subunits and increased cellular GCL activity and GSH levels. A heterodimerization-competent, enzymatically deficient GCLC-TAT mutant was also generated in an attempt to create a dominant-negative suppressor of GCL. Transduction of cells with a catalytically inactive GCLC(E103A)-TAT mutant decreased cellular GCL activity in a dose-dependent manner. TAT-mediated manipulation of cellular GCL activity was also functionally relevant as transduction with wild-type GCLC(WT)-TAT or mutant GCLC(E103A)-TAT conferred protection or enhanced sensitivity to H{sub 2}O{sub 2}-induced cell death, respectively. These findings demonstrate that TAT-mediated transduction of wild-type or dominant-inhibitory mutants of the GCL subunits is a viable means of manipulating cellular GCL activity to assess the effects of altered GSH biosynthetic capacity.

  15. apoE3[K146N/R147W] acts as a dominant negative apoE form that prevents remnant clearance and inhibits the biogenesis of HDL.

    PubMed

    Fotakis, Panagiotis; Vezeridis, Alexander; Dafnis, Ioannis; Chroni, Angeliki; Kardassis, Dimitris; Zannis, Vassilis I

    2014-07-01

    The K146N/R147W substitutions in apoE3 were described in patients with a dominant form of type III hyperlipoproteinemia. The effects of these mutations on the in vivo functions of apoE were studied by adenovirus-mediated gene transfer in different mouse models. Expression of the apoE3[K146N/R147W] mutant in apoE-deficient (apoE(-/-)) or apoA-I-deficient (apoA-I(-/-))×apoE(-/-) mice exacerbated the hypercholesterolemia and increased plasma apoE and triglyceride levels. In apoE(-/-) mice, the apoE3[K146N/R147W] mutant displaced apoA-I from the VLDL/LDL/HDL region and caused the accumulation of discoidal apoE-containing HDL. The WT apoE3 cleared the cholesterol of apoE(-/-) mice without induction of hypertriglyceridemia and promoted formation of spherical HDL. A unique property of the truncated apoE3[K146N/R147W]202 mutant, compared with similarly truncated apoE forms, is that it did not correct the hypercholesterolemia. The contribution of LPL and LCAT in the induction of the dyslipidemia was studied. Treatment of apoE(-/-) mice with apoE3[K146N/R147W] and LPL corrected the hypertriglyceridemia, but did not prevent the formation of discoidal HDL. Treatment with LCAT corrected hypertriglyceridemia and generated spherical HDL. The combined data indicate that the K146N/R147W substitutions convert the full-length and the truncated apoE3[K146N/R147W] mutant into a dominant negative ligand that prevents receptor-mediated remnant clearance, exacerbates the dyslipidemia, and inhibits the biogenesis of HDL. PMID:24776540

  16. The direct effect of Focal Adhesion Kinase (FAK), dominant-negative FAK, FAK-CD and FAK siRNA on gene expression and human MCF-7 breast cancer cell tumorigenesis

    PubMed Central

    2009-01-01

    Background Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays an important role in survival signaling. FAK has been shown to be overexpressed in breast cancer tumors at early stages of tumorigenesis. Methods To study the direct effect of FAK on breast tumorigenesis, we developed Tet-ON (tetracycline-inducible) system of MCF-7 breast cancer cells stably transfected with FAK or dominant-negative, C-terminal domain of FAK (FAK-CD), and also FAKsiRNA with silenced FAK MCF-7 stable cell line. Increased expression of FAK in isogenic Tet-inducible MCF-7 cells caused increased cell growth, adhesion and soft agar colony formation in vitro, while expression of dominant-negative FAK inhibitor caused inhibition of these cellular processes. To study the role of induced FAK and FAK-CD in vivo, we inoculated these Tet-inducible cells in nude mice to generate tumors in the presence or absence of doxycycline in the drinking water. FAKsiRNA-MCF-7 cells were also injected into nude mice to generate xenograft tumors. Results Induction of FAK resulted in significant increased tumorigenesis, while induced FAK-CD resulted in decreased tumorigenesis. Taq Man Low Density Array assay demonstrated specific induction of FAKmRNA in MCF-7-Tet-ON-FAK cells. DMP1, encoding cyclin D binding myb-like protein 1 was one of the genes specifically affected by Tet-inducible FAK or FAK-CD in breast xenograft tumors. In addition, silencing of FAK in MCF-7 cells with FAK siRNA caused increased cell rounding, decreased cell viability in vitro and inhibited tumorigenesis in vivo. Importantly, Affymetrix microarray gene profiling analysis using Human Genome U133A GeneChips revealed >4300 genes, known to be involved in apoptosis, cell cycle, and adhesion that were significantly down- or up-regulated (p < 0.05) by FAKsiRNA. Conclusion Thus, these data for the first time demonstrate the direct effect of FAK expression and function on MCF-7 breast cancer tumorigenesis in vivo and reveal

  17. Adenovirus-mediated gene transfer of dominant negative ras(asn17) in 3T3L1 adipocytes does not alter insulin-stimulated P13-kinase activity or glucose transport.

    PubMed

    Gnudi, L; Frevert, E U; Houseknecht, K L; Erhardt, P; Kahn, B B

    1997-01-01

    Recent studies suggest that the ras-map kinase and PI3-kinase cascades converge. We sought to determine whether PI3-kinase is downstream of ras in insulin signaling in a classic insulin target cell. We generated a recombinant adenovirus encoding dominant negative ras by cloning the human H-ras cDNA with a ser to asn substitution at amino acid 17 (ras(asn17)) into the pACCMVpLpA vector and cotransfecting 293 cells with the pJM17 plasmid containing the adenoviral genome. Efficiency of gene transfer was assessed by infecting fully differentiated 3T3L1 adipocytes with a recombinant adenovirus expressing beta-galactosidase (beta-gal); greater than 70% of cells were infected. Infection of adipocytes with ras(asn17) resulted in 10-fold greater expression than endogenous ras. This high efficiency gene transfer allowed biochemical assays. Insulin stimulation of ras-GTP formation was inhibited in ras(asn17)-expressing cells. Map kinase gel mobility shift revealed that insulin (1 UM) or epidermal growth factor (100 ng/ml) resulted in the appearance of a hyperphosphorylated species of p42 map kinase in uninfected cells and those expressing beta-gal but not in cells expressing ras(asn17). In contrast, insulin increased IRS-1-associated PI3-kinase activity approximately 10-fold in control cells and high level overexpression of ras(asn17) did not impair this effect. Similarly, insulin and epidermal growth factor activation of total (no immunoprecipitation) PI3-kinase activity in both cytosol and total cellular membranes and insulin stimulation of glucose transport were not affected by expression of dominant negative ras. Thus, adenovirus-mediated gene transfer is effective for studying insulin signaling in fully differentiated insulin target cells. Inhibition of ras activation abolishes insulin-stimulated phosphorylation of map kinase but does not affect insulin stimulation of PI3-kinase activity. In normal cell physiology, PI3-kinase does not appear to be downstream of ras in

  18. Genotyping of methicillin-resistant Staphylococcus aureus in the Sultan Qaboos University Hospital, Oman reveals the dominance of Panton–Valentine leucocidin-negative ST6-IV/t304 clone

    PubMed Central

    Udo, E E; Al-Lawati, B A-H; Al-Muharmi, Z; Thukral, S S

    2014-01-01

    The objective of this study was to determine the prevalence and distribution of methicillin-resistant Staphylococcus aureus (MRSA) genotypes circulating at a tertiary hospital in the Sultanate of Oman. A total of 79 MRSA isolates were obtained from different clinical samples and investigated using antibiogram, pulsed-field gel electrophoresis (PFGE), staphylococcal chromosome cassette mec (SCCmec), Spa typing and multilocus sequence typing (MLST). The isolates were susceptible to linezolid, vancomycin, teicoplanin, tigecycline and mupirocin but were resistant to tetracycline (30.4%), erythromycin (26.6%), clindamycin (24.1%), trimethoprim (19.0%), ciprofloxacin (17.7%), fusidic acid (15.2%) and gentamicin (12.7%). Molecular typing revealed 19 PFGE patterns, 26 Spa types and 21 sequence types. SCCmec-IV (86.0%) was the dominant SCCmec type, followed by SCCmec-V (10.1%). SCCmec-III (2.5%) and SCCmec-II (1.3%) were less common. ST6-IV/t304 (n = 30) and ST1295-IV/t690 (n = 12) were the dominant genotypes followed by ST772-V/t657 (n = 5), ST30-IV/t019/t021 (n = 5), ST22-IV/t852 (n = 4), ST80-IV/t044 (n = 3) and 18 single genotypes that were isolated sporadically. On the basis of SCCmec typing and MLST, 91.2% of the isolates were classified as community-associated MRSA and 8.8% of the isolates (consisting of four ST22-IV/t852, one ST239-III/t632, one ST5-III/t311 and one ST5-II/t003) were classified as healthcare-associated MRSA. The study has revealed the dominance of a Panton–Valentine leucocidin-negative ST6-IV/t304 clone and provided insights into the distribution of antibiotic resistance in MRSA at the tertiary hospital in Oman. It also highlights the importance of surveillance in detecting the emergence of new MRSA clones in a healthcare facility. PMID:25356354

  19. A systematic review of the mismatch negativity as an index for auditory sensory memory: From basic research to clinical and developmental perspectives.

    PubMed

    Bartha-Doering, Lisa; Deuster, Dirk; Giordano, Vito; am Zehnhoff-Dinnesen, Antoinette; Dobel, Christian

    2015-09-01

    Auditory sensory memory is an important ability for successful language acquisition and processing. The mismatch negativity (MMN) in response to auditory stimuli has been proposed as an objective tool to measure the existence of auditory sensory memory traces. By increasing interstimulus intervals, attenuation of MMN peak amplitude and increased MMN peak latency have been suggested to reflect duration and decay of sensory memory traces. The aim of the present study is to conduct a systematic review of studies investigating sensory memory duration with MMN. Searches of electronic databases yielded 743 articles. Of these, 37 studies met final eligibility criteria. Results point to maturational changes in the time span of auditory sensory memory from birth on with a peak in young adulthood, as well as to a decrease of sensory memory duration in healthy aging. Furthermore, this review suggests that sensory memory decline is related to diverse neurological, psychiatric, and pediatric diseases, including Alzheimer's disease, alcohol abuse, schizophrenia, and language disorders. This review underlines that the MMN provides a unique window to the cognitive processes of auditory sensory memory. However, further studies combining electrophysiological and behavioral data, and further studies in clinical populations are needed, also on individual levels, to validate the MMN as a clinical tool for the assessment of sensory memory duration.

  20. Basic helix-loop-helix transcription factors JASMONATE-ASSOCIATED MYC2-LIKE1 (JAM1), JAM2, and JAM3 are negative regulators of jasmonate responses in Arabidopsis.

    PubMed

    Sasaki-Sekimoto, Yuko; Jikumaru, Yusuke; Obayashi, Takeshi; Saito, Hikaru; Masuda, Shinji; Kamiya, Yuji; Ohta, Hiroyuki; Shirasu, Ken

    2013-09-01

    Jasmonates regulate transcriptional reprogramming during growth, development, and defense responses. Jasmonoyl-isoleucine, an amino acid conjugate of jasmonic acid (JA), is perceived by the protein complex composed of the F-box protein CORONATINE INSENSITIVE1 (COI1) and JASMONATE ZIM DOMAIN (JAZ) proteins, leading to the ubiquitin-dependent degradation of JAZ proteins. This activates basic helix-loop-helix-type MYC transcription factors to regulate JA-responsive genes. Here, we show that the expression of genes encoding other basic helix-loop-helix transcription factors, JASMONATE ASSOCIATED MYC2-LIKE1 (JAM1), JAM2, and JAM3, is positively regulated in a COI1- and MYC2-dependent manner in Arabidopsis (Arabidopsis thaliana). However, contrary to myc2, the jam1jam2jam3 triple mutant exhibited shorter roots when treated with methyl jasmonate (MJ), indicating enhanced responsiveness to JA. Our genome-wide expression analyses revealed that key jasmonate metabolic genes as well as a set of genes encoding transcription factors that regulate the JA-responsive metabolic genes are negatively regulated by JAMs after MJ treatment. Consistently, loss of JAM genes resulted in higher accumulation of anthocyanin in MJ-treated plants as well as higher accumulation of JA and 12-hydroxyjasmonic acid in wounded plants. These results show that JAMs negatively regulate the JA responses in a manner that is mostly antagonistic to MYC2.

  1. Basic Helix-Loop-Helix Transcription Factors JASMONATE-ASSOCIATED MYC2-LIKE1 (JAM1), JAM2, and JAM3 Are Negative Regulators of Jasmonate Responses in Arabidopsis1[W][OPEN

    PubMed Central

    Sasaki-Sekimoto, Yuko; Jikumaru, Yusuke; Obayashi, Takeshi; Saito, Hikaru; Masuda, Shinji; Kamiya, Yuji; Ohta, Hiroyuki; Shirasu, Ken

    2013-01-01

    Jasmonates regulate transcriptional reprogramming during growth, development, and defense responses. Jasmonoyl-isoleucine, an amino acid conjugate of jasmonic acid (JA), is perceived by the protein complex composed of the F-box protein CORONATINE INSENSITIVE1 (COI1) and JASMONATE ZIM DOMAIN (JAZ) proteins, leading to the ubiquitin-dependent degradation of JAZ proteins. This activates basic helix-loop-helix-type MYC transcription factors to regulate JA-responsive genes. Here, we show that the expression of genes encoding other basic helix-loop-helix transcription factors, JASMONATE ASSOCIATED MYC2-LIKE1 (JAM1), JAM2, and JAM3, is positively regulated in a COI1- and MYC2-dependent manner in Arabidopsis (Arabidopsis thaliana). However, contrary to myc2, the jam1jam2jam3 triple mutant exhibited shorter roots when treated with methyl jasmonate (MJ), indicating enhanced responsiveness to JA. Our genome-wide expression analyses revealed that key jasmonate metabolic genes as well as a set of genes encoding transcription factors that regulate the JA-responsive metabolic genes are negatively regulated by JAMs after MJ treatment. Consistently, loss of JAM genes resulted in higher accumulation of anthocyanin in MJ-treated plants as well as higher accumulation of JA and 12-hydroxyjasmonic acid in wounded plants. These results show that JAMs negatively regulate the JA responses in a manner that is mostly antagonistic to MYC2. PMID:23852442

  2. Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1.

    PubMed

    Matsushita, Kazuyuki; Kitamura, Kouichi; Rahmutulla, Bahityar; Tanaka, Nobuko; Ishige, Takayuki; Satoh, Mamoru; Hoshino, Tyuji; Miyagi, Satoru; Mori, Takeshi; Itoga, Sakae; Shimada, Hideaki; Tomonaga, Takeshi; Kito, Minoru; Nakajima-Takagi, Yaeko; Kubo, Shuji; Nakaseko, Chiaki; Hatano, Masahiko; Miki, Takashi; Matsuo, Masafumi; Fukuyo, Masaki; Kaneda, Atsushi; Iwama, Atsushi; Nomura, Fumio

    2015-03-10

    FUSE-binding protein (FBP)-interacting repressor (FIR) is a c-myc transcriptional suppressor. A splice variant of FIR that lacks exon 2 in the transcriptional repressor domain (FIRΔexon2) upregulates c-myc transcription by inactivating wild-type FIR. The ratio of FIRΔexon2/FIR mRNA was increased in human colorectal cancer and hepatocellular carcinoma tissues. Because FIRΔexon2 is considered to be a dominant negative regulator of FIR, FIR heterozygous knockout (FIR⁺/⁻) C57BL6 mice were generated. FIR complete knockout (FIR⁻/⁻) was embryonic lethal before E9.5; therefore, it is essential for embryogenesis. This strongly suggests that insufficiency of FIR is crucial for carcinogenesis. FIR⁺/⁻ mice exhibited prominent c-myc mRNA upregulation, particularly in the peripheral blood (PB), without any significant pathogenic phenotype. Furthermore, elevated FIRΔexon2/FIR mRNA expression was detected in human leukemia samples and cell lines. Because the single knockout of TP53 generates thymic lymphoma, FIR⁺/⁻TP53⁻/⁻ generated T-cell type acute lymphocytic/lymphoblastic leukemia (T-ALL) with increased organ or bone marrow invasion with poor prognosis. RNA-sequencing analysis of sorted thymic lymphoma cells revealed that the Notch signaling pathway was activated significantly in FIR⁺/⁻TP53⁻/⁻ compared with that in FIR⁺/⁺TP53⁻/⁻ mice. Notch1 mRNA expression in sorted thymic lymphoma cells was confirmed using qRT-PCR. In addition, flow cytometry revealed that c-myc mRNA was negatively correlated with FIR but positively correlated with Notch1 in sorted T-ALL/thymic lymphoma cells. Moreover, the knockdown of TP53 or c-myc using siRNA decreased Notch1 expression in cancer cells. In addition, an adenovirus vector encoding FIRΔexon2 cDNA increased bleomycin-induced DNA damage. Taken together, these data suggest that the altered expression of FIRΔexon2 increased Notch1 at least partially by activating c-Myc via a TP53-independent pathway. In

  3. Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1

    PubMed Central

    Rahmutulla, Bahityar; Tanaka, Nobuko; Ishige, Takayuki; Satoh, Mamoru; Hoshino, Tyuji; Miyagi, Satoru; Mori, Takeshi; Itoga, Sakae; Shimada, Hideaki; Tomonaga, Takeshi; Kito, Minoru; Nakajima-Takagi, Yaeko; Kubo, Shuji; Nakaseko, Chiaki; Hatano, Masahiko; Miki, Takashi; Matsuo, Masafumi; Fukuyo, Masaki; Kaneda, Atsushi; Iwama, Atsushi; Nomura, Fumio

    2015-01-01

    FUSE-binding protein (FBP)-interacting repressor (FIR) is a c-myc transcriptional suppressor. A splice variant of FIR that lacks exon 2 in the transcriptional repressor domain (FIRΔexon2) upregulates c-myc transcription by inactivating wild-type FIR. The ratio of FIRΔexon2/FIR mRNA was increased in human colorectal cancer and hepatocellular carcinoma tissues. Because FIRΔexon2 is considered to be a dominant negative regulator of FIR, FIR heterozygous knockout (FIR+/−) C57BL6 mice were generated. FIR complete knockout (FIR−/−) was embryonic lethal before E9.5; therefore, it is essential for embryogenesis. This strongly suggests that insufficiency of FIR is crucial for carcinogenesis. FIR+/− mice exhibited prominent c-myc mRNA upregulation, particularly in the peripheral blood (PB), without any significant pathogenic phenotype. Furthermore, elevated FIRΔexon2/FIR mRNA expression was detected in human leukemia samples and cell lines. Because the single knockout of TP53 generates thymic lymphoma, FIR+/−TP53−/− generated T-cell type acute lymphocytic/lymphoblastic leukemia (T-ALL) with increased organ or bone marrow invasion with poor prognosis. RNA-sequencing analysis of sorted thymic lymphoma cells revealed that the Notch signaling pathway was activated significantly in FIR+/−TP53−/− compared with that in FIR+/+TP53−/− mice. Notch1 mRNA expression in sorted thymic lymphoma cells was confirmed using qRT-PCR. In addition, flow cytometry revealed that c-myc mRNA was negatively correlated with FIR but positively correlated with Notch1 in sorted T-ALL/thymic lymphoma cells. Moreover, the knockdown of TP53 or c-myc using siRNA decreased Notch1 expression in cancer cells. In addition, an adenovirus vector encoding FIRΔexon2 cDNA increased bleomycin-induced DNA damage. Taken together, these data suggest that the altered expression of FIRΔexon2 increased Notch1 at least partially by activating c-Myc via a TP53-independent pathway. In conclusion

  4. The TACPyAT repeats in the chalcone synthase promoter of Petunia hybrida act as a dominant negative cis-acting module in the control of organ-specific expression.

    PubMed

    van der Meer, I M; Brouwer, M; Spelt, C E; Mol, J N; Stuitje, A R

    1992-07-01

    Analysis of the expression of the GUS reporter gene driven by various regions of the Petunia hybrida chalcone synthase (chsA) promoter revealed that the developmental and organ-specific expression of the chsA gene is conferred by a TATA proximal module located between -67 and -53, previously designated as the TACPyAT repeats. Histochemical analysis of GUS reporter gene expression revealed that the organ-specific 67 bp promoter fragment directs the same cell-type specificity as a 530 bp promoter, whereas additional enhancer sequences are present within the more TATA distal region. Moreover, the region between -800 and -530 is also involved in extending the cell-type specificity to the trichomes of flower organs and of young seedlings. The mechanism by which the TACPyAT repeats modulate expression during plant development was studied by analysing the expression of the GUS gene driven by chimeric promoters consisting of the CaMV 35S enhancer (domain B, -750 to -90) fused to various chsA 5' upstream sequences. Detailed enzymatic and histochemical analysis revealed that in the presence of the TACPyAT module the CaMV 35S region only enhances GUS activity in those organs in which the chsA promoter is normally active. Furthermore, this analysis shows that enhancement in the presence of the CaMV 35S domain B is accomplished by increasing the number of cell types expressing the GUS gene within the organ, rather than enhancement of the chsA cell-type-specific expression within these organs. Deletion of the TACPyAT sequences in the chimeric promoter construct completely restores the well-documented CaMV 35S domain B cell-type specificity, showing that the TACPyAT module acts as a dominant negative cis-acting element which controls both organ and developmental regulation of the chsA promoter activity.

  5. Irf6 directly regulates Klf17 in zebrafish periderm and Klf4 in murine oral epithelium, and dominant-negative KLF4 variants are present in patients with cleft lip and palate

    PubMed Central

    Liu, Huan; Leslie, Elizabeth J.; Jia, Zhonglin; Smith, Tiffany; Eshete, Mekonen; Butali, Azeez; Dunnwald, Martine; Murray, Jeffrey; Cornell, Robert A.

    2016-01-01

    Non-syndromic (NS) cleft lip with or without cleft palate (CL/P) is a common disorder with a strong genetic underpinning. Genome-wide association studies have detected common variants associated with this disorder, but a large portion of the genetic risk for NSCL/P is conferred by unidentified rare sequence variants. Mutations in IRF6 (Interferon Regulatory Factor 6) and GRHL3 (Grainyhead-like 3) cause Van der Woude syndrome, which includes CL/P. Both genes encode members of a regulatory network governing periderm differentiation in model organisms. Here, we report that Krüppel-like factor 17 (Klf17), like Grhl3, acts downstream of Irf6 in this network in zebrafish periderm. Although Klf17 expression is absent from mammalian oral epithelium, a close homologue, Klf4, is expressed in this tissue and is required for the differentiation of epidermis. Chromosome configuration capture and reporter assays indicated that IRF6 directly regulates an oral-epithelium enhancer of KLF4. To test whether rare missense variants of KLF4 contribute risk for NSCL/P, we sequenced KLF4 in approximately 1000 NSCL/P cases and 300 controls. By one statistical test, missense variants of KLF4 as a group were enriched in cases versus controls. Moreover, two patient-derived KLF4 variants disrupted periderm differentiation upon forced expression in zebrafish embryos, suggesting that they have dominant-negative effect. These results indicate that rare NSCL/P risk variants can be found in members of the gene regulatory network governing periderm differentiation. PMID:26692521

  6. Effects of A-CREB, a dominant negative inhibitor of CREB, on the expression of c-fos and other immediate early genes in the rat SON during hyperosmotic stimulation in vivo

    PubMed Central

    Lubelski, Daniel; Ponzio, Todd A.; Gainer, Harold

    2016-01-01

    Intraperitoneal administration of hypertonic saline to the rat supraoptic nucleus (SON) increases the expression of several immediate early genes (IEG) and the vasopressin gene. These increases have usually been attributed to action of the cyclic-AMP Response Element Binding Protein (CREB). In this paper, we study the role of CREB in these events in vivo by delivering a potent dominant-negative form of CREB, known as A-CREB, to the rat SON through the use of an adeno-associated viral (AAV) vector. Preliminary experiments on HEK 293 cells in vitro showed that the A-CREB vector that we used completely eliminated CREB-induced c-fos expression. We stereotaxically injected this AAV-A-CREB into one SON and a control AAV into the contralateral SON of the same rat. Two weeks following these injections we injected hypertonic saline intraperitoneally into the rat. Using this paradigm, we could measure the relative effects of inhibiting CREB on the induced expression of c-fos, ngfi-a, ngfi-b, and vasopressin genes in the A-CREB AAV injected SON versus the control AAV injected SON in the same rat. We found only a small (20%) decrease of c-fos expression and a 30% decrease of ngfi-b expression in the presence of the A-CREB. There were no significant changes in expression found in the other IEGs nor in vasopressin that were produced by the A-CREB. This suggests that CREB may play only a minor role in the expression of IEGs and vasopressin in the osmotically activated SON in vivo. PMID:22079318

  7. Molecular identification of the dominant-negative, splicing isoform of the two-pore domain K(+) channel K(2P)5.1 in lymphoid cells and enhancement of its expression by splicing inhibition.

    PubMed

    Endo, Kyoko; Kurokawa, Natsumi; Kito, Hiroaki; Nakakura, Sawa; Fujii, Masanori; Ohya, Susumu

    2015-12-01

    The two-pore domain background K(+) channel K2P5.1 is expected as a possible therapeutic target for autoimmune and inflammatory disorders and cancers because it plays an important role in maintaining the resting membrane potential and regulation of Ca(2+) signaling in T lymphocytes and cancer cells. However, the lack of selective K2P5.1 blockers has led to difficulties conducting experimental studies on this K(+) channel. We identified a novel splicing isoform of K2P5.1, K2P5.1B from the mammalian spleen, which lacked the N-terminus of full-length K2P5.1A. A co-immunoprecipitation assay using mice spleen lysates revealed an interaction between K2P5.1A and K2P5.1B in the cytoplasmic C-terminal domain. In a heterologous HEK293 expression system, K2P5.1B inhibited the trafficking of K2P5.1A to the plasma membrane. The alkaline pHe-induced hyperpolarizing response was significantly suppressed in K2P5.1B-transfected human leukemia K562 cells. Enhancement in cell proliferation by the overexpression of K2P5.1A in K562 was significantly prevented by the transfection of K2P5.1B. The spliceosome inhibitor pladienolide B significantly enhanced the relative expression of K2P5.1B in K562, resulting in decreases in the activity of K2P5.1A. K2P5.1B suppresses the function of the K2P5.1 K(+) channel in a dominant-negative manner, suggesting that the mRNA splicing mechanisms underlying the transcriptional regulation of K2P5.1B may be a new therapeutic strategy for autoimmune and inflammatory disorders and cancers. PMID:26475531

  8. Sex-linked dominant

    MedlinePlus

    Inheritance - sex-linked dominant; Genetics - sex-linked dominant; X-linked dominant; Y-linked dominant ... can be either an autosomal chromosome or a sex chromosome. It also depends on whether the trait ...

  9. BASIC Programming.

    ERIC Educational Resources Information Center

    Jennings, Carol Ann

    Designed for use by both secondary- and postsecondary-level business teachers, this curriculum guide consists of 10 units of instructional materials dealing with Beginners All-Purpose Symbol Instruction Code (BASIC) programing. Topics of the individual lessons are numbering BASIC programs and using the PRINT, END, and REM statements; system…

  10. Schizophrenia Basics

    MedlinePlus

    ... I know with schizophrenia? For More Information Share Schizophrenia Basics Download PDF Download ePub Order a free hardcopy What is schizophrenia? Schizophrenia is a serious mental disorder that affects ...

  11. The Basics

    ERIC Educational Resources Information Center

    Indrisano, Roselmina; And Others

    1976-01-01

    These articles are presented as an aide in teaching basic subjects. This issue examines reading diagnosis, food preservation, prime numbers, electromagnets, acting out in language arts, self-directed spelling activities, and resources for environmental education. (Editor/RK)

  12. Fluoridation Basics

    MedlinePlus

    ... Water Fluoridation Journal Articles for Community Water Fluoridation Water Fluoridation Basics Recommend on Facebook Tweet Share Compartir ... because of tooth decay. History of Fluoride in Water In the 1930s, scientists examined the relationship between ...

  13. Basic Finance

    NASA Technical Reports Server (NTRS)

    Vittek, J. F.

    1972-01-01

    A discussion of the basic measures of corporate financial strength, and the sources of the information is reported. Considered are: balance sheet, income statement, funds and cash flow, and financial ratios.

  14. Compound heterozygosity for COL7A1 mutations in twins with dystrophic epidermolysis bullosa: A recessive paternal deletion/insertion mutation and a dominant negative maternal glycine substitution result in a severe phenotype

    SciTech Connect

    Christiano, A.M.; Uitto, J.; Anton-Lamprecht, I.; Ebschner, U.; Amano, S.; Burgeson, R.E.

    1996-04-01

    We have previously demonstrated genetic linkage between the type VII collagen gene (COL7A1) and the dominant (DDEB) and recessive (RDEB) forms of dystrophic epidermolysis bullosa (DEB) and have subsequently identified pathogenetic mutations in several families. Mutations in DDEB identified thus far are glycine substitutions in the collagenous domain of COL7A1, while the most severe forms of RDEB result from premature termination codon (PTC) mutations on both alleles. In this study, we performed mutation analysis in the COL7A1 gene in twins who displayed a severe DEB phenotype. Mutational analysis revealed a paternal 2-bp deletion/1-bp insertion in exon 56, designated 5103CC{yields}G, which results in a frameshift and downstream PTC. Analysis of the maternal COL7A1 allele revealed a glycine-to-arginine substitution in exon 91 (G2351R). Careful questioning of the mother revealed that she and her father had a history of shedding of toenails and occasional poorly heating erosions, consistent with a mild form of DDEB. Immunoprecipitation of type VII collagen from fibroblasts of the twins revealed a marked reduction in intracellular protein production, consistent with the drastic reduction in mRNA transcript from the paternal mutant allele, while the majority of polypeptides bearing the glycine substitution appeared to be degraded intracellularly. Thus, the severe RDEB phenotype in the probands results from compound heterozygosity for one glycine substitution and one PTC mutation in COL7A1. 40 refs., 7 figs.

  15. DOS basics

    SciTech Connect

    O`Connor, P.

    1994-09-01

    DOS is an acronym for Disk Operating System. It is actually a set of programs that allows you to control your personal computer. DOS offers the capabilities to create and manage files; organize and maintain information placed on disks; use application programs such as WordPerfect, Lotus 123, Excel, Windows, etc. In addition, DOS provides the basic utilities needed to copy files from one area to another, delete files and list files. The latest version of DOS also offers more advanced features that include hard disk compression and memory management. Basic DOS commands are discussed.

  16. Compound heterozygosity for COL7A1 mutations in twins with dystrophic epidermolysis bullosa: a recessive paternal deletion/insertion mutation and a dominant negative maternal glycine substitution result in a severe phenotype.

    PubMed Central

    Christiano, A. M.; Anton-Lamprecht, I.; Amano, S.; Ebschner, U.; Burgeson, R. E.; Uitto, J.

    1996-01-01

    We have previously demonstrated genetic linkage between the type VII collagen gene (COL7A1) and the dominant (DDEB) and recessive (RDEB) forms of dystrophic epidermolysis bullosa (DEB) and have subsequently identified pathogenetic mutations in several families. Mutations in DDEB identified thus far are glycine substitutions in the collagenous domain of COL7A1, while the most severe forms of RDEB result from premature termination codon (PTC) mutations on both alleles. In this study, we performed mutation analysis in the COL7A1 gene in twins who displayed a severe DEB phenotype. Mutational analysis revealed a paternal 2-bp deletion/1-bp insertion in exon 56, designated 5103CC-->G, which results in a frameshift and downstream PTC. Analysis of the maternal COL7A1 allele revealed a glycine-to-arginine substitution in exon 91 (G2351R). Careful questioning of the mother revealed that she and her father had a history of shedding of toenails and occasional poorly healing erosions, consistent with a mild form of DDEB. Immunoprecipitation of type VII collagen from fibroblasts of the twins revealed a marked reduction in intracellular protein production, consistent with the drastic reduction in mRNA transcript from the paternal mutant allele, while the majority of polypeptides bearing the glycine substitution appeared to be degraded intracellularly. Thus, the severe RDEB phenotype in the probands results from compound heterozygosity for one glycine substitution and one PTC mutation in COL7A1. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:8644730

  17. Ethanol Basics

    SciTech Connect

    2015-01-30

    Ethanol is a widely-used, domestically-produced renewable fuel made from corn and other plant materials. More than 96% of gasoline sold in the United States contains ethanol. Learn more about this alternative fuel in the Ethanol Basics Fact Sheet, produced by the U.S. Department of Energy's Clean Cities program.

  18. Body Basics

    MedlinePlus

    ... more about how the body works, what basic human anatomy is, and what happens when parts of the body don't function properly. Blood Bones, Muscles, and Joints Brain and Nervous System Digestive System Endocrine System Eyes Female Reproductive System ...

  19. Basic brownfields

    SciTech Connect

    Jacobs, B.L.

    1997-12-31

    This article is a basic guide to the brownfields problem. It will define the problem and will attempt to identify the various causes thereof. It also will review federal brownfields initiatives and state brownfields reforms in Kentucky, Ohio, Pennsylvania, and West Virginia.

  20. Armchair BASIC.

    ERIC Educational Resources Information Center

    Fox, Annie; Fox, David

    1983-01-01

    A first lesson in learning the computer programing language BASIC, this article explains how to give instructions to the computer; the commands PRINT, NEW, LIST, and RUN; and how to do simple line editing. There is a short quiz at the end. (EAO)

  1. Basic Education.

    ERIC Educational Resources Information Center

    Robinson, Virginia, Ed.

    1984-01-01

    This issue of "Basic Education" is devoted to the arts in education as a concern that should be addressed in a time of new priorities for the curriculum. Five articles and a book review are included. The opening article, "The State of the Arts in Education: Envisioning Active Participation By All" (Virginia Robinson), emphasizes that the study of…

  2. Basic Backwardness.

    ERIC Educational Resources Information Center

    Weingartner, Charles

    This paper argues that the "back to basics" movement is regressive and that regression is the characteristic mode of fear-ridden personalities. It is argued that many people in American society today have lost their ability to laugh and do not have the sense of humor which is crucial to a healthy mental state. Such topics as necrophilia, mental…

  3. Basic Horticulture.

    ERIC Educational Resources Information Center

    Geer, Barbra Farabough

    This learning packet contains teaching suggestions and student learning materials for a course in basic horticulture aimed at preparing students for employment in a number of horticulture areas. The packet includes nine sections and twenty instructional units. Following the standard format established for Oklahoma vocational education materials in…

  4. Basic Science.

    ERIC Educational Resources Information Center

    Mercer County Community Coll., Trenton, NJ.

    Instructional materials are provided for a course that covers basic concepts of physics and chemistry. Designed for use in a workplace literacy project developed by Mercer County Community College (New Jersey) and its partners, the course describes applications of these concepts to real-life situations, with an emphasis on applications of…

  5. Education: The Basics. The Basics

    ERIC Educational Resources Information Center

    Wood, Kay

    2011-01-01

    Everyone knows that education is important, we are confronted daily by discussion of it in the media and by politicians, but how much do we really know about education? "Education: The Basics" is a lively and engaging introduction to education as an academic subject, taking into account both theory and practice. Covering the schooling system, the…

  6. The social dominance paradox.

    PubMed

    Cook, Jennifer Louise; den Ouden, Hanneke E M; Heyes, Cecilia M; Cools, Roshan

    2014-12-01

    Dominant individuals report high levels of self-sufficiency, self-esteem, and authoritarianism. The lay stereotype suggests that such individuals ignore information from others, preferring to make their own choices. However, the nonhuman animal literature presents a conflicting view, suggesting that dominant individuals are avid social learners, whereas subordinates focus on learning from private experience. Whether dominant humans are best characterized by the lay stereotype or the animal view is currently unknown. Here, we present a "social dominance paradox": using self-report scales and computerized tasks, we demonstrate that socially dominant people explicitly value independence, but, paradoxically, in a complex decision-making task, they show an enhanced reliance (relative to subordinate individuals) on social learning. More specifically, socially dominant people employed a strategy of copying other agents when the agents' responses had a history of being correct. However, in humans, two subtypes of dominance have been identified: aggressive and social. Aggressively dominant individuals, who are as likely to "get their own way" as socially dominant individuals but who do so through the use of aggressive or Machiavellian tactics, did not use social information, even when it was beneficial to do so. This paper presents the first study of dominance and social learning in humans and challenges the lay stereotype in which all dominant individuals ignore others' views. The more subtle perspective we offer could have important implications for decision making in both the boardroom and the classroom. PMID:25454588

  7. Sunspace basics

    SciTech Connect

    Not Available

    1994-11-01

    Anyone who lives in a home with a sunspace will tell you that the sunspace is the most enjoyable room in the house. Many times the homeowner`s only regret is that the sunspace is not larger. Although aesthetics often drive the decision to add a sunspace or include one in a new home design, sunspaces can also provide supplemental space heating and a healthy environment for plants and people. In fact, a well-designed sunspace can provide up to 60% of a home`s winter heating requirements. This publication addresses basic elements of sunspace design; design considerations for supplemental space heating, growing plants, and use as a living space; design guidelines including siting, heat distribution, and glazing angles; and major sunspace components including glazing options, thermal mass, insulation, and climate controls. A list of sources for more information is also provided.

  8. Genetic Dominance & Cellular Processes

    ERIC Educational Resources Information Center

    Seager, Robert D.

    2014-01-01

    In learning genetics, many students misunderstand and misinterpret what "dominance" means. Understanding is easier if students realize that dominance is not a mechanism, but rather a consequence of underlying cellular processes. For example, metabolic pathways are often little affected by changes in enzyme concentration. This means that…

  9. Inflation Basics

    SciTech Connect

    Green, Dan

    2014-03-01

    inflation since metrical fluctuations, both scalar and tensor, are also produced in inflationary models. Thus, the time appears to be appropriate for a very basic and simple exposition of the inflationary model written from a particle physics perspective. Only the simplest scalar model will be explored because it is easy to understand and contains all the basic elements of the inflationary model.

  10. Autosomal dominant vitreoretinochoroidopathy (ADVIRC).

    PubMed Central

    Blair, N P; Goldberg, M F; Fishman, G A; Salzano, T

    1984-01-01

    We report the second family recognised to have autosomal dominant vitreoretinochoroidopathy. The clinical features were (1) autosomal dominant inheritance; (2) peripheral, coarse pigmentary degeneration of the fundus for 360 degrees, with a relatively discrete posterior border in the equatorial region (this finding may be pathognomonic); (3) superficial punctate yellowish-white opacities in the retina; (4) various vascular abnormalities; (5) breakdown of the blood-retinal barrier; (6) retinal neovascularisation; (7) vitreous abnormalities; and (8) choroidal atrophy. Visual reduction was mainly due to macular oedema or vitreous haemorrhage. Images PMID:6689931

  11. Boson dominance in nuclei

    SciTech Connect

    Palumbo, Fabrizio

    2005-07-01

    We present a new method of bosonization of fermion systems applicable when the partition function is dominated by composite bosons. By restricting the partition function to such states, we obtain a Euclidean bosonic action from which we derive the Hamiltonian. Such a procedure respects all the fermion symmetries, particularly the fermion number conservation, and provides a boson mapping of all fermion operators.

  12. Iron dominated magnets

    SciTech Connect

    Fischer, G.E.

    1985-07-01

    These two lectures on iron dominated magnets are meant for the student of accelerator science and contain general treatments of the subjects design and construction. The material is arranged in the categories: General Concepts and Cost Considerations, Profile Configuration and Harmonics, Magnetic Measurements, a few examples of ''special magnets'' and Materials and Practices. Extensive literature is provided.

  13. Apical Dominance in Plants

    ERIC Educational Resources Information Center

    Tucker, D. J.

    1974-01-01

    Describes a tentative hypothesis for the control of plant branching (apical dominance). Explores the mechanism by which apical buds inhibit the growth of axillary buds on the same shoot. Presents an up-to-date picture of the problem and gives economic implications of the study. (BR)

  14. Negative necrotaxis.

    PubMed

    Ragot, R

    1993-01-01

    We studied necrotaxis in several strains of protists and compared the reaction of living cells in the vicinity of cells killed by a ruby laser. Negative necrotaxis was observed for the unicellular green alga Euglena gracilis, whereas Chlamydomonas was shown to exhibit positive necrotaxis. The cellular colony Pandorina morum exhibited no reaction to the killing of nearby colonies. Both the colorless cryptomonad Chilomonas paramecium and the ciliate Tetrahymena pyriformis exhibited negative necrotaxis following the lysis of vitally stained specimens of their own species. They also exhibited negative necrotaxis following the lysis of Euglena cells. It was also demonstrated that the cellular content of Euglena cells lysed by heat or by a mechanical procedure acts as a repellent to intact Euglena cells. These results suggest that the negative necrotaxis provoked in Euglena by the laser irradiation is probably due to the chemotactic effect produced by the release of cell content in the extracellular medium. This cell content could, according to its chemical composition, act either as a repellent, an attractant, or be inactive. The sensitivity of cells (specific or nonspecific ion channels or chemoreceptors) are also of prime importance in the process.

  15. The molecular basis of genetic dominance.

    PubMed Central

    Wilkie, A O

    1994-01-01

    Studies of mutagenesis in many organisms indicate that the majority (over 90%) of mutations are recessive to wild type. If recessiveness represents the 'default' state, what are the distinguishing features that make a minority of mutations give rise to dominant or semidominant characters? This review draws on the rapid expansion in knowledge of molecular and cellular biology to classify the molecular mechanisms of dominant mutation. The categories discussed include (1) reduced gene dosage, expression, or protein activity (haploinsufficiency); (2) increased gene dosage; (3) ectopic or temporally altered mRNA expression; (4) increased or constitutive protein activity; (5) dominant negative effects; (6) altered structural proteins; (7) toxic protein alterations; and (8) new protein functions. This provides a framework for understanding the basis of dominant genetic phenomena in humans and other organisms. Images PMID:8182727

  16. Intrinsic Negative Mass from Nonlinearity

    NASA Astrophysics Data System (ADS)

    Di Mei, F.; Caramazza, P.; Pierangeli, D.; Di Domenico, G.; Ilan, H.; Agranat, A. J.; Di Porto, P.; DelRe, E.

    2016-04-01

    We propose and provide experimental evidence of a mechanism able to support negative intrinsic effective mass. The idea is to use a shape-sensitive nonlinearity to change the sign of the mass in the leading linear propagation equation. Intrinsic negative-mass dynamics is reported for light beams in a ferroelectric crystal substrate, where the diffusive photorefractive nonlinearity leads to a negative-mass Schrödinger equation. The signature of inverted dynamics is the observation of beams repelled from strongly guiding integrated waveguides irrespective of wavelength and intensity and suggests shape-sensitive nonlinearity as a basic mechanism leading to intrinsic negative mass.

  17. Dominating Biological Networks

    PubMed Central

    Milenković, Tijana; Memišević, Vesna; Bonato, Anthony; Pržulj, Nataša

    2011-01-01

    Proteins are essential macromolecules of life that carry out most cellular processes. Since proteins aggregate to perform function, and since protein-protein interaction (PPI) networks model these aggregations, one would expect to uncover new biology from PPI network topology. Hence, using PPI networks to predict protein function and role of protein pathways in disease has received attention. A debate remains open about whether network properties of “biologically central (BC)” genes (i.e., their protein products), such as those involved in aging, cancer, infectious diseases, or signaling and drug-targeted pathways, exhibit some topological centrality compared to the rest of the proteins in the human PPI network. To help resolve this debate, we design new network-based approaches and apply them to get new insight into biological function and disease. We hypothesize that BC genes have a topologically central (TC) role in the human PPI network. We propose two different concepts of topological centrality. We design a new centrality measure to capture complex wirings of proteins in the network that identifies as TC those proteins that reside in dense extended network neighborhoods. Also, we use the notion of domination and find dominating sets (DSs) in the PPI network, i.e., sets of proteins such that every protein is either in the DS or is a neighbor of the DS. Clearly, a DS has a TC role, as it enables efficient communication between different network parts. We find statistically significant enrichment in BC genes of TC nodes and outperform the existing methods indicating that genes involved in key biological processes occupy topologically complex and dense regions of the network and correspond to its “spine” that connects all other network parts and can thus pass cellular signals efficiently throughout the network. To our knowledge, this is the first study that explores domination in the context of PPI networks. PMID:21887225

  18. Thermophoretically Dominated Aerosol Coagulation

    NASA Astrophysics Data System (ADS)

    Rosner, Daniel E.; Arias-Zugasti, Manuel

    2011-01-01

    A theory of aerosol coagulation due to size-dependent thermophoresis is presented. This previously overlooked effect is important when local temperature gradients are large, the sol population is composed of particles of much greater thermal conductivity than the carrier gas, with mean diameters much greater than the prevailing gas mean free path, and an adequate “spread” in sizes (as in metallurgical mists or fumes). We illustrate this via a population-balance analysis of the evolution of an initially log-normal distribution when this mechanism dominates ordinary Brownian diffusion.

  19. Premature Reassurance and the Basic Writer.

    ERIC Educational Resources Information Center

    Kiefer, Kathleen E.

    College basic writing teachers involved in student/teacher conferences should be aware of the negative effects that result from premature reassurance, assuring students of success too quickly and/or beyond reasonable expectations. The attitudes of basic writers can be divided into three general categories: (1) those who have always had trouble in…

  20. Adjective Metaphors Evoke Negative Meanings

    PubMed Central

    Sakamoto, Maki; Utsumi, Akira

    2014-01-01

    Previous metaphor studies have paid much attention to nominal metaphors and predicative metaphors, but little attention has been given to adjective metaphors. Although some studies have focused on adjective metaphors, they only examined differences in the acceptability of various types of adjective metaphors. This paper explores the cognitive effects evoked by adjective metaphors. Three psychological experiments revealed that (1) adjective metaphors, especially those modified by color adjectives, tend to evoke negative effect; (2) although the meanings of metaphors are basically affected by the meanings of their vehicles, when a vehicle has a neutral meaning, negative meanings are evoked most frequently for adjective metaphors compared to nominal and predicative metaphors; (3) negative meanings evoked by adjective metaphors are related to poeticness, and poetic metaphors evoke negative meanings more easily than less poetic metaphors. Our research sheds new light on studies of the use of metaphor, which is one of the most basic human cognitive abilities. PMID:24586480

  1. Adjective metaphors evoke negative meanings.

    PubMed

    Sakamoto, Maki; Utsumi, Akira

    2014-01-01

    Previous metaphor studies have paid much attention to nominal metaphors and predicative metaphors, but little attention has been given to adjective metaphors. Although some studies have focused on adjective metaphors, they only examined differences in the acceptability of various types of adjective metaphors. This paper explores the cognitive effects evoked by adjective metaphors. Three psychological experiments revealed that (1) adjective metaphors, especially those modified by color adjectives, tend to evoke negative effect; (2) although the meanings of metaphors are basically affected by the meanings of their vehicles, when a vehicle has a neutral meaning, negative meanings are evoked most frequently for adjective metaphors compared to nominal and predicative metaphors; (3) negative meanings evoked by adjective metaphors are related to poeticness, and poetic metaphors evoke negative meanings more easily than less poetic metaphors. Our research sheds new light on studies of the use of metaphor, which is one of the most basic human cognitive abilities.

  2. Rings dominate western Gulf

    NASA Astrophysics Data System (ADS)

    Vidal L., Francisco V.; Vidal L., Victor M. V.; Molero, José María Pérez

    Surface and deep circulation of the central and western Gulf of Mexico is controlled by interactions of rings of water pinched from the gulf's Loop Current. The discovery was made by Mexican oceanographers who are preparing a full-color, 8-volume oceanographic atlas of the gulf.Anticyclonic warm-core rings pinch off the Loop Current at a rate of about one to two per year, the scientists of the Grupo de Estudios Oceanográficos of the Instituto de Investigaciones Eléctricas (GEO-IIE) found. The rings migrate west until they collide with the continental shelf break of the western gulf, almost always between 22° and 23°N latitude. On their westward travel they transfer angular momentum and vorticity to the surrounding water, generating cyclonic circulations and vortex pairs that completely dominate the entire surface and deep circulation of the central and western gulf.

  3. From growth to basic needs.

    PubMed

    Streeten, P

    1979-09-01

    Despite growing hostility and basic misconceptions, the concept of "basic human needs" has superseded former approaches, including concentration on growth, creation of employment, and redistribution of benefits to the poor, as the approach by which mass deprivation may be reduced. The new approach can be defined briefly as one which is designed to improve, first, the income earning opportunities for the poor; second, the public services that reach the poor; third, the flow of goods and services to meet the needs of all members of the household; and fourth, participation of the poor in the ways in which their needs are met. All four pillars must be built on a sustainable basis. In addition, basic needs must be met in a shorter period and at a lower level of earned income per capita than has generally been true in the past, or than would have been achieved via the income expansion associated with growth alone. The basic needs approach is concerned with particular goods and services directed at particular, identified human beings. Another advantage of the basic needs approach is that it is a more positive concept than the double negatives of eliminating or reducing unemployment, alleviating poverty, or reducing inequality. The basic needs approach spells out in considerable detail human needs in terms of health, food, education, water, shelter, transport, simple household goods, as well as non-material needs like participation, cultural identity, and a sense of purpose in life and work, which interact with the material needs. PMID:12261287

  4. On the Dominance of Attitude Emotionality.

    PubMed

    Rocklage, Matthew D; Fazio, Russell H

    2016-02-01

    Many situations in our lives require us to make relatively quick decisions as whether to approach or avoid a person or object, buy or pass on a product, or accept or reject an offer. These decisions are particularly difficult when there are both positive and negative aspects to the object. How do people go about navigating this conflict to come to a summary judgment? Using the Evaluative Lexicon (EL), we demonstrate across three studies, 7,700 attitude expressions, and nearly 50 different attitude objects that when positivity and negativity conflict, the valence that is based more on emotion is more likely to dominate. Furthermore, individuals are also more consistent in the expression of their univalent summary judgments when they involve greater emotionality. In sum, valence that is based on emotion tends to dominate when resolving ambivalence and also helps individuals to remain consistent when offering quick judgments.

  5. Adult Basic Education Basic Computer Literacy Handbook.

    ERIC Educational Resources Information Center

    Manini, Catalina M.; Cervantes, Juan

    This handbook, in both English and Spanish versions, is intended for use with adult basic education (ABE) students. It contains five sections of basic computer literacy activities and information about the ABE computer literacy course offered at Dona Ana Community College (DACC) in New Mexico. The handbook begins with forewords by the handbook's…

  6. The Relationships Between Cerebral Dominance and Different Mental Abilities.

    ERIC Educational Resources Information Center

    Reynolds, Carl; Bartek, Elmer

    Using a sample of 77 10th grade boys, the researchers studied the relationships between the mental abilities measured by the Differential Aptitude Tests and cerebral dominance (CD: the extent to which one hemisphere of the brain dominates the other for control of behavior). The surprise finding was that CD was negatively related to spatial…

  7. Negative Mass Propulsion

    NASA Astrophysics Data System (ADS)

    Winterberg, F.

    Schrödinger's analysis of the Dirac equation gives a hint for the existence of negative masses hidden behind positive masses. But their use for propulsion by reducing the inertia of matter for example, in the limit of macroscopic bodied with zero rest mass, depends on a technical solution to free them from their imprisonment by positive masses. It appears that there are basically two ways this might be achieved: 1. By the application of strong electromagnetic or gravitational fields or by high particle energies. 2. By searching for places in the universe where nature has already done this separation, and from where the negative masses can be mined. The first of these two possibilities is for all practical means excluded, because if possible at all, it would depend on electromagnetic or gravitational fields with strength beyond what is technically attainable, or on extremely large likewise not attainable particle energies. With regard to the 2nd possibility, it has been observed that non-baryonic cold dark matter tends to accumulate near the center of galaxies, or places in the universe which have a large gravitational potential well. Because of the equivalence principle of general relativity, the attraction towards the center of a gravitational potential well, produced by a positive mass, is for negative masses the same as for positive masses, and large amounts of negative masses might have over billions of years been trapped in these gravitational potential wells. Now it just happens that the center of the moon is a potential well, not too deep that it cannot be reached by making a tunnel through the moon, not possible for the deeper potential well of the earth, where the temperature and pressure are too high. Making a tunnel through the moon, provided there is a good supply of negative mass, could revolutionize interstellar space flight. A sequence of thermonuclear shape charges would make such tunnel technically feasible.

  8. BASIC Tools: Structured Programming Techniques in BASIC.

    ERIC Educational Resources Information Center

    Moyer, Patrick C.

    1985-01-01

    Structured programing is an attempt to formalize the logic and structure of computer programs. Examples of structured programing techniques in BASIC are provided. Two major disadvantages of this style of programing for the personal user are noted. (JN)

  9. Finger Enslaving in the Dominant and Non-Dominant Hand

    PubMed Central

    Wilhelm, Luke A.; Martin, Joel R.; Latash, Mark L.; Zatsiorsky, Vladimir M.

    2014-01-01

    During single-finger force production, the non-instructed fingers unintentionally produce force (finger enslaving). In this study, enslaving effects were compared between the dominant and non-dominant hands. The test consisted of a series of maximum voluntary contractions with different finger combinations. Enslaving matrices were calculated by means of training an artificial neural network. The dominant hand was found to be stronger, but there was found to be no difference between the overall enslaving effects in the dominant and non-dominant hands. There was no correlation between the magnitude of finger enslaving and the performance in such tests as the Edinburgh Handedness Inventory, the Grooved Pegboard test, and the Jebsen-Taylor Hand Function test. Each one of those three tests showed a significant difference between the dominant and non-dominant hand performances. Eleven subjects were retested after two months, and it was found that enslaving effects did not fluctuate significantly between the two testing sessions. While the dominant and non-dominant hands are involved differently in everyday tasks, e.g. in writing or eating, this practice does not cause significant differences in enslaving between the hands. PMID:24360253

  10. Finger enslaving in the dominant and non-dominant hand.

    PubMed

    Wilhelm, Luke A; Martin, Joel R; Latash, Mark L; Zatsiorsky, Vladimir M

    2014-02-01

    During single-finger force production, the non-instructed fingers unintentionally produce force (finger enslaving). In this study, enslaving effects were compared between the dominant and non-dominant hands. The test consisted of a series of maximum voluntary contractions with different finger combinations. Enslaving matrices were calculated by means of training an artificial neural network. The dominant hand was found to be stronger, but there was found to be no difference between the overall enslaving effects in the dominant and non-dominant hands. There was no correlation between the magnitude of finger enslaving and the performance in such tests as the Edinburgh Handedness Inventory, the Grooved Pegboard test, and the Jebsen-Taylor Hand Function test. Each one of those three tests showed a significant difference between the dominant and non-dominant hand performances. Eleven subjects were retested after two months, and it was found that enslaving effects did not fluctuate significantly between the two testing sessions. While the dominant and non-dominant hands are involved differently in everyday tasks, e.g. in writing or eating, this practice does not cause significant differences in enslaving between the hands. PMID:24360253

  11. PASCAL vs BASIC

    ERIC Educational Resources Information Center

    Mundie, David A.

    1978-01-01

    A comparison between PASCAL and BASIC as general purpose microprocessor languages rates PASCAL above BASIC in such points as program structure, data types, structuring methods, control structures, procedures and functions, and ease in learning. (CMV)

  12. Health Insurance Basics

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Health Insurance Basics KidsHealth > For Teens > Health Insurance Basics Print ... thought advanced calculus was confusing. What Exactly Is Health Insurance? Health insurance is a plan that people buy ...

  13. Factors affecting the reproductive success of dominant male meerkats.

    PubMed

    Spong, Göran F; Hodge, Sarah J; Young, Andrew J; Clutton-Brock, Tim H

    2008-05-01

    Identifying traits that affect the reproductive success of individuals is fundamental for our understanding of evolutionary processes. In cooperative breeders, a dominant male typically restricts mating access to the dominant female for extended periods, resulting in pronounced variation in reproductive success among males. This may result in strong selection for traits that increase the likelihood of dominance acquisition, dominance retention and reproductive rates while dominant. However, despite considerable research on reproductive skew, few studies have explored the factors that influence these three processes among males in cooperative species. Here we use genetic, behavioural and demographic data to investigate the factors affecting reproductive success in dominant male meerkats (Suricata suricatta). Our data show that dominant males sire the majority of all offspring surviving to 1 year. A male's likelihood of becoming dominant is strongly influenced by age, but not by weight. Tenure length and reproductive rate, both important components of dominant male reproductive success, are largely affected by group size and composition, rather than individual traits. Dominant males in large groups have longer tenures, but after this effect is controlled, male tenure length also correlates negatively to the number of adult females in the group. Male reproductive rate also declines as the number of intra- and extra-group competitors increases. As the time spent in the dominant position and reproductive rate while dominant explain > 80% of the total variance in reproductive success, group composition thus has major implications for male reproductive success.

  14. Factors affecting the reproductive success of dominant male meerkats.

    PubMed

    Spong, Göran F; Hodge, Sarah J; Young, Andrew J; Clutton-Brock, Tim H

    2008-05-01

    Identifying traits that affect the reproductive success of individuals is fundamental for our understanding of evolutionary processes. In cooperative breeders, a dominant male typically restricts mating access to the dominant female for extended periods, resulting in pronounced variation in reproductive success among males. This may result in strong selection for traits that increase the likelihood of dominance acquisition, dominance retention and reproductive rates while dominant. However, despite considerable research on reproductive skew, few studies have explored the factors that influence these three processes among males in cooperative species. Here we use genetic, behavioural and demographic data to investigate the factors affecting reproductive success in dominant male meerkats (Suricata suricatta). Our data show that dominant males sire the majority of all offspring surviving to 1 year. A male's likelihood of becoming dominant is strongly influenced by age, but not by weight. Tenure length and reproductive rate, both important components of dominant male reproductive success, are largely affected by group size and composition, rather than individual traits. Dominant males in large groups have longer tenures, but after this effect is controlled, male tenure length also correlates negatively to the number of adult females in the group. Male reproductive rate also declines as the number of intra- and extra-group competitors increases. As the time spent in the dominant position and reproductive rate while dominant explain > 80% of the total variance in reproductive success, group composition thus has major implications for male reproductive success. PMID:18410290

  15. Whose Basics? Whose Competencies?

    ERIC Educational Resources Information Center

    Squires, Robert

    Among the advocates of the "Back to Basics" trend there seems to be little concensus as to what exactly constitutes the "basics." It is clear, however, that what most people mean by "basics" is mechanical skills, punctuation, spelling and grammar. The task of teachers of language is to foster an understanding of how language can be and has been…

  16. Basic Cake Decorating Workbook.

    ERIC Educational Resources Information Center

    Bogdany, Mel

    Included in this student workbook for basic cake decorating are the following: (1) Drawings of steps in a basic way to ice a layer cake, how to make a paper cone, various sizes of flower nails, various sizes and types of tin pastry tubes, and special rose tubes; (2) recipes for basic decorating icings (buttercream, rose paste, and royal icing);…

  17. Brain Dominance & Self-Actualization.

    ERIC Educational Resources Information Center

    Bernhoft, Franklin O.

    Numerous areas associated with brain dominance have been researched since Bogen and Sperry's work with split-brain patients in the 1960s, but only slight attention has been given to the connection between brain dominance and personality. No study appears in the literature seeking to understand optimal mental health as defined by Maslow's…

  18. Dominant Leadership Style in Schools

    ERIC Educational Resources Information Center

    Rajbhandari, Mani Man Singh

    2006-01-01

    The dominant leadership style is defined by the situation and the kind of organizational environment and climate. This, however, does not sufficiently define the leadership qualities in school organizations. There are other factors which also determine the dominant leadership style, which are the traits and style, teachers commitments, pass out…

  19. Dominance Hierarchies in Leptothorax Ants

    NASA Astrophysics Data System (ADS)

    Cole, Blaine J.

    1981-04-01

    The social organization of Leptothorax allardycei is unique among ant species thus far studied. The workers form linear dominance hierarchies characterized by routine displays of dominance, avoidance behavior, and even fighting. The high-ranking ants are favored in liquid food exchange, have greater ovarian development, and produce 20 percent of the eggs.

  20. Dominance Hierarchies in Young Children

    ERIC Educational Resources Information Center

    Edelman, Murray S.; Omark, Donald R.

    1973-01-01

    This study uses the ethological approach of seeking species characteristics and phylogenetic continuities in an investigation of human behavior. Among primates a striking consistency is the presence of some form of dominance hierarchy in many species. The present study examines peer group dominance hierarchies as they are perceived by children in…

  1. Cesium cation affinities and basicities

    NASA Astrophysics Data System (ADS)

    Gal, Jean-François; Maria, Pierre-Charles; Massi, Lionel; Mayeux, Charly; Burk, Peeter; Tammiku-Taul, Jaana

    2007-11-01

    This review focuses on the quantitative data related to cesium cation interaction with neutral or negatively charged ligands. The techniques used for measuring the cesium cation affinity (enthalpies, CCA), and cesium cation basicities (Gibbs free energies, CCB) are briefly described. The quantum chemical calculations methods that were specifically designed for the determination of cesium cation adduct structures and the energetic aspects of the interaction are discussed. The experimental results, obtained essentially from mass spectrometry techniques, and complemented by thermochemical data, are tabulated and commented. In particular, the correlations between cesium cation affinities and lithium cation affinities for the various kinds of ligands (rare gases, polyatomic neutral molecules, among them aromatic compounds and negative ions) serve as a basis for the interpretation of the diverse electrostatic modes of interaction. A brief account of some recent analytical applications of ion/molecule reactions with Cs+, as well as other cationization approaches by Cs+, is given.

  2. The Basic and Semi-Basic

    ERIC Educational Resources Information Center

    Spitler, Gail

    1978-01-01

    Presented is a paradigm for teaching basic and semibasic arithmetic facts to children with arithmetic difficulties, in which the student progresses from the use of concrete materials such as blocks, to the use of diagrams such as tally marks, to a reasoning process, to responding in an automatic manner. (DLS)

  3. Cosmology with negative absolute temperatures

    NASA Astrophysics Data System (ADS)

    Vieira, J. P. P.; Byrnes, Christian T.; Lewis, Antony

    2016-08-01

    Negative absolute temperatures (NAT) are an exotic thermodynamical consequence of quantum physics which has been known since the 1950's (having been achieved in the lab on a number of occasions). Recently, the work of Braun et al. [1] has rekindled interest in negative temperatures and hinted at a possibility of using NAT systems in the lab as dark energy analogues. This paper goes one step further, looking into the cosmological consequences of the existence of a NAT component in the Universe. NAT-dominated expanding Universes experience a borderline phantom expansion (w < ‑1) with no Big Rip, and their contracting counterparts are forced to bounce after the energy density becomes sufficiently large. Both scenarios might be used to solve horizon and flatness problems analogously to standard inflation and bouncing cosmologies. We discuss the difficulties in obtaining and ending a NAT-dominated epoch, and possible ways of obtaining density perturbations with an acceptable spectrum.

  4. Cosmology with negative absolute temperatures

    NASA Astrophysics Data System (ADS)

    Vieira, J. P. P.; Byrnes, Christian T.; Lewis, Antony

    2016-08-01

    Negative absolute temperatures (NAT) are an exotic thermodynamical consequence of quantum physics which has been known since the 1950's (having been achieved in the lab on a number of occasions). Recently, the work of Braun et al. [1] has rekindled interest in negative temperatures and hinted at a possibility of using NAT systems in the lab as dark energy analogues. This paper goes one step further, looking into the cosmological consequences of the existence of a NAT component in the Universe. NAT-dominated expanding Universes experience a borderline phantom expansion (w < -1) with no Big Rip, and their contracting counterparts are forced to bounce after the energy density becomes sufficiently large. Both scenarios might be used to solve horizon and flatness problems analogously to standard inflation and bouncing cosmologies. We discuss the difficulties in obtaining and ending a NAT-dominated epoch, and possible ways of obtaining density perturbations with an acceptable spectrum.

  5. Exploring Dominant Types of Explanations Built by General Chemistry Students

    ERIC Educational Resources Information Center

    Talanquer, Vicente

    2010-01-01

    The central goal of our study was to explore the nature of the explanations generated by science and engineering majors with basic training in chemistry to account for the colligative properties of solutions. The work was motivated by our broader interest in the characterisation of the dominant types of explanations that science college students…

  6. American Media Domination and Audience Preference: A 60-Year Perspective.

    ERIC Educational Resources Information Center

    Bjork, Ulf Jonas

    The debate over American dominance of mass media exports gained new momentum in the late 1980s, when the European Community moved toward restricting the number of television programs imported from non-European countries. Research suggests that Europeans enjoy American television programs such as "Dallas" because the series embody basic myths and…

  7. Measuring Language Dominance and Bilingual Proficiency Development of Tarahumara Children.

    ERIC Educational Resources Information Center

    Paciotto, Carla

    This paper examines the language dominance and oral bilingual proficiency of Tarahumara-Spanish speaking students from Chihuahua, Mexico, within the framework of Cummins' model of bilingual proficiency development. Cummins' model distinguishes between basic interpersonal communicative skills (BICS) and cognitive academic language proficiency…

  8. Lateral Dominance and Reading Disability.

    ERIC Educational Resources Information Center

    Harris, Albert J.

    1979-01-01

    Theory and research on the relation of lateral dominance to the causation of reading disability are reviewed. Both direct and indirect measures of cerebral hemisphere functioning are considered. (SBH)

  9. Construction & Basic Skills.

    ERIC Educational Resources Information Center

    BCEL Newsletter for the Business and Literacy Communities, 1991

    1991-01-01

    Basic skills education has become a pressing need in the construction industry as jobs become more complex and fewer workers have needed skills. However, the construction industry lags in spending on training for entry-level workers. The Home Builders Institute (HBI) is testing a pilot basic skills program that it hopes will prove useful to the…

  10. Basic Science Training Program.

    ERIC Educational Resources Information Center

    Brummel, Clete

    These six learning modules were developed for Lake Michigan College's Basic Science Training Program, a workshop to develop good study skills while reviewing basic science. The first module, which was designed to provide students with the necessary skills to study efficiently, covers the following topics: time management; an overview of a study…

  11. Basic Electronics I.

    ERIC Educational Resources Information Center

    Robertson, L. Paul

    Designed for use in basic electronics programs, this curriculum guide is comprised of twenty-nine units of instruction in five major content areas: Orientation, Basic Principles of Electricity/Electronics, Fundamentals of Direct Current, Fundamentals of Alternating Current, and Applying for a Job. Each instructional unit includes some or all of…

  12. BASIC Beats PASCAL.

    ERIC Educational Resources Information Center

    Ever, Jacob

    1981-01-01

    Features of two versions of the BASIC programing language are compared with the features of the PASCAL programing language. The application chosen for comparison was a word processor. The conclusion was that PASCAL had the best language features, but BASIC had better systems capabilities. (MP)

  13. Fluency with Basic Addition

    ERIC Educational Resources Information Center

    Garza-Kling, Gina

    2011-01-01

    Traditionally, learning basic facts has focused on rote memorization of isolated facts, typically through the use of flash cards, repeated drilling, and timed testing. However, as many experienced teachers have seen, "drill alone does not develop mastery of single-digit combinations." In contrast, a fluency approach to learning basic addition…

  14. Basic Stuff Series.

    ERIC Educational Resources Information Center

    Bain, Linda, Ed.; And Others

    1981-01-01

    The Basic Stuff project is an effort to include more general concepts such as the effects of exercise, the learning of a new skill, and psychological factors influencing performance. The Basic Stuff Series attempts to summarize for teachers appropriate concepts and teaching methods. (JN)

  15. Basic Skills for Life.

    ERIC Educational Resources Information Center

    Department for Education and Employment, London (England).

    This booklet describes existing and planned government initiatives to address the long-standing issue of low achievement in basic literacy and numeracy skills in England. The booklet begins with a brief explanation of the economic and social importance of basic functional literacy and numeracy skills. Part 1 is a discussion of English government…

  16. Exponentiation: A New Basic?

    ERIC Educational Resources Information Center

    Davis, Brent

    2015-01-01

    For centuries, the basic operations of school mathematics have been identified as addition, subtraction, multiplication, and division. Notably, these operations are "basic," not because they are foundational to mathematics knowledge, but because they were vital to a newly industrialized and market-driven economy several hundred years…

  17. Romanian Basic Course.

    ERIC Educational Resources Information Center

    Defense Language Inst., Washington, DC.

    The "Romanian Basic Course," consisting of 89 lesson units in eight volumes, is designed to train native English language speakers to Level 3 proficiency in comprehension, speaking, reading, and writing Romanian (based on a 1-5 scale in which Level 5 is native speaker proficiency). Volume 1, which introduces basic sentences in dialog form with…

  18. TOOLS AND BASIC MACHINES.

    ERIC Educational Resources Information Center

    George Washington Univ., Washington, DC. School of Education.

    THIS BASIC READER IS A PART OF AN EXPERIMENTAL CURRICULUM DEVELOPMENT PROJECT DESCRIBED IN VT 004 454, TO DEVELOP AND EVALUATE SPECIAL NEW TRAINING MATERIALS TO TEACH BASIC VOCATIONAL TALENT SKILLS TO DISADVANTAGED STUDENTS WHICH WERE TESTED ON APPROXIMATELY 2,500 EIGHTH AND NINTH GRADERS IN EIGHT SCHOOL SYSTEMS ACROSS THE NATION. THIS READER WAS…

  19. Neural mechanisms of social dominance.

    PubMed

    Watanabe, Noriya; Yamamoto, Miyuki

    2015-01-01

    In a group setting, individuals' perceptions of their own level of dominance or of the dominance level of others, and the ability to adequately control their behavior based on these perceptions are crucial for living within a social environment. Recent advances in neural imaging and molecular technology have enabled researchers to investigate the neural substrates that support the perception of social dominance and the formation of a social hierarchy in humans. At the systems' level, recent studies showed that dominance perception is represented in broad brain regions which include the amygdala, hippocampus, striatum, and various cortical networks such as the prefrontal, and parietal cortices. Additionally, neurotransmitter systems such as the dopaminergic and serotonergic systems, modulate and are modulated by the formation of the social hierarchy in a group. While these monoamine systems have a wide distribution and multiple functions, it was recently found that the Neuropeptide B/W contributes to the perception of dominance and is present in neurons that have a limited projection primarily to the amygdala. The present review discusses the specific roles of these neural regions and neurotransmitter systems in the perception of dominance and in hierarchy formation.

  20. Neural mechanisms of social dominance

    PubMed Central

    Watanabe, Noriya; Yamamoto, Miyuki

    2015-01-01

    In a group setting, individuals' perceptions of their own level of dominance or of the dominance level of others, and the ability to adequately control their behavior based on these perceptions are crucial for living within a social environment. Recent advances in neural imaging and molecular technology have enabled researchers to investigate the neural substrates that support the perception of social dominance and the formation of a social hierarchy in humans. At the systems' level, recent studies showed that dominance perception is represented in broad brain regions which include the amygdala, hippocampus, striatum, and various cortical networks such as the prefrontal, and parietal cortices. Additionally, neurotransmitter systems such as the dopaminergic and serotonergic systems, modulate and are modulated by the formation of the social hierarchy in a group. While these monoamine systems have a wide distribution and multiple functions, it was recently found that the Neuropeptide B/W contributes to the perception of dominance and is present in neurons that have a limited projection primarily to the amygdala. The present review discusses the specific roles of these neural regions and neurotransmitter systems in the perception of dominance and in hierarchy formation. PMID:26136644

  1. BASIC: Updating a Familiar Language.

    ERIC Educational Resources Information Center

    Eyman, David H.

    1988-01-01

    Discusses reasons for learning to program in BASIC, various versions of BASIC, BASIC compilers, and adherence to proposed standards. Brief reviews of six BASIC software packages are included. (12 references) (MES)

  2. Measuring social behavior: social dominance.

    PubMed

    Craig, J V

    1986-04-01

    Social dominance develops more slowly when young animals are kept in intact peer groups where they need not compete for resources. Learned generalizations may cause smaller and weaker animals to accept subordinate status readily when confronted with strangers that would be formidable opponents. Sexual hormones and sensitivity to them can influence the onset of aggression and status attained. After dominance orders are established, they tend to be stable in female groups but are less so in male groups. Psychological influences can affect dominance relationships when strangers meet and social alliances within groups may affect relative status of individuals. Whether status associated with agonistic behavior is correlated with control of space and scarce resources needs to be determined for each species and each kind of resource. When such correlations exists, competitive tests and agonistic behavior associated with gaining access to scarce resources can be useful to the observer in learning about dominance relationships rapidly. Examples are given to illustrate how estimates of social dominance can be readily attained and some strengths and weaknesses of the various methods. PMID:3519554

  3. Small membranes under negative surface tension.

    PubMed

    Avital, Yotam Y; Farago, Oded

    2015-03-28

    We use computer simulations and a simple free energy model to study the response of a bilayer membrane to the application of a negative (compressive) mechanical tension. Such a tension destabilizes the long wavelength undulation modes of giant vesicles, but it can be sustained when small membranes and vesicles are considered. Our negative tension simulation results reveal two regimes-(i) a weak negative tension regime characterized by stretching-dominated elasticity and (ii) a strong negative tension regime featuring bending-dominated elastic behavior. This resembles the findings of the classic Evans and Rawicz micropipette aspiration experiment in giant unilamellar vesicles (GUVs) [E. Evans and W. Rawicz, Phys, Rev. Lett. 64, 2094 (1990)]. However, in GUVs the crossover between the two elasticity regimes occurs at a small positive surface tension, while in smaller membranes it takes place at a moderate negative tension. Another interesting observation concerning the response of a small membrane to negative surface tension is related to the relationship between the mechanical and fluctuation tensions, which are equal to each other for non-negative values. When the tension decreases to negative values, the fluctuation tension γ drops somewhat faster than the mechanical tension τ in the small negative tension regime, before it saturates (and becomes larger than τ) for large negative tensions. The bending modulus exhibits an "opposite" trend. It remains almost unchanged in the stretching-dominated elastic regime, and decreases in the bending-dominated regime. Both the amplitudes of the thermal height undulations and the projected area variations diverge at the onset of mechanical instability.

  4. Trait Dominance Promotes Reflexive Staring at Masked Angry Body Postures

    PubMed Central

    Hortensius, Ruud; van Honk, Jack; de Gelder, Beatrice; Terburg, David

    2014-01-01

    It has been shown that dominant individuals sustain eye-contact when non-consciously confronted with angry faces, suggesting reflexive mechanisms underlying dominance behaviors. However, dominance and submission can be conveyed and provoked by means of not only facial but also bodily features. So far few studies have investigated the interplay of body postures with personality traits and behavior, despite the biological relevance and ecological validity of these postures. Here we investigate whether non-conscious exposure to bodily expressions of anger evokes reflex-like dominance behavior. In an interactive eye-tracking experiment thirty-two participants completed three social dominance tasks with angry, happy and neutral facial, bodily and face and body compound expressions that were masked from consciousness. We confirmed our predictions of slower gaze-aversion from both non-conscious bodily and compound expressions of anger compared to happiness in high dominant individuals. Results from a follow-up experiment suggest that the dominance behavior triggered by exposure to bodily anger occurs with basic detection of the category, but not recognition of the emotional content. Together these results suggest that dominant staring behavior is reflexively driven by non-conscious perception of the emotional content and triggered by not only facial but also bodily expression of anger. PMID:25549321

  5. Gravity-Induced Vacuum Dominance

    SciTech Connect

    Lima, William C. C.; Vanzella, Daniel A. T.

    2010-04-23

    It has been widely believed that, except in very extreme situations, the influence of gravity on quantum fields should amount to just small, subdominant contributions. This view seemed to be endorsed by the seminal results obtained over the last decades in the context of renormalization of quantum fields in curved spacetimes. Here, however, we argue that this belief is false by showing that there exist well-behaved spacetime evolutions where the vacuum energy density of free quantum fields is forced, by the very same background spacetime, to become dominant over any classical energy-density component. By estimating the time scale for the vacuum energy density to become dominant, and therefore for backreaction on the background spacetime to become important, we argue that this (infrared) vacuum dominance may bear unexpected astrophysical and cosmological implications.

  6. Highly dominating, highly authoritarian personalities.

    PubMed

    Altemeyer, Bob

    2004-08-01

    The author considered the small part of the population whose members score highly on both the Social Dominance Orientation scale and the Right-Wing Authoritarianism scale. Studies of these High SDO-High RWAs, culled from samples of nearly 4000 Canadian university students and over 2600 of their parents and reported in the present article, reveal that these dominating authoritarians are among the most prejudiced persons in society. Furthermore, they seem to combine the worst elements of each kind of personality, being power-hungry, unsupportive of equality, manipulative, and amoral, as social dominators are in general, while also being religiously ethnocentric and dogmatic, as right-wing authoritarians tend to be. The author suggested that, although they are small in number, such persons can have considerable impact on society because they are well-positioned to become the leaders of prejudiced right-wing political movements.

  7. E-Mail Basics.

    ERIC Educational Resources Information Center

    Cohen, Sacha

    1996-01-01

    Offers electronic mail basics, mail etiquette and tips, interesting World Wide Web sites, and how to do a Web search. Includes Web sites that offer beginner tutorials and a glossary of Internet terms. (JOW)

  8. Basic poster discussion: summary.

    PubMed

    Widdicombe, John

    2011-06-01

    Twelve posters were presented in the section on Basic Research. They were discussed in a session chaired by Paul Davenport (Gainesville, US) and Marian Kollarik (Boston, US), with each poster presenter first briefly describing his/her poster.

  9. Video Screen Capture Basics

    ERIC Educational Resources Information Center

    Dunbar, Laura

    2014-01-01

    This article is an introduction to video screen capture. Basic information of two software programs, QuickTime for Mac and BlueBerry Flashback Express for PC, are also discussed. Practical applications for video screen capture are given.

  10. HIV Treatment: The Basics

    MedlinePlus

    HIV Treatment HIV Treatment: The Basics (Last updated 3/1/2016; last reviewed 3/1/2016) Key Points Antiretroviral therapy (ART) ... reduces the risk of HIV transmission . How do HIV medicines work? HIV attacks and destroys the infection- ...

  11. Wth Basic Art Materials

    ERIC Educational Resources Information Center

    Herberholz, Barbara

    2010-01-01

    In this article, the author presents a checklist of basic materials for two-dimensional activities that are necessary for an elementary-school art program. She also provides a few tips on how to use them.

  12. Dominant resistance against plant viruses

    PubMed Central

    de Ronde, Dryas; Butterbach, Patrick; Kormelink, Richard

    2014-01-01

    To establish a successful infection plant viruses have to overcome a defense system composed of several layers. This review will overview the various strategies plants employ to combat viral infections with main emphasis on the current status of single dominant resistance (R) genes identified against plant viruses and the corresponding avirulence (Avr) genes identified so far. The most common models to explain the mode of action of dominant R genes will be presented. Finally, in brief the hypersensitive response (HR) and extreme resistance (ER), and the functional and structural similarity of R genes to sensors of innate immunity in mammalian cell systems will be described. PMID:25018765

  13. Meningitis - gram-negative

    MedlinePlus

    Gram-negative meningitis ... Acute bacterial meningitis can be caused by Gram-negative bacteria. Meningococcal and H. influenzae meningitis are caused by Gram-negative bacteria and are covered in detail in other articles. This article ...

  14. Second to fourth digit ratio, testosterone and perceived male dominance.

    PubMed Central

    Neave, Nick; Laing, Sarah; Fink, Bernhard; Manning, John T

    2003-01-01

    Previous studies have shown that male faces with extreme features associated with testosterone are perceived as dominant and masculine. Women have been reported to prefer more masculinized male faces as they may consider testosterone markers to be an 'honest' indication of good health, and such considerations may underlie their aesthetic preferences. However, pronounced testosterone facial markers are also associated with dominance, and several negative personality traits. This suggests that female aesthetic preferences may be an adaptive compromise between positive attributes associated with higher than average testosterone, and negative attributes associated with more extreme masculinization. This current study attempts to clarify the role of hormone markers in female perceptions of dominance, masculinity and attractiveness, in male facial images. Recent evidence suggests that the relative length of the 2nd to 4th finger (2D : 4D ratio) is a pointer to prenatal testosterone levels and may thus serve as a window to the prenatal hormonal environment. We measured 2D : 4D in a sample of male college students and took salivary samples to analyse circulating levels of testosterone. Women rated facial images of these males for dominance, masculinity and attractiveness. Our results show that male 2D : 4D was significantly negatively related to perceived dominance and masculinity but not attractiveness. Circulating testosterone levels were not related to dominance, masculinity or attractiveness. These findings suggest that: (i) high prenatal levels of testosterone serve to 'organize' male facial features to subsequently reflect dominance and masculine characteristics presumably activated during puberty; and (ii) attractiveness is not directly related to testosterone levels. We conclude that facial dominance and masculinity reflect a male's perceived status rather than his physical attraction to women. PMID:14561281

  15. Dominance and Age in Bilingualism

    ERIC Educational Resources Information Center

    Birdsong, David

    2014-01-01

    The present article examines the relationship between age and dominance in bilingual populations. Age in bilingualism is understood as the point in development at which second language (L2) acquisition begins and as the chronological age of users of two languages. Age of acquisition (AoA) is a factor in determining which of a bilingual's two…

  16. From Design for Dominance to Design for Dialogue

    ERIC Educational Resources Information Center

    Keitges, Mark J.

    2012-01-01

    The increasing complexity of the network society is the result of a particular approach to design: that of mastery, control, ease of use and interconnectedness. The author analyzes this design approach for its negative and positive aspects, which he labels as "designing for dominance" and "designing for dialogue", respectively. Both of these…

  17. Leaf economics spectrum-productivity relationships in intensively grazed pastures depend on dominant species identity.

    PubMed

    Mason, Norman W H; Orwin, Kate; Lambie, Suzanne; Woodward, Sharon L; McCready, Tiffany; Mudge, Paul

    2016-05-01

    Plant functional traits are thought to drive variation in primary productivity. However, there is a lack of work examining how dominant species identity affects trait-productivity relationships. The productivity of 12 pasture mixtures was determined in a 3-year field experiment. The mixtures were based on either the winter-active ryegrass (Lolium perenne) or winter-dormant tall fescue (Festuca arundinacea). Different mixtures were obtained by adding forb, legume, and grass species that differ in key leaf economics spectrum (LES) traits to the basic two-species dominant grass-white clover (Trifolium repens) mixtures. We tested for correlations between community-weighted mean (CWM) trait values, functional diversity, and productivity across all plots and within those based on either ryegrass or tall fescue. The winter-dormant forb species (chicory and plantain) had leaf traits consistent with high relative growth rates both per unit leaf area (high leaf thickness) and per unit leaf dry weight (low leaf dry matter content). Together, the two forb species achieved reasonable abundance when grown with either base grass (means of 36% and 53% of total biomass, respectively, with ryegrass tall fescue), but they competed much more strongly with tall fescue than with ryegrass. Consequently, they had a net negative impact on productivity when grown with tall fescue, and a net positive effect when grown with ryegrass. Strongly significant relationships between productivity and CWM values for LES traits were observed across ryegrass-based mixtures, but not across tall fescue-based mixtures. Functional diversity did not have a significant positive effect on productivity for any of the traits. The results show dominant species identity can strongly modify trait-productivity relationships in intensively grazed pastures. This was due to differences in the intensity of competition between dominant species and additional species, suggesting that resource-use complementarity is a

  18. Decontamination: back to basics.

    PubMed

    Meredith, Susan J; Sjorgen, Geoff

    2008-07-01

    My invitation from this Journal's Editor, Felicia Cox, to provide a paper for this themed issue, included the sentence 'I was wondering if you or a colleague would like to contribute a back to basics article on the relevant standards and guidelines for decontamination, including what is compliance?'. The reason it is so interesting to me is that the term 'back to basics' implies reverting to a simpler time in life - when by just sticking to the rules, life became easier. However, with decontamination this is not actually true. PMID:18710126

  19. The Price of "Black Dominance."

    ERIC Educational Resources Information Center

    Hoberman, John

    2000-01-01

    Discusses the harmful effects of stereotyping black males as athletes, noting that over-identification with athletes and the world of physical performance limits black children's development by discouraging academic achievement. Examines the negative influence of mass media focus on black athletes, rappers, and stylized ghetto blackness. Discusses…

  20. Basic Pneumatics. Instructor's Guide.

    ERIC Educational Resources Information Center

    Fessehaye, Michael

    This instructor's guide is designed for use by industrial vocational teachers in teaching a course on basic pneumatics. Covered in the individual units are the following topics: an introduction to pneumatics (including the operation of a service station hoist); fundamentals and physical laws; air compressors (positive displacement compressors;…

  1. Basic Drafting: Book Two.

    ERIC Educational Resources Information Center

    Davis, Ronald; And Others

    The second of a two-book course in drafting, this manual consists of 12 topics in the following units: sketching techniques, geometric constructions, orthographic views, dimensioning procedures, basic tolerancing, auxiliary views, sectional views, inking tools and techniques, axonometrics, oblique, perspective, and computer-aided drafting.…

  2. Basic Electronics II.

    ERIC Educational Resources Information Center

    Willison, Neal A.; Shelton, James K.

    Designed for use in basic electronics programs, this curriculum guide is comprised of 15 units of instruction. Unit titles are Review of the Nature of Matter and the P-N Junction, Rectifiers, Filters, Special Semiconductor Diodes, Bipolar-Junction Diodes, Bipolar Transistor Circuits, Transistor Amplifiers, Operational Amplifiers, Logic Devices,…

  3. Projectable Basic Electronics Kit.

    ERIC Educational Resources Information Center

    H'ng, John; And Others

    1982-01-01

    Outlines advantages derived from constructing and using a Projectable Basic Electronics Kit and provides: (1) list of components; (2) diagrams of 10 finished components (resistor; capacitor; diode; switch; bulb; transistor; meter; variable capacitor; coil; connecting terminal); and (3) diode and transistor activities. (JN)

  4. Developing Basic Electronics Aptitudes.

    ERIC Educational Resources Information Center

    Lakeshore Technical Coll., Cleveland, WI.

    This curriculum guide provides materials for basic training in electrical and electronic theory to enable participants to analyze circuits and use test equipment to verify electrical operations and to succeed in the beginning electrical and electronic courses in the Lakeshore Technical College (Wisconsin) electronics programs. The course includes…

  5. Internet Training: The Basics.

    ERIC Educational Resources Information Center

    Gallo, Gail; Wichowski, Chester P.

    This paper outlines the basic information teachers need to know to use the World Wide Web for research and communication, using Netscape 3.04. Topics covered include the following: what is the World Wide Web?; what is a browser?; accessing the Web; moving around a web document; the Uniform Resource Locator (URL); Bookmarks; saving and printing a…

  6. Microeconomic Analysis with BASIC.

    ERIC Educational Resources Information Center

    Tom, C. F. Joseph

    Computer programs written in BASIC for the study of microeconomic analysis with special emphasis in economic decisions on price, output, and profit of a business firm are described. A very brief overview of the content of each of the 28 computer programs comprising the course is provided; four of the programs are then discussed in greater detail.…

  7. River Bank Basics.

    ERIC Educational Resources Information Center

    Zar-Kessler, Arnold

    1982-01-01

    Discusses how the science faculty at one rural Massachusetts school responded to the state mandate requiring basic competency testing for all students. The approach taken (includes unit on Connecticut River) does not call for major changes in science course format, only in broadening definition of the responsibilities of science teaching.…

  8. Focus on Basics, 1997.

    ERIC Educational Resources Information Center

    Focus on Basics, 1997

    1997-01-01

    Together, these four newsletters contain 36 articles devoted to adult literacy research and practice and the relationship between them. The following articles are included: "A Productive Partnership" (Richard J. Murnane, Bob Bickerton); "Welcome to 'Focus on Basics'" (Barbara Garner); "Applying Research on the Last Frontier" (Karen Backlund, Kathy…

  9. Basic Internet Software Toolkit.

    ERIC Educational Resources Information Center

    Buchanan, Larry

    1998-01-01

    Once schools are connected to the Internet, the next step is getting network workstations configured for Internet access. This article describes a basic toolkit comprising software currently available on the Internet for free or modest cost. Lists URLs for Web browser, Telnet, FTP, file decompression, portable document format (PDF) reader,…

  10. Basic Electricity. Part 1.

    ERIC Educational Resources Information Center

    Kilmer, Donald C.

    A primarily illustrated introduction to the basics of electricity is presented in this guide, the first of a set of four designed for the student interested in a vocation in electrical work. This guide is intended for the first-year student and provides mostly diagrams with accompanying defintions/information in three units, each covering one of…

  11. Basic Skills Assessment

    ERIC Educational Resources Information Center

    Yin, Alexander C.; Volkwein, J. Fredericks

    2010-01-01

    After surveying 1,827 students in their final year at eighty randomly selected two-year and four-year public and private institutions, American Institutes for Research (2006) reported that approximately 30 percent of students in two-year institutions and nearly 20 percent of students in four-year institutions have only basic quantitative…

  12. Basic Media in Education.

    ERIC Educational Resources Information Center

    Harrell, John

    Intended as a guide to the use of different media for use in the classroom, this document demonstrates alternative approaches that may be taken to depicting and communicating images and concepts to others. Some basic tools and materials--including a ruler, matte knife, rubber cement, stapler, felt-tip pens, paint brushes, and lettering pens--are…

  13. Basic Experiments in Telecommunications.

    ERIC Educational Resources Information Center

    Andresen, S. G.

    Presented is a set of laboratory experiments developed to provide students with demonstrations and hands-on experiences with a variety of basic communications methods. These experiments may be used with students who have training in engineering, as well as those with social sciences who have no engineering background. Detailed exercises dealing…

  14. Canadian Adult Basic Education.

    ERIC Educational Resources Information Center

    Brooke, W. Michael, Comp.

    "Trends," a publication of the Canadian Association for Adult Education, is a collection of abstracts on selected subjects affecting adult education; this issue is on adult basic education (ABE). It covers teachers and teacher training, psychological factors relating to the ABE teacher and students, manuals for teachers, instructional materials,…

  15. Basic Drafting: Book One.

    ERIC Educational Resources Information Center

    Davis, Ronald; And Others

    The first of a two-book course in drafting, this manual consists of 13 topics in the following units: introduction to drafting, general safety, basic tools and lines, major equipment, applying for a job, media, lettering, reproduction, drawing sheet layout, architect's scale usage, civil engineer's scale usage, mechanical engineer's scale usage,…

  16. Basic Math I.

    ERIC Educational Resources Information Center

    Mercer County Community Coll., Trenton, NJ.

    This document offers instructional materials for a 60-hour course on basic math operations involving decimals, fractions, and proportions as applied in the workplace. The course, part of a workplace literacy project developed by Mercer County Community College (New Jersey) and its partners, contains the following: course outline; 17 lesson…

  17. Ethanol Basics (Fact Sheet)

    SciTech Connect

    Not Available

    2015-01-01

    Ethanol is a widely-used, domestically-produced renewable fuel made from corn and other plant materials. More than 96% of gasoline sold in the United States contains ethanol. Learn more about this alternative fuel in the Ethanol Basics Fact Sheet, produced by the U.S. Department of Energy's Clean Cities program.

  18. Basic Nuclear Physics.

    ERIC Educational Resources Information Center

    Bureau of Naval Personnel, Washington, DC.

    Basic concepts of nuclear structures, radiation, nuclear reactions, and health physics are presented in this text, prepared for naval officers. Applications to the area of nuclear power are described in connection with pressurized water reactors, experimental boiling water reactors, homogeneous reactor experiments, and experimental breeder…

  19. Basic Soils. Revision.

    ERIC Educational Resources Information Center

    Montana State Univ., Bozeman. Dept. of Agricultural and Industrial Education.

    This curriculum guide is designed for use in teaching a course in basic soils that is intended for college freshmen. Addressed in the individual lessons of the unit are the following topics: the way in which soil is formed, the physical properties of soil, the chemical properties of soil, the biotic properties of soil, plant-soil-water…

  20. Flattening basic blocks.

    SciTech Connect

    Utke, J.; Mathematics and Computer Science

    2006-01-01

    The application of cross country elimination strategies requires access to the computational graph or at least subgraphs for certain scopes, e.g. a basic block. Under the presence of aliased variables the construction of these (sub)graphs encounters ambiguities. We propose an algorithm to construct ambiguity free subgraphs.

  1. Lippincott Basic Reading Program.

    ERIC Educational Resources Information Center

    Monterey Peninsula Unified School District, Monterey, CA.

    This program, included in "Effective Reading Programs...," serves 459 students in grades 1-3 at 15 elementary schools. The program employs a diagnostic-prescriptive approach to instruction in a nongraded setting through the use of the Lippincott Basic Reading program. When a child enters the program, he is introduced to a decoding process that…

  2. Basic Self-Esteem.

    ERIC Educational Resources Information Center

    Kaeter, Margaret

    1993-01-01

    Training employees in basic skills necessitates sensitivity to their self-esteem. This can be achieved if the organizational culture supports training, the program is voluntary, it uses the group's strengths, it challenges them on an adult level, it does not resemble traditional schooling, and it builds in quick success. (SK)

  3. Basics of Weight Control

    MedlinePlus

    ... to: • Eat and drink fewer calories • Increase physical activity • Combine the two for the best results The foods you eat and the beverages you drink provide energy and nutrients. The basic required nutrients are: water, carbohydrates, proteins, fats, dietary fibers, vitamins, and minerals. ...

  4. Adult Basic Education Curriculum.

    ERIC Educational Resources Information Center

    Massachusetts Career Development Inst., Springfield.

    This booklet, aimed at adult basic education students, pinpoints and summarizes a few common spelling rules to help make spelling easier, and includes a component on using the dictionary. In the text, each rule is presented with many examples. Exercises follow each spelling rule, allowing students the opportunity to apply the rule to specific…

  5. Swahili Basic Course.

    ERIC Educational Resources Information Center

    Defense Language Inst., Washington, DC.

    This basic audiolingual course in standard Swahili appears in six volumes, Lesson Units 1-56. Units consist of a "blueprint" prefatory page outlining the phonological, morphological, and syntactic structures and new vocabulary to be presented; perception drills; Swahili dialog with cartoon guides and English translation; pattern and recombination…

  6. Turkish Basic Course.

    ERIC Educational Resources Information Center

    Defense Language Inst., Washington, DC.

    These 14 volumes of the Defense Language Institute's basic course in Turkish consist of 112 lesson units designed to train native English language speakers to Level 3 proficiency in comprehending, speaking, reading, and writing Turkish. (Native-speaker fluency is Level 5.) An introduction to the sound system, vowel harmony, and syllable division…

  7. Korean Basic Course.

    ERIC Educational Resources Information Center

    Defense Language Inst., Washington, DC.

    These 11 volumes of the Korean Basic Course comprise 112 lesson units designed to train native English language speakers to Level 3 proficiency in comprehension and speaking and Level 2 proficiency in reading and writing Korean. (Level 5 on this scale is native-speaker level.) Intended for classroom use in the Defense Language Institute intensive…

  8. Assessing Basic Fact Fluency

    ERIC Educational Resources Information Center

    Kling, Gina; Bay-Williams, Jennifer M.

    2014-01-01

    In this article, the authors share a variety of ways to formatively assess basic fact fluency. The define fluency, raise some issues related to timed testing, and then share a collection of classroom-tested ideas for authentic fact fluency assessment. This article encourages teachers to try a variety of alternative assessments from this sampling,…

  9. Computer Programming: BASIC.

    ERIC Educational Resources Information Center

    Fisher, Patience; And Others

    This guide was prepared to help teachers of the Lincoln Public School's introductory computer programming course in BASIC to make the necessary adjustments for changes made in the course since the purchase of microcomputers and such peripheral devices as television monitors and disk drives, and the addition of graphics. Intended to teach a…

  10. Basic Skills: Visual Arts.

    ERIC Educational Resources Information Center

    Kentucky State Dept. of Education, Frankfort.

    A curriculum guide for the visual arts is presented. The goal of elementary and middle school education in the four arts disciplines is the development of basic understanding and skills by every student. In secondary education the aim is to continue a sequential curriculum for those students who study the arts. This document is intended as a guide…

  11. FULA BASIC COURSE.

    ERIC Educational Resources Information Center

    SWIFT, LLOYD B.; AND OTHERS

    THIS BEGINNING COURSE IS AN INTRODUCTION TO FULA (KNOWN VARIOUSLY AS FULANI, FUL, PEUL, OR PHEUL), A NIGER-CONGO LANGUAGE SPOKEN THROUGHOUT THE GRASSLAND AREAS OF WEST AFRICA FROM THE ATLANTIC TO CAMEROUN. THE TEXT IS ONE OF A SERIES OF SHORT BASIC COURSES IN SELECTED AFRICAN LANGUAGES BEING PREPARED BY THE FOREIGN SERVICE INSTITUTE. IT IS…

  12. Basic Engineer Equipment Mechanic.

    ERIC Educational Resources Information Center

    Marine Corps Inst., Washington, DC.

    This student guide, one of a series of correspondence training courses designed to improve the job performance of members of the Marine Corps, deals with the skills needed by basic engineer equipment mechanics. Addressed in the four individual units of the course are the following topics: mechanics and their tools (mechanics, hand tools, and power…

  13. Sara Basic Course.

    ERIC Educational Resources Information Center

    Thayer, James E.; Maraby, Julien

    The basic plan of this course in Sara is modeled after "An Experimental Course in Hausa" (FSI 1965). The course uses short cycles consisting of mimicry followed by conversations built on the same vocabulary and syntactic pattern. The format has been condensed and altered. The course contains 95 cycles and would require approximately 50 hours to…

  14. Mutational and functional analysis of dominant SPT2 (SIN1) suppressor alleles in Saccharomyces cerevisiae.

    PubMed Central

    Lefebvre, L; Smith, M

    1993-01-01

    The Saccharomyces cerevisiae SPT2 gene was identified by genetic screens for mutations which are suppressors of Ty and delta insertional mutations at the HIS4 locus. The ability of spt2 mutations to suppress the transcriptional interference caused by the delta promoter insertion his-4-912 delta correlates with an increase in wild-type HIS4 mRNA levels. The SPT2 gene is identical to SIN1, which codes for a factor genetically defined as a negative regulator of HO transcription. Mutations in SPT2/SIN1 suppress the effects of trans-acting mutations in SWI genes and of partial deletions in the C-terminal domain of the largest subunit of RNA polymerase II. Nuclear localization and protein sequence similarities suggested that the SPT2/SIN1 protein may be related to the nonhistone chromosomal protein HMG1. To assess the significance of this structural similarity and identify domains of SPT2 functionally important in the regulation of his4-912 delta, we have studied recessive and dominant spt2 mutations created by in vitro mutagenesis. We show here that several alleles carrying C-terminal deletions as well as point mutations in the C-terminal domain of the SPT2 protein exhibit a dominant suppressor phenotype. C-terminal basic residues necessary for wild-type SPT2 protein function which are absent from HMG1 have been identified. The competence of these mutant SPT2 proteins to interfere with the maintenance of the His- (Spt+) phenotype of a his4-912 delta SPT2+ strain is lost by deletion of internal HMG1-like sequences and is sensitive to the wild-type SPT2+ gene dosage. Using cross-reacting antipeptide polyclonal antibodies, we demonstrate that the intracellular level of the wild-type SPT2 protein is not affected in presence of dominant mutations and furthermore that the reversion of the dominance by internal deletion of HMG1-like sequences is not mediated by altered production or stability of the mutant polypeptides. Our results suggest that the products of dominant alleles

  15. Basic lubrication equations

    NASA Technical Reports Server (NTRS)

    Hamrock, B. J.; Dowson, D.

    1981-01-01

    Lubricants, usually Newtonian fluids, are assumed to experience laminar flow. The basic equations used to describe the flow are the Navier-Stokes equation of motion. The study of hydrodynamic lubrication is, from a mathematical standpoint, the application of a reduced form of these Navier-Stokes equations in association with the continuity equation. The Reynolds equation can also be derived from first principles, provided of course that the same basic assumptions are adopted in each case. Both methods are used in deriving the Reynolds equation, and the assumptions inherent in reducing the Navier-Stokes equations are specified. Because the Reynolds equation contains viscosity and density terms and these properties depend on temperature and pressure, it is often necessary to couple the Reynolds with energy equation. The lubricant properties and the energy equation are presented. Film thickness, a parameter of the Reynolds equation, is a function of the elastic behavior of the bearing surface. The governing elasticity equation is therefore presented.

  16. Basic Emotions: A Reconstruction

    PubMed Central

    Mason, William A.; Capitanio, John P.

    2016-01-01

    Emotionality is a basic feature of behavior. The argument over whether the expression of emotions is based primarily on culture (constructivism, nurture) or biology (natural forms, nature) will never be resolved because both alternatives are untenable. The evidence is overwhelming that at all ages and all levels of organization, the development of emotionality is epigenetic: The organism is an active participant in its own development. To ascribe these effects to “experience” was the best that could be done for many years. With the rapid acceleration of information on how changes in organization are actually brought about, it is a good time to review, update, and revitalize our views of experience in relation to the concept of basic emotion. PMID:27110280

  17. Basics of Biosafety

    NASA Technical Reports Server (NTRS)

    Wong, Willy

    2009-01-01

    This slide presentation reviews the basics of biosafety and the importance of assuring proper biosafety practices. The objectives of the presentation are to review regulations about biosafety, and the different biosafety levels; the biosafety facilities at Johnson Space Center; the usage and maintenance of the biosafety cabinet, the proper methods to handle biologically hazardous materials upon exposure, and the methods of cleanup in the event of a spill, and the training requirements that are mandated for personnel handling biologically hazardous materials.

  18. The basic anaesthesia machine.

    PubMed

    Gurudatt, Cl

    2013-09-01

    After WTG Morton's first public demonstration in 1846 of use of ether as an anaesthetic agent, for many years anaesthesiologists did not require a machine to deliver anaesthesia to the patients. After the introduction of oxygen and nitrous oxide in the form of compressed gases in cylinders, there was a necessity for mounting these cylinders on a metal frame. This stimulated many people to attempt to construct the anaesthesia machine. HEG Boyle in the year 1917 modified the Gwathmey's machine and this became popular as Boyle anaesthesia machine. Though a lot of changes have been made for the original Boyle machine still the basic structure remains the same. All the subsequent changes which have been brought are mainly to improve the safety of the patients. Knowing the details of the basic machine will make the trainee to understand the additional improvements. It is also important for every practicing anaesthesiologist to have a thorough knowledge of the basic anaesthesia machine for safe conduct of anaesthesia.

  19. The Basic Anaesthesia Machine

    PubMed Central

    Gurudatt, CL

    2013-01-01

    After WTG Morton's first public demonstration in 1846 of use of ether as an anaesthetic agent, for many years anaesthesiologists did not require a machine to deliver anaesthesia to the patients. After the introduction of oxygen and nitrous oxide in the form of compressed gases in cylinders, there was a necessity for mounting these cylinders on a metal frame. This stimulated many people to attempt to construct the anaesthesia machine. HEG Boyle in the year 1917 modified the Gwathmey's machine and this became popular as Boyle anaesthesia machine. Though a lot of changes have been made for the original Boyle machine still the basic structure remains the same. All the subsequent changes which have been brought are mainly to improve the safety of the patients. Knowing the details of the basic machine will make the trainee to understand the additional improvements. It is also important for every practicing anaesthesiologist to have a thorough knowledge of the basic anaesthesia machine for safe conduct of anaesthesia. PMID:24249876

  20. Negative ion generator

    DOEpatents

    Stinnett, Regan W.

    1984-01-01

    A negative ion generator is formed from a magnetically insulated transmission line having a coating of graphite on the cathode for producing negative ions and a plurality of apertures on the opposed anode for the release of negative ions. Magnetic insulation keeps electrons from flowing from the cathode to the anode. A transverse magnetic field removes electrons which do escape through the apertures from the trajectory of the negative ions.

  1. Negative ion generator

    DOEpatents

    Stinnett, R.W.

    1984-05-08

    A negative ion generator is formed from a magnetically insulated transmission line having a coating of graphite on the cathode for producing negative ions and a plurality of apertures on the opposed anode for the release of negative ions. Magnetic insulation keeps electrons from flowing from the cathode to the anode. A transverse magnetic field removes electrons which do escape through the apertures from the trajectory of the negative ions. 8 figs.

  2. Sentential Negation in English

    ERIC Educational Resources Information Center

    Mowarin, Macaulay

    2009-01-01

    This paper undertakes a detailed analysis of sentential negation in the English language with Chomsky's Government-Binding theory of Transformational Grammar as theoretical model. It distinguishes between constituent and sentential negation in English. The essay identifies the exact position of Negation phrase in an English clause structure. It…

  3. A New Method to Assess Eye Dominance

    ERIC Educational Resources Information Center

    Valle-Inclan, Fernando; Blanco, Manuel J.; Soto, David; Leiros, Luz

    2008-01-01

    People usually show a stable preference for one of their eyes when monocular viewing is required ("sighting dominance") or under dichoptic stimulation conditions ("sensory eye-dominance"). Current procedures to assess this "eye dominance" are prone to error. Here we present a new method that provides a continuous measure of eye dominance and…

  4. Negative incidental emotions augment fairness sensitivity.

    PubMed

    Liu, Cuizhen; Chai, Jing Wen; Yu, Rongjun

    2016-01-01

    Previous studies have shown that task-unrelated emotions induced incidentally exert carryover effects on individuals' subsequent decisions in financial negotiations. However, the specificity of these emotion effects are not clear. In three experiments, we systematically investigated the role of seven transiently induced basic emotions (disgust, sadness, anger, fear, happiness, surprise and neutral) on rejection of unfair offers using the ultimatum game. We found that all negative emotions (disgust, sadness, anger and fear), but not happiness or surprise, significantly increased rejection rates, suggesting that the effect of incidental negative emotions on fairness is not specific to the type of negative emotion. Our findings highlight the role of fleeting emotions in biasing decision-making processes and suggest that all incidental negative emotions exert similar effects on fairness sensitivity, possibly by potentiating attention towards negative aspects of the situation. PMID:27101931

  5. Negative incidental emotions augment fairness sensitivity

    PubMed Central

    Liu, Cuizhen; Chai, Jing Wen; Yu, Rongjun

    2016-01-01

    Previous studies have shown that task-unrelated emotions induced incidentally exert carryover effects on individuals’ subsequent decisions in financial negotiations. However, the specificity of these emotion effects are not clear. In three experiments, we systematically investigated the role of seven transiently induced basic emotions (disgust, sadness, anger, fear, happiness, surprise and neutral) on rejection of unfair offers using the ultimatum game. We found that all negative emotions (disgust, sadness, anger and fear), but not happiness or surprise, significantly increased rejection rates, suggesting that the effect of incidental negative emotions on fairness is not specific to the type of negative emotion. Our findings highlight the role of fleeting emotions in biasing decision-making processes and suggest that all incidental negative emotions exert similar effects on fairness sensitivity, possibly by potentiating attention towards negative aspects of the situation. PMID:27101931

  6. A Composite Element that Binds Basic Helix Loop Helix and Basic Leucine Zipper Transcription Factors Is Important for Gonadotropin-Releasing Hormone Regulation of the Follicle-Stimulating Hormone β Gene

    PubMed Central

    Ciccone, Nick A.; Lacza, Charlemagne T.; Hou, Melody Y.; Gregory, Susan J.; Kam, Kyung-Yoon; Xu, Shuyun; Kaiser, Ursula B.

    2008-01-01

    Although FSH plays an essential role in controlling gametogenesis, the biology of FSHβ transcription remains poorly understood, but is known to involve the complex interplay of multiple endocrine factors including GnRH. We have identified a GnRH-responsive element within the rat FSHβ promoter containing an E-box and partial cAMP response element site that are bound by the basic helix loop helix transcription factor family members, upstream stimulating factor (USF)-1/USF-2, and the basic leucine zipper member, cAMP response element-binding protein (CREB), respectively. Expression studies with CREB, USF-1/USF-2, and activating protein-1 demonstrated that the USF transcription factors increased basal transcription, an effect not observed if the cognate binding site was mutated. Conversely, expression of a dominant negative CREB mutant or CREB knockdown attenuated induction by GnRH, whereas dominant negative Fos or USF had no effect on the GnRH response. GnRH stimulation specifically induced an increase in phosphorylated CREB occupation of the FSHβ promoter, leading to the recruitment of CREB-binding protein to enhance gene transcription. In conclusion, a composite element bound by both USF and CREB serves to integrate signals for basal and GnRH-stimulated transcription of the rat FSHβ gene. PMID:18550775

  7. Numerically dominant denitrifying bacteria from world soils.

    PubMed

    Gamble, T N; Betlach, M R; Tiedje, J M

    1977-04-01

    Nineteen soils, three freshwater lake sediments, and oxidized poultry manure were examined to determine the dominant denitrifier populations. The samples, most shown or expected to support active denitrification, were from eight countries and included rice paddy, temperate agricultural, rain forest, organic, and waste-treated soils. Over 1,500 organisms that could grow anaerobically on nitrate agar were isolated. After purification, 146 denitrifiers were obtained, as verified by production of N(2) from NO(3) (-). These isolates were characterized by 52 properties appropriate for the Pseudomonas-Alcaligenes group. Numerical taxonomic procedures were used to group the isolates and compare them with nine known denitrifier species. The major group isolated was representative of Pseudonomas fluorescens biotype II. The second most prevalent group was representative of Alcaligenes. Other Pseudomonas species as well as members of the genus Flavobacterium, the latter previously not known to denitrify, also were identified. One-third of the isolates could not utilize glucose or other carbohydrates as sole carbon sources. Significantly, none of the numerically dominant denitrifiers we isolated resembled the most studied species: Pseudomonas denitrificans, Pseudomonas perfectomarinus, and Paracoccus denitrificans. Denitrification appears to be a property of a very diverse group of gram-negative, motile bacteria, as shown by the large number (22.6%) of ungrouped organisms. The diversity of denitrifiers from a given sample was usually high, with at least two groups present. Denitrifiers, nitrite accumulators, and organisms capable of anaerobic growth were present in the ratio of 0.20+/-0.23:0.81+/-0.23:1. There were few correlations between their numbers and the sample characteristics measured. However, the temperatures at which isolates could grow were significantly related to the temperatures of the environments from which they were isolated. Regression analysis revealed few

  8. Basic Hitchhiker Payload Requirements

    NASA Technical Reports Server (NTRS)

    Horan, Stephen

    1999-01-01

    This document lists the requirements for the NMSU Hitchhiker experiment payload that were developed as part of the EE 498/499 Capstone Design class during the 1999-2000 academic year. This document is used to describe the system needs as described in the mission document. The requirements listed here are those primarily used to generate the basic electronic and data processing requirements developed in the class design document. The needs of the experiment components are more fully described in the draft NASA hitchhiker customer requirements document. Many of the details for the overall payload are given in full detail in the NASA hitchhiker documentation.

  9. Basic genetics for dermatologists.

    PubMed

    Kumaran, Muthu Sendhil; De, Dipankar

    2013-01-01

    During the past few decades, advances in the field of molecular genetics have enriched us in understanding the pathogenesis of diseases, their identification, and appropriate therapeutic interventions. In the last 20 years, genetic basis of more than 350 monogenic skin diseases have been elucidated and is counting. The widespread use of molecular genetics as a tool in diagnosis is not practiced routinely due to genetic heterogenicity, limited access and low sensitivity. In this review, we have presented the very basics of genetics so as to enable dermatologists to have working understanding of medical genetics.

  10. Basic Religious Beliefs and Personality Traits

    PubMed Central

    Rajaei, Ali Reza; Sarvarazemy, Ahmad

    2012-01-01

    Objective Spiritual beliefs can help people find meaning of life, and can also influence their feelings, behaviors and mental health. The present research studied the relationship between basic religious beliefs (Human, Existence and God) and five personality factors: neuroticism, extraversion, openness, agreeableness, conscientiousness. Method One hundred seventy eight students of Islamic Azad University in Torbat-jam were randomly selected and completed the basic religious beliefs and NEO Questionnaires. Results Data showed that basic religious beliefs have a significant negative correlation with neuroticism (r=-0.29),and a significant positive relationship with extraversion(r=0.28),openness(r=0.14),agreeableness (r=0.29),and conscientiousness (r=0.48). Also, the results of the regression analysis showed that basic religious beliefs can anticipate neuroticism, extraversion, agreeableness and conscientiousness, but they cannot anticipate the openness factor significantly. Conclusion The findings of this study demonstrate that basic religious beliefs have a positive relationship with good characteristics that help people resolve the challenges of their lives and identity crisis. Thus, the results of this study support the idea of Religious Cognitive–Emotional Theory that religiosity is correlated with positive personality traits. PMID:22952550

  11. Basic space payload fastener

    NASA Technical Reports Server (NTRS)

    Vranish, J. M.; Gorevan, Stephen

    1995-01-01

    A new basic space fastener has been developed and tested by the GSFC. The purposes of this fastener are to permit assembly and servicing in space by astronauts and/or robots and to facilitate qualification of payloads on Earth prior to launch by saving time and money during the systems integration and component testing and qualification processes. The space fastener is a rework of the basic machine screw such that crossthreading is impossible; it is self-locking and will not work its way out during launch (vibration proof); it will not wear out despite repeated use; it occupies a small foot print which is comparable to its machine screw equivalent, and it provides force and exhibits strength comparable to its machine screw equivalent. Construction is ultra-simple and cost effective and the principle is applicable across the full range of screw sizes ranging from a #10 screw to 2.5 cm (1 in) or more. In this paper, the fastener principles of operation will be discussed along with test results and construction details. The new fastener also has considerable potential in the commercial sector. A few promising applications will be presented.

  12. Basic and clinical immunology

    NASA Technical Reports Server (NTRS)

    Chinen, Javier; Shearer, William T.

    2003-01-01

    Progress in immunology continues to grow exponentially every year. New applications of this knowledge are being developed for a broad range of clinical conditions. Conversely, the study of primary and secondary immunodeficiencies is helping to elucidate the intricate mechanisms of the immune system. We have selected a few of the most significant contributions to the fields of basic and clinical immunology published between October 2001 and October 2002. Our choice of topics in basic immunology included the description of T-bet as a determinant factor for T(H)1 differentiation, the role of the activation-induced cytosine deaminase gene in B-cell development, the characterization of CD4(+)CD25(+) regulatory T cells, and the use of dynamic imaging to study MHC class II transport and T-cell and dendritic cell membrane interactions. Articles related to clinical immunology that were selected for review include the description of immunodeficiency caused by caspase 8 deficiency; a case series report on X-linked agammaglobulinemia; the mechanism of action, efficacy, and complications of intravenous immunoglobulin; mechanisms of autoimmunity diseases; and advances in HIV pathogenesis and vaccine development. We also reviewed two articles that explore the possible alterations of the immune system caused by spaceflights, a new field with increasing importance as human space expeditions become a reality in the 21st century.

  13. Negative Ion Density Fronts

    SciTech Connect

    Igor Kaganovich

    2000-12-18

    Negative ions tend to stratify in electronegative plasmas with hot electrons (electron temperature Te much larger than ion temperature Ti, Te > Ti ). The boundary separating a plasma containing negative ions, and a plasma, without negative ions, is usually thin, so that the negative ion density falls rapidly to zero-forming a negative ion density front. We review theoretical, experimental and numerical results giving the spatio-temporal evolution of negative ion density fronts during plasma ignition, the steady state, and extinction (afterglow). During plasma ignition, negative ion fronts are the result of the break of smooth plasma density profiles during nonlinear convection. In a steady-state plasma, the fronts are boundary layers with steepening of ion density profiles due to nonlinear convection also. But during plasma extinction, the ion fronts are of a completely different nature. Negative ions diffuse freely in the plasma core (no convection), whereas the negative ion front propagates towards the chamber walls with a nearly constant velocity. The concept of fronts turns out to be very effective in analysis of plasma density profile evolution in strongly non-isothermal plasmas.

  14. Basic memory module

    NASA Technical Reports Server (NTRS)

    Tietze, F. C.

    1974-01-01

    Construction and electrical characterization of the 4096 x 2-bit Basic Memory Module (BMM) are reported for the Space Ultrareliable Modular Computer (SUMC) program. The module uses four 2K x 1-bit N-channel FET, random access memory chips, called array chips, and two sense amplifier chips, mounted and interconnected on a ceramic substrate. Four 5% tolerance power supplies are required. At the Module, the address, chip select, and array select lines require a 0-8.5 V MOS signal level. The data output, read-strobe, and write-enable lines operate at TTl levels. Although the module is organized as 4096 x 2 bits, it can be used in a 8196 x 1-bit application with appropriate external connections. A 4096 x 1-bit organization can be obtained by depopulating chips.

  15. Basic properties and variability

    NASA Technical Reports Server (NTRS)

    Querci, Francois R.

    1987-01-01

    Giant and supergiant M, S, and C stars are discussed in this survey of research. Basic properties as determined by spectra, chemical composition, photometry, or variability type are discussed. Space motions and space distributions of cool giants are described. Distribution of these stars in our galaxy and those nearby is discussed. Mira variables in particular are surveyed with emphasis on the following topics: (1) phase lag phenomenon; (2) Mira light curves; (3) variations in color indices; (4) determination of multiple periods; (5) correlations between quantities such as period length, light-curve shape, infrared (IR) excess, and visible and IR color diagram; (6) semiregular (SR) variables and different time scales in SR light variations; (7) irregular variable Lb and Lc stars; (8) different time-scale light variations; (9) hydrogen-deficient carbon (HdC) stars, in particular RCB stars; and (10) irreversible changes and rapid evolution in red variable stars.

  16. BasicODT

    2007-09-25

    BasicODT is a Monte Carlo simulation that numerically implements One-Dimensional Turbulence (ODT), a stochastic model of turbulent flow that was developed by the author of the code. This code is set up to simulate channel flow, which is the flow between two parallel flat walls driven by a fixed pressure gradient, with no-slip conditions at the walls. The code writes output files containing flow statistics gathered during the simulation. The code is accompanied by documentationmore » that explains how ODT modeling principles are numerically implemented within the code. The code and documentation are intended as an introduction to ODT for use as a learning tool for people who are unfamiliar with the model and its numerical implementation. ODT is fully described in published literature.« less

  17. Basic obstetric pharmacology.

    PubMed

    Zhao, Yang; Hebert, Mary F; Venkataramanan, Raman

    2014-12-01

    Pregnancy is associated with a variety of physiological changes that can alter the pharmacokinetics and pharmacodynamics of several drugs. However, limited data exists on the pharmacokinetics and pharmacodynamics of the majority of the medications used in pregnancy. In this article, we first describe basic concepts (drug absorption, bioavailability, distribution, metabolism, elimination, and transport) in pharmacokinetics. Then, we discuss several physiological changes that occur during pregnancy that theoretically affect absorption, distribution, metabolism, and elimination. Further, we provide a brief review of the literature on the clinical pharmacokinetic studies performed in pregnant women in recent years. In general, pregnancy increases the clearance of several drugs and correspondingly decreases drug exposure during pregnancy. Based on current drug exposure measurements during pregnancy, alterations in the dose or dosing regimen of certain drugs are essential during pregnancy. More pharmacological studies in pregnant women are needed to optimize drug therapy in pregnancy.

  18. Atomic Basic Blocks

    NASA Astrophysics Data System (ADS)

    Scheler, Fabian; Mitzlaff, Martin; Schröder-Preikschat, Wolfgang

    Die Entscheidung, einen zeit- bzw. ereignisgesteuerten Ansatz für ein Echtzeitsystem zu verwenden, ist schwierig und sehr weitreichend. Weitreichend vor allem deshalb, weil diese beiden Ansätze mit äußerst unterschiedlichen Kontrollflussabstraktionen verknüpft sind, die eine spätere Migration zum anderen Paradigma sehr schwer oder gar unmöglich machen. Wir schlagen daher die Verwendung einer Zwischendarstellung vor, die unabhängig von der jeweils verwendeten Kontrollflussabstraktion ist. Für diesen Zweck verwenden wir auf Basisblöcken basierende Atomic Basic Blocks (ABB) und bauen darauf ein Werkzeug, den Real-Time Systems Compiler (RTSC) auf, der die Migration zwischen zeit- und ereignisgesteuerten Systemen unterstützt.

  19. Plant invasions differentially affected by diversity and dominant species in native- and exotic-dominated grasslands.

    PubMed

    Xu, Xia; Polley, H Wayne; Hofmockel, Kirsten; Daneshgar, Pedram P; Wilsey, Brian J

    2015-12-01

    Plant invasions are an increasingly serious global concern, especially as the climate changes. Here, we explored how plant invasions differed between native- and novel exotic-dominated grasslands with experimental addition of summer precipitation in Texas in 2009. Exotic species greened up earlier than natives by an average of 18 days. This was associated with a lower invasion rate early in the growing season compared to native communities. However, invasion rate did not differ significantly between native and exotic communities across all sampling times. The predictors of invasion rate differed between native and exotic communities, with invasion being negatively influenced by species richness in natives and by dominant species in exotics. Interestingly, plant invasions matched the bimodal pattern of precipitation in Temple, Texas, and did not respond to the pulse of precipitation during the summer. Our results suggest that we will need to take different approaches in understanding of invasion between native and exotic grasslands. Moreover, with anticipated increasing variability in precipitation under global climate change, plant invasions may be constrained in their response if the precipitation pulses fall outside the normal growing period of invaders.

  20. Plant invasions differentially affected by diversity and dominant species in native- and exotic-dominated grasslands.

    PubMed

    Xu, Xia; Polley, H Wayne; Hofmockel, Kirsten; Daneshgar, Pedram P; Wilsey, Brian J

    2015-12-01

    Plant invasions are an increasingly serious global concern, especially as the climate changes. Here, we explored how plant invasions differed between native- and novel exotic-dominated grasslands with experimental addition of summer precipitation in Texas in 2009. Exotic species greened up earlier than natives by an average of 18 days. This was associated with a lower invasion rate early in the growing season compared to native communities. However, invasion rate did not differ significantly between native and exotic communities across all sampling times. The predictors of invasion rate differed between native and exotic communities, with invasion being negatively influenced by species richness in natives and by dominant species in exotics. Interestingly, plant invasions matched the bimodal pattern of precipitation in Temple, Texas, and did not respond to the pulse of precipitation during the summer. Our results suggest that we will need to take different approaches in understanding of invasion between native and exotic grasslands. Moreover, with anticipated increasing variability in precipitation under global climate change, plant invasions may be constrained in their response if the precipitation pulses fall outside the normal growing period of invaders. PMID:27069615

  1. Basic Blood Tests (For Parents)

    MedlinePlus

    ... What to Say Vaccines: Which Ones & When? Smart School Lunches Emmy-Nominated Video "Cerebral Palsy: Shannon's Story" 5 Things to Know About Zika & Pregnancy Basic Blood Chemistry Tests KidsHealth > For Parents > Basic Blood Chemistry Tests ...

  2. Influence of refractive correction on ocular dominance

    NASA Astrophysics Data System (ADS)

    Nakayama, Nanami; Kawamorita, Takushi; Uozato, Hiroshi

    2010-07-01

    We investigated the effects of refractive correction and refractive defocus on the assessment of sensory ocular dominance. In 25 healthy subjects (4 males and 21 females) aged between 20 and 31 years, a quantitative measurement of sensory ocular dominance was performed with refractive correction and the addition of a positive lens on the dominant eye. Sensory ocular dominance was measured with a chart using binocular rivalry targets. The reversal point changed after the addition of a +1.00 D lens on the dominant eye in all subjects. However, sighting ocular dominance and stereopsis did not change after the addition of a positive lens on the dominant eye ( P > 0:05, Wilcoxon test). These results suggest that refractive correction affects sensory ocular dominance, indicating the possible development of a new type of occlusion for amblyopia in the future.

  3. Negative Questions in Chinese

    ERIC Educational Resources Information Center

    Yat-shing, Cheung

    1974-01-01

    Mainly concerned with where negative questions in Chinese originate.An abstract treatment allows the derviation of all questions from a general underlying structure with disjunctive pattern and accounts for the discordance between the answer to a negative question and its answer particle. (Author/RM)

  4. 38 CFR 4.69 - Dominant hand.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2013-07-01 2013-07-01 false Dominant hand. 4.69... DISABILITIES Disability Ratings The Musculoskeletal System § 4.69 Dominant hand. Handedness for the purpose of.... Only one hand shall be considered dominant. The injured hand, or the most severely injured hand, of...

  5. 38 CFR 4.69 - Dominant hand.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false Dominant hand. 4.69... DISABILITIES Disability Ratings The Musculoskeletal System § 4.69 Dominant hand. Handedness for the purpose of.... Only one hand shall be considered dominant. The injured hand, or the most severely injured hand, of...

  6. 38 CFR 4.69 - Dominant hand.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2014-07-01 2014-07-01 false Dominant hand. 4.69... DISABILITIES Disability Ratings The Musculoskeletal System § 4.69 Dominant hand. Handedness for the purpose of.... Only one hand shall be considered dominant. The injured hand, or the most severely injured hand, of...

  7. 38 CFR 4.69 - Dominant hand.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2012-07-01 2012-07-01 false Dominant hand. 4.69... DISABILITIES Disability Ratings The Musculoskeletal System § 4.69 Dominant hand. Handedness for the purpose of.... Only one hand shall be considered dominant. The injured hand, or the most severely injured hand, of...

  8. 5 CFR 532.305 - Dominant industry.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 5 Administrative Personnel 1 2012-01-01 2012-01-01 false Dominant industry. 532.305 Section 532... SYSTEMS Determining Rates for Principal Types of Positions § 532.305 Dominant industry. (a)(1) A specialized industry is a “dominant industry” if the number of wage employees in the wage area who are...

  9. 5 CFR 532.305 - Dominant industry.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Dominant industry. 532.305 Section 532... SYSTEMS Determining Rates for Principal Types of Positions § 532.305 Dominant industry. (a)(1) A specialized industry is a “dominant industry” if the number of wage employees in the wage area who are...

  10. 5 CFR 532.305 - Dominant industry.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 5 Administrative Personnel 1 2013-01-01 2013-01-01 false Dominant industry. 532.305 Section 532... SYSTEMS Determining Rates for Principal Types of Positions § 532.305 Dominant industry. (a)(1) A specialized industry is a “dominant industry” if the number of wage employees in the wage area who are...

  11. 5 CFR 532.305 - Dominant industry.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 5 Administrative Personnel 1 2011-01-01 2011-01-01 false Dominant industry. 532.305 Section 532... SYSTEMS Determining Rates for Principal Types of Positions § 532.305 Dominant industry. (a)(1) A specialized industry is a “dominant industry” if the number of wage employees in the wage area who are...

  12. 5 CFR 532.305 - Dominant industry.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Dominant industry. 532.305 Section 532... SYSTEMS Determining Rates for Principal Types of Positions § 532.305 Dominant industry. (a)(1) A specialized industry is a “dominant industry” if the number of wage employees in the wage area who are...

  13. Bulk viscous matter-dominated Universes: asymptotic properties

    SciTech Connect

    Avelino, Arturo; García-Salcedo, Ricardo; Gonzalez, Tame; Nucamendi, Ulises; Quiros, Israel E-mail: rigarcias@ipn.mx E-mail: ulises@ifm.umich.mx

    2013-08-01

    By means of a combined use of the type Ia supernovae and H(z) data tests, together with the study of the asymptotic properties in the equivalent phase space — through the use of the dynamical systems tools — we demonstrate that the bulk viscous matter-dominated scenario is not a good model to explain the accepted cosmological paradigm, at least, under the parametrization of bulk viscosity considered in this paper. The main objection against such scenarios is the absence of conventional radiation and matter-dominated critical points in the phase space of the model. This entails that radiation and matter dominance are not generic solutions of the cosmological equations, so that these stages can be implemented only by means of unique and very specific initial conditions, i. e., of very unstable particular solutions. Such a behavior is in marked contradiction with the accepted cosmological paradigm which requires of an earlier stage dominated by relativistic species, followed by a period of conventional non-relativistic matter domination, during which the cosmic structure we see was formed. Also, we found that the bulk viscosity is positive just until very late times in the cosmic evolution, around z < 1. For earlier epochs it is negative, been in tension with the local second law of thermodynamics.

  14. Basic concepts of epigenetics

    PubMed Central

    Mazzio, Elizabeth A

    2012-01-01

    Through epigenetic modifications, specific long-term phenotypic consequences can arise from environmental influence on slowly evolving genomic DNA. Heritable epigenetic information regulates nucleosomal arrangement around DNA and determines patterns of gene silencing or active transcription. One of the greatest challenges in the study of epigenetics as it relates to disease is the enormous diversity of proteins, histone modifications and DNA methylation patterns associated with each unique maladaptive phenotype. This is further complicated by a limitless combination of environmental cues that could alter the epigenome of specific cell types, tissues, organs and systems. In addition, complexities arise from the interpretation of studies describing analogous but not identical processes in flies, plants, worms, yeast, ciliated protozoans, tumor cells and mammals. This review integrates fundamental basic concepts of epigenetics with specific focus on how the epigenetic machinery interacts and operates in continuity to silence or activate gene expression. Topics covered include the connection between DNA methylation, methyl-CpG-binding proteins, transcriptional repression complexes, histone residues, histone modifications that mediate gene repression or relaxation, histone core variant stability, H1 histone linker flexibility, FACT complex, nucleosomal remodeling complexes, HP1 and nuclear lamins. PMID:22395460

  15. Basic science of osteoarthritis.

    PubMed

    Cucchiarini, Magali; de Girolamo, Laura; Filardo, Giuseppe; Oliveira, J Miguel; Orth, Patrick; Pape, Dietrich; Reboul, Pascal

    2016-12-01

    Osteoarthritis (OA) is a prevalent, disabling disorder of the joints that affects a large population worldwide and for which there is no definitive cure. This review provides critical insights into the basic knowledge on OA that may lead to innovative end efficient new therapeutic regimens. While degradation of the articular cartilage is the hallmark of OA, with altered interactions between chondrocytes and compounds of the extracellular matrix, the subchondral bone has been also described as a key component of the disease, involving specific pathomechanisms controlling its initiation and progression. The identification of such events (and thus of possible targets for therapy) has been made possible by the availability of a number of animal models that aim at reproducing the human pathology, in particular large models of high tibial osteotomy (HTO). From a therapeutic point of view, mesenchymal stem cells (MSCs) represent a promising option for the treatment of OA and may be used concomitantly with functional substitutes integrating scaffolds and drugs/growth factors in tissue engineering setups. Altogether, these advances in the fundamental and experimental knowledge on OA may allow for the generation of improved, adapted therapeutic regimens to treat human OA. PMID:27624438

  16. [Basic research in pulmonology].

    PubMed

    Gea, Joaquim

    2008-11-01

    This is a review of the articles dealing with basic science published in recent issues of Archivos de Bronconeumología. Of particular interest with regard to chronic obstructive pulmonary disease were an article on extrapulmonary inflammation and oxidative stress and another on bronchial remodeling. The articles relating to asthma included a review on the use of drugs that block free immunoglobulin-E and an article about the contribution of experimental models to our knowledge of this disease. Two of the most interesting articles on the topic of lung cancer dealt with gene therapy and resistance to chemotherapy. Also notable were 2 studies that investigated ischemia-reperfusion injury. One evaluated tissue resistance to injury while the other analyzed the role played by interleukin-8 in this process. On the topic of pulmonary fibrosis, an article focused on potential biomarkers of progression and prognosis; others dealt with the contribution of experimental models to our understanding of this disorder and the fibrogenic role of transforming growth factor b. In the context of both sleep apnea syndrome and pulmonary infection, studies investigating the role of oxidative stress were published. Finally, 2 studies analyzed the diagnosis and treatment of tuberculosis and other pulmonary infections. PMID:19007569

  17. Negative Coulomb Drag in Double Bilayer Graphene.

    PubMed

    Li, J I A; Taniguchi, T; Watanabe, K; Hone, J; Levchenko, A; Dean, C R

    2016-07-22

    We report on an experimental measurement of Coulomb drag in a double quantum well structure consisting of bilayer-bilayer graphene, separated by few layer hexagonal boron nitride. At low temperatures and intermediate densities, a novel negative drag response with an inverse sign is observed, distinct from the momentum and energy drag mechanisms previously reported in double monolayer graphene. By varying the device aspect ratio, the negative drag component is suppressed and a response consistent with pure momentum drag is recovered. In the momentum drag dominated regime, excellent quantitative agreement with the density and temperature dependence predicted for double bilayer graphene is found. PMID:27494491

  18. Negative Coulomb Drag in Double Bilayer Graphene.

    PubMed

    Li, J I A; Taniguchi, T; Watanabe, K; Hone, J; Levchenko, A; Dean, C R

    2016-07-22

    We report on an experimental measurement of Coulomb drag in a double quantum well structure consisting of bilayer-bilayer graphene, separated by few layer hexagonal boron nitride. At low temperatures and intermediate densities, a novel negative drag response with an inverse sign is observed, distinct from the momentum and energy drag mechanisms previously reported in double monolayer graphene. By varying the device aspect ratio, the negative drag component is suppressed and a response consistent with pure momentum drag is recovered. In the momentum drag dominated regime, excellent quantitative agreement with the density and temperature dependence predicted for double bilayer graphene is found.

  19. Negative Coulomb Drag in Double Bilayer Graphene

    NASA Astrophysics Data System (ADS)

    Li, J. I. A.; Taniguchi, T.; Watanabe, K.; Hone, J.; Levchenko, A.; Dean, C. R.

    2016-07-01

    We report on an experimental measurement of Coulomb drag in a double quantum well structure consisting of bilayer-bilayer graphene, separated by few layer hexagonal boron nitride. At low temperatures and intermediate densities, a novel negative drag response with an inverse sign is observed, distinct from the momentum and energy drag mechanisms previously reported in double monolayer graphene. By varying the device aspect ratio, the negative drag component is suppressed and a response consistent with pure momentum drag is recovered. In the momentum drag dominated regime, excellent quantitative agreement with the density and temperature dependence predicted for double bilayer graphene is found.

  20. Radiative Torques: Analytical Model And Basic Properties

    NASA Astrophysics Data System (ADS)

    Hoang, Thiem; Lazarian, A.

    2007-05-01

    We attempt to get a physical insight into grain alignment processes by studying basic properties of radiative torques (RATs). For this purpose we consider a simple toy model of a helical grain that reproduces well the basic features of RATs. The model grain consists of a reflecting spheroidal body with a reflecting mirror attached at an angle to it. Being very simple, the model allows analytical description of RATs that act upon it. We show a good correspondence of RATs obtained for this model and those of irregular grains calculated by DDSCAT. Our analysis of the role of different torque components for grain alignment reveals that one of the three RAT components does not affect the alignment, but induces only for grain precession. The other two components provide a generic alignment with grain long axes perpendicular to the light radiation, if the radiation dominates the grain precession, and perpendicular to magnetic field, otherwise. The latter coincides with the famous predictions of the Davis-Greenstein process, but our model does not invoke paramagnetic relaxation. In addition, we find that a substantial part of grains subjected to RATs gets aligned with low angular momentum, which testifies, that most of the grains in diffuse interstellar medium do not rotate fast, i.e. rotate with thermal or even sub-thermal velocities. For the radiation-dominated environments, we find that the alignment can take place on the time scale much shorter than the time of gaseous damping of grain rotation.

  1. Negative electrodes for lithium cells and batteries

    DOEpatents

    Vaughey, John T.; Fransson, Linda M.; Thackeray, Michael M.

    2005-02-15

    A negative electrode is disclosed for a non-aqueous electrochemical cell. The electrode has an intermetallic compound as its basic structural unit with the formula M.sub.2 M' in which M and M' are selected from two or more metal elements including Si, and the M.sub.2 M' structure is a Cu.sub.2 Sb-type structure. Preferably M is Cu, Mn and/or Li, and M' is Sb. Also disclosed is a non-aqueous electrochemical cell having a negative electrode of the type described, an electrolyte and a positive electrode. A plurality of cells may be arranged to form a battery.

  2. Kriging without negative weights

    SciTech Connect

    Szidarovszky, F.; Baafi, E.Y.; Kim, Y.C.

    1987-08-01

    Under a constant drift, the linear kriging estimator is considered as a weighted average of n available sample values. Kriging weights are determined such that the estimator is unbiased and optimal. To meet these requirements, negative kriging weights are sometimes found. Use of negative weights can produce negative block grades, which makes no practical sense. In some applications, all kriging weights may be required to be nonnegative. In this paper, a derivation of a set of nonlinear equations with the nonnegative constraint is presented. A numerical algorithm also is developed for the solution of the new set of kriging equations.

  3. Negative birefringent polyimide films

    NASA Technical Reports Server (NTRS)

    Harris, Frank W. (Inventor); Cheng, Stephen Z. D. (Inventor)

    1994-01-01

    A negative birefringent film, useful in liquid crystal displays, and a method for controlling the negative birefringence of a polyimide film is disclosed which allows the matching of an application to a targeted amount of birefringence by controlling the degree of in-plane orientation of the polyimide by the selection of functional groups within both the diamine and dianhydride segments of the polyimide which affect the polyimide backbone chain rigidity, linearity, and symmetry. The higher the rigidity, linearity and symmetry of the polyimide backbone, the larger the value of the negative birefringence of the polyimide film.

  4. DNA Shape Dominates Sequence Affinity in Nucleosome Formation

    NASA Astrophysics Data System (ADS)

    Freeman, Gordon S.; Lequieu, Joshua P.; Hinckley, Daniel M.; Whitmer, Jonathan K.; de Pablo, Juan J.

    2014-10-01

    Nucleosomes provide the basic unit of compaction in eukaryotic genomes, and the mechanisms that dictate their position at specific locations along a DNA sequence are of central importance to genetics. In this Letter, we employ molecular models of DNA and proteins to elucidate various aspects of nucleosome positioning. In particular, we show how DNA's histone affinity is encoded in its sequence-dependent shape, including subtle deviations from the ideal straight B-DNA form and local variations of minor groove width. By relying on high-precision simulations of the free energy of nucleosome complexes, we also demonstrate that, depending on DNA's intrinsic curvature, histone binding can be dominated by bending interactions or electrostatic interactions. More generally, the results presented here explain how sequence, manifested as the shape of the DNA molecule, dominates molecular recognition in the problem of nucleosome positioning.

  5. Golgi membrane dynamics after induction of a dominant-negative mutant Sar1 GTPase in tobacco.

    PubMed

    Osterrieder, Anne; Hummel, Eric; Carvalho, Claudine M; Hawes, Chris

    2010-01-01

    An inducible system has been established in Nicotiana tabacum plants allowing controlled expression of Sar1-GTP and thus the investigation of protein dynamics after inhibition of endoplasmic reticulum (ER) to Golgi transport. Complete Golgi disassembly and redistribution of Golgi markers into the ER was observed within 18-24h after induction. At the ultrastructural level Sar1-GTP expression led to a decrease in Golgi stack size followed by Golgi fragmentation and accumulation of vesicle remnants. Induction of Sar1-GTP resulted in redistribution of the green fluorescent protein (GFP)-tagged Arabidopsis golgins AtCASP and GC1 (golgin candidate 1, an Arabidopsis golgin 84 isoform) into the ER or cytoplasm, respectively. Additionally, both fusion proteins were observed in punctate structures, which co-located with a yellow fluorescent protein (YFP)-tagged version of Sar1-GTP. The Sar1-GTP-inducible system is compared with constitutive Sar1-GTP expression and brefeldin A treatment, and its potential for the study of the composition of ER exit sites and early cis-Golgi structures is discussed. PMID:19861656

  6. MicroRNA-146a: A Dominant, Negative Regulator of the Innate Immune Response

    PubMed Central

    Saba, Reuben; Sorensen, Debra L.; Booth, Stephanie A.

    2014-01-01

    MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that can play critical roles as regulators of numerous pathways and biological processes including the immune response. Emerging as one of the most important miRNAs to orchestrate immune and inflammatory signaling, often through its recognized target genes, IRAK1 and TRAF6, is microRNA-146a (miR-146a). MiR-146a is one, of a small number of miRNAs, whose expression is strongly induced following challenge of cells with bacterial endotoxin, and prolonged expression has been linked to immune tolerance, implying that it acts as a fine-tuning mechanism to prevent an overstimulation of the inflammatory response. In other cells, miR-146a has been shown to play a role in the control of the differentiation of megakaryocytic and monocytic lineages, adaptive immunity, and cancer. In this review, we discuss the central role prescribed to miR-146a in innate immunity. We particularly focus on the role played by miR-146a in the regulation and signaling mediated by one of the main pattern recognition receptors, toll/IL-1 receptors (TLRs). Additionally, we also discuss the role of miR-146a in several classes of autoimmune pathologies where this miRNA has been shown to be dysregulated, as well as its potential role in the pathobiology of neurodegenerative diseases. PMID:25484882

  7. A dominant negative form of p63 inhibits apoptosis in a p53-independent manner

    SciTech Connect

    Lee, Hae-ock; Lee, Jung-Hwa; Choi, Eunhee; Seol, Ja Young; Yun, Yungdae; Lee, Hyunsook . E-mail: HL212@snu.ac.kr

    2006-05-26

    Stem cells are a source of differentiated cells in multiple tissues. If genetic alterations occur in stem cells, the problem persists and malignant cancers may arise. {delta}Np63{alpha}-a homologue of the tumor suppressor p53-is exclusively expressed in proliferating undifferentiated epithelial cells and cancer cells of epidermal origin. Here, we show that {delta}Np63{alpha} antagonizes DNA damage-induced apoptosis in a p53-independent manner. We found that upon cellular injury, {delta}Np63{alpha} must be downregulated before apoptotic program can be activated. The 5637 cell line has abundant levels of {delta}Np63{alpha} and mutant p53, and it is resistant to DNA damage-induced apoptosis. The knockdown of {delta}Np63{alpha} by RNA interference sensitized these cells to apoptosis upon genotoxic insult. This suggests that {delta}Np63{alpha} plays an anti-apoptotic role regardless of the p53 status. Considering the frequent mutations of p53 in tumor cells, our results provide important implications for the treatment of cancers in which p63 is amplified.

  8. Susceptibility to hepatotoxicity in transgenic mice that express a dominant-negative human keratin 18 mutant.

    PubMed Central

    Ku, N O; Michie, S A; Soetikno, R M; Resurreccion, E Z; Broome, R L; Oshima, R G; Omary, M B

    1996-01-01

    Keratins 8 and 18 (K8/18) are intermediate filament phosphoglycoproteins that are expressed preferentially in simple-type epithelia. We recently described transgenic mice that express point-mutant human K18 (Ku, N.-O., S. Michie, R.G. Oshima, and M.B. Omary. 1995. J. Cell Biol. 131:1303-1314) and develop chronic hepatitis and hepatocyte fragility in association with hepatocyte keratin filament disruption. Here we show that mutant K18 expressing transgenic mice are highly susceptible to hepatotoxicity after acute administration of acetaminophen (400 mg/Kg) or chronic ingestion of griseofulvin (1.25% wt/wt of diet). The predisposition to hepatotoxicity results directly from the keratin mutation since nontransgenic or transgenic mice that express normal human K18 are more resistant. Hepatotoxicity was manifested by a significant difference in lethality, liver histopathology, and biochemical serum testing. Keratin glycosylation decreased in all griseofulvin-fed mice, whereas keratin phosphorylation increased dramatically preferentially in mice expressing normal K18. The phosphorylation increase in normal K18 after griseofulvin feeding appears to involve sites that are different to those that increase after partial hepatectomy. Our results indicate that hepatocyte intermediate filament disruption renders mice highly susceptible to hepatotoxicity, and raises the possibility that K18 mutations may predispose to drug hepatotoxicity. The dramatic phosphorylation increase in nonmutant keratins could provide survival advantage to hepatocytes. PMID:8770877

  9. A dominant-negative transgene defines a role for p56lck in thymopoiesis.

    PubMed Central

    Levin, S D; Anderson, S J; Forbush, K A; Perlmutter, R M

    1993-01-01

    The lymphocyte-specific protein tyrosine kinase p56lck participates in T cell signaling through functional interactions with components of the T cell antigen receptor complex and the interleukin-2 receptor. Additional insight into the function of p56lck has now been obtained through the generation of transgenic animals expressing high levels of a catalytically inactive form of this kinase (p56lckR273). Mice bearing the lckR273 transgene manifested a severe defect in the production of virtually all T lymphocytes. Those exceptional CD3+ cells that escaped the effects of the lckR273 transgene were confined primarily to the T cell subset that expresses gamma/delta T cell receptors. Remarkably, construction of a dose-response curve for the effects of the lckR273 transgene revealed that developmental arrest of thymocytes occurred at a discrete stage in the normal T cell maturation pathway, corresponding to a point at which thymoblasts ordinarily begin a series of mitotic divisions that result in expansion and maturation. These results suggest that p56lck normally regulates T cell production by metering the replicative potential of immature thymoblasts. Images PMID:8385609

  10. Ubiquitin depletion and dominant-negative VPS4 inhibit rhabdovirus budding without affecting alphavirus budding.

    PubMed

    Taylor, Gwen M; Hanson, Phyllis I; Kielian, Margaret

    2007-12-01

    The budding reactions of a number of enveloped viruses use the cellular machinery involved in the formation of the luminal vesicles of endosomal multivesicular bodies (MVB). Budding of these viruses is dependent on the presence of specific late-domain motifs in membrane-associated viral proteins. Such budding reactions usually involve ubiquitin and are blocked by expression of an ATPase-deficient form of VPS4, a cellular AAA+ ATPase believed to be required late in the MVB pathway for the disassembly/release of the MVB machinery. Here we examined the role of the MVB pathway in the budding of the late-domain-containing rhabdovirus vesicular stomatitis virus (VSV) and the alphavirus Semliki Forest virus (SFV). We tested early and late steps in the MVB pathway by depleting ubiquitin with the proteasome inhibitor MG-132 and by using cell lines inducibly expressing VPS4A or VPS4B protein. As previously shown, VSV budding was strongly dependent on ubiquitin. In contrast to the findings of previous studies with VPS4A, expression of ATPase-deficient mutants of either VPS4A or VPS4B inhibited VSV budding. Inhibition by VPS4 required the presence of the PPPY late domain on the VSV matrix protein and resulted in the accumulation of nonreleased VSV particles at the plasma membrane. In contrast, SFV budding was independent of both ubiquitin and the activity of VPS4, perhaps reflecting the important role of the highly organized envelope protein lattice during alphavirus budding.

  11. Dominant negative effect of polyglutamine expansion perturbs normal function of ataxin-3 in neuronal cells

    PubMed Central

    Neves-Carvalho, Andreia; Logarinho, Elsa; Freitas, Ana; Duarte-Silva, Sara; Costa, Maria do Carmo; Silva-Fernandes, Anabela; Martins, Margarida; Serra, Sofia Cravino; Lopes, André T.; Paulson, Henry L.; Heutink, Peter; Relvas, João B.; Maciel, Patrícia

    2015-01-01

    The physiological function of Ataxin-3 (ATXN3), a deubiquitylase (DUB) involved in Machado–Joseph Disease (MJD), remains elusive. In this study, we demonstrate that ATXN3 is required for neuronal differentiation and for normal cell morphology, cytoskeletal organization, proliferation and survival of SH-SY5Y and PC12 cells. This cellular phenotype is associated with increased proteasomal degradation of α5 integrin subunit (ITGA5) and reduced activation of integrin signalling and is rescued by ITGA5 overexpression. Interestingly, silencing of ATXN3, overexpression of mutant versions of ATXN3 lacking catalytic activity or bearing an expanded polyglutamine (polyQ) tract led to partially overlapping phenotypes. In vivo analysis showed that both Atxn3 knockout and MJD transgenic mice had decreased levels of ITGA5 in the brain. Furthermore, abnormal morphology and reduced branching were observed both in cultured neurons expressing shRNA for ATXN3 and in those obtained from MJD mice. Our results show that ATXN3 rescues ITGA5 from proteasomal degradation in neurons and that polyQ expansion causes a partial loss of this cellular function, resulting in reduced integrin signalling and neuronal cytoskeleton modifications, which may be contributing to neurodegeneration. PMID:25143392

  12. Basic science of pain.

    PubMed

    DeLeo, Joyce A

    2006-04-01

    The origin of the theory that the transmission of pain is through a single channel from the skin to the brain can be traced to the philosopher and scientist René Descartes. This simplified scheme of the reflex was the beginning of the development of the modern doctrine of reflexes. Unfortunately, Descartes' reflex theory directed both the study and treatment of pain for more than 330 years. It is still described in physiology and neuroscience textbooks as fact rather than theory. The gate control theory proposed by Melzack and Wall in 1965 rejuvenated the field of pain study and led to further investigation into the phenomena of spinal sensitization and central nervous system plasticity, which are the potential pathophysiologic correlates of chronic pain. The processing of pain takes place in an integrated matrix throughout the neuroaxis and occurs on at least three levels-at peripheral, spinal, and supraspinal sites. Basic strategies of pain control monopolize on this concept of integration by attenuation or blockade of pain through intervention at the periphery, by activation of inhibitory processes that gate pain at the spinal cord and brain, and by interference with the perception of pain. This article discusses each level of pain modulation and reviews the mechanisms of action of opioids and potential new analgesics. A brief description of animal models frames a discussion about recent advances regarding the role of glial cells and central nervous system neuroimmune activation and innate immunity in the etiology of chronic pain states. Future investigation into the discovery and development of novel, nonopioid drug therapy may provide needed options for the millions of patients who suffer from chronic pain syndromes, including syndromes in which the pain originates from peripheral nerve, nerve root, spinal cord, bone, muscle, and disc.

  13. Negative electrode composition

    DOEpatents

    Kaun, Thomas D.; Chilenskas, Albert A.

    1982-01-01

    A secondary electrochemical cell and a negative electrode composition for use therewith comprising a positive electrode containing an active material of a chalcogen or a transiton metal chalcogenide, a negative electrode containing a lithium-aluminum alloy and an amount of a ternary alloy sufficient to provide at least about 5 percent overcharge capacity relative to a negative electrode solely of the lithium-aluminum alloy, the ternary alloy comprising lithium, aluminum, and iron or cobalt, and an electrolyte containing lithium ions in contact with both of the positive and the negative electrodes. The ternary alloy is present in the electrode in the range of from about 5 percent to about 50 percent by weight of the electrode composition and may include lithium-aluminum-nickel alloy in combination with either the ternary iron or cobalt alloys. A plurality of series connected cells having overcharge capacity can be equalized on the discharge side without expensive electrical equipment.

  14. Logo and Negative Numbers.

    ERIC Educational Resources Information Center

    Strawn, Candace A.

    1998-01-01

    Describes LOGO's turtle graphics capabilities based on a sixth-grade classroom's activities with negative numbers and Logo programming. A sidebar explains LOGO and offers suggestions to teachers for using LOGO effectively. (LRW)

  15. No to negative data

    SciTech Connect

    Wiley, H. S.

    2008-04-01

    A frequent criticism in biology is that we don’t publish our negative data. As a result, the literature has become biased towards papers that favor specific hypotheses1. Some scientists have become so concerned about this trend that they have created journals dedicated to publishing negative results (e.g. the Journal of Negative Results in Biomedicine). Personally, I don’t think they should bother. I say this because I believe negative results are not worth publishing. Rest assured that I do not include drug studies that show a lack of effectiveness towards a specific disease or condition. This type of finding is significant in a societal context, not a scientific one, and thus we all have a vested interest in seeing this type of result published. I am talking about a set of experimental results that fail to support a particular hypothesis. The problem with these types of negative results is that they don’t actually advance science. Science is a set of ideas that can be supported by observations. A negative result does not support any specific idea, but only tells you what isn’t right. Well, there are only a small number of potential hypotheses that are correct, but essentially an infinite number of ideas are not correct. I don’t want to waste my time reading a paper about what doesn’t happen, just about those things that do. I can remember a positive result because I can associate it with a specific concept. What do I do with a negative one? It is hard enough to following the current literature. A flood of negative results would make that task all but impossible

  16. Negative affixes in medical English.

    PubMed

    Dzuganova, B

    2006-01-01

    Many medical terms have negative meaning expressed by means of a negative prefix or suffix. The most frequently used negative prefixes are: a-, dis-, in-, non-, and un-. There is only one negative suffix -less (Ref. 15). PMID:17125069

  17. Hand Dominance and Common Hand Conditions.

    PubMed

    Lutsky, Kevin; Kim, Nayoung; Medina, Juana; Maltenfort, Mitchell; Beredjiklian, Pedro K

    2016-05-01

    The goals of this study were to (1) assess how frequently patients present for evaluation of common hand disorders in relation to hand dominance and (2) evaluate the effect of hand dominance on function in patients with these conditions. The authors hypothesized that (1) the majority of patients who seek evaluation would have a condition that affects the dominant hand, and (2) disability scores would be worse if the dominant hand is involved. They retrospectively reviewed the records of consecutive patients who presented for treatment to their institution with unilateral symptoms of 5 common disorders of the hand: carpal tunnel syndrome (CTS), de Quervain's tenosynovitis (DEQ), lateral epicondylitis (LE), hand osteoarthritis (OA), and trigger finger (TF). The authors assessed the effect of diagnosis and hand dominance on Disabilities of the Arm, Shoulder and Hand (DASH) scores. The study group comprised 1029 patients (379 men and 650 women) with a mean age of 59.5 years. Ninety percent were right-hand dominant. The dominant and nondominant hands were affected with relatively equal frequency for CTS, DEQ, OA, and TF (range, 45%-53%). Patients with LE had a significantly higher incidence of dominant hand involvement. Men had lower DASH scores than women by an average of 7.9 points, and DASH scores were significantly but slightly higher for the overall group (3.2 points) when the dominant side was affected. Men with LE and women with TF and OA had significantly higher DASH scores when their dominant extremity was affected. Common hand disorders such as CTS, DEQ, OA, and TF affect the dominant and nondominant hands in roughly equivalent proportions, whereas LE is more common on the dominant side. Dominant hand involvement results in significantly worse DASH scores, although the magnitude of this is relatively small. Women have significantly higher DASH scores than men for the conditions evaluated. [Orthopedics. 2016; 39(3):e444-e448.].

  18. Do ambient urban odors evoke basic emotions?

    PubMed Central

    Glass, Sandra T.; Lingg, Elisabeth; Heuberger, Eva

    2013-01-01

    Fragrances, such as plant odors, have been shown to evoke autonomic response patterns associated with Ekman's (Ekman et al., 1983) basic emotions happiness, surprise, anger, fear, sadness, and disgust. Inducing positive emotions by odors in highly frequented public spaces could serve to improve the quality of life in urban environments. Thus, the present study evaluated the potency of ambient odors connoted with an urban environment to evoke basic emotions on an autonomic and cognitive response level. Synthetic mixtures representing the odors of disinfectant, candles/bees wax, summer air, burnt smell, vomit and musty smell as well as odorless water as a control were presented five times in random order to 30 healthy, non-smoking human subjects with intact sense of smell. Skin temperature, skin conductance, breathing rate, forearm muscle activity, blink rate, and heart rate were recorded simultaneously. Subjects rated the odors in terms of pleasantness, intensity and familiarity and gave verbal labels to each odor as well as cognitive associations with the basic emotions. The results showed that the amplitude of the skin conductance response (SCR) varied as a function of odor presentation. Burnt smell and vomit elicited significantly higher electrodermal responses than summer air. Also, a negative correlation was revealed between the amplitude of the SCR and hedonic odor valence indicating that the magnitude of the electrodermal response increased with odor unpleasantness. The analysis of the cognitive associations between odors and basic emotions showed that candles/bees wax and summer air were specifically associated with happiness whereas burnt smell and vomit were uniquely associated with disgust. Our findings suggest that city odors may evoke specific cognitive associations of basic emotions and that autonomic activity elicited by such odors is related to odor hedonics. PMID:24860522

  19. Do ambient urban odors evoke basic emotions?

    PubMed

    Glass, Sandra T; Lingg, Elisabeth; Heuberger, Eva

    2014-01-01

    Fragrances, such as plant odors, have been shown to evoke autonomic response patterns associated with Ekman's (Ekman et al., 1983) basic emotions happiness, surprise, anger, fear, sadness, and disgust. Inducing positive emotions by odors in highly frequented public spaces could serve to improve the quality of life in urban environments. Thus, the present study evaluated the potency of ambient odors connoted with an urban environment to evoke basic emotions on an autonomic and cognitive response level. Synthetic mixtures representing the odors of disinfectant, candles/bees wax, summer air, burnt smell, vomit and musty smell as well as odorless water as a control were presented five times in random order to 30 healthy, non-smoking human subjects with intact sense of smell. Skin temperature, skin conductance, breathing rate, forearm muscle activity, blink rate, and heart rate were recorded simultaneously. Subjects rated the odors in terms of pleasantness, intensity and familiarity and gave verbal labels to each odor as well as cognitive associations with the basic emotions. The results showed that the amplitude of the skin conductance response (SCR) varied as a function of odor presentation. Burnt smell and vomit elicited significantly higher electrodermal responses than summer air. Also, a negative correlation was revealed between the amplitude of the SCR and hedonic odor valence indicating that the magnitude of the electrodermal response increased with odor unpleasantness. The analysis of the cognitive associations between odors and basic emotions showed that candles/bees wax and summer air were specifically associated with happiness whereas burnt smell and vomit were uniquely associated with disgust. Our findings suggest that city odors may evoke specific cognitive associations of basic emotions and that autonomic activity elicited by such odors is related to odor hedonics.

  20. Anxiety and feedback negativity.

    PubMed

    Gu, Ruolei; Huang, Yu-Xia; Luo, Yue-Jia

    2010-09-01

    It has been suggested that anxious individuals are more prone to feel that negative outcomes are particularly extreme and to interpret ambiguous outcomes as negative compared to nonanxious individuals. Previous studies have demonstrated that the feedback negativity (FN) component of event-related brain potential (ERP) is sensitive to outcome evaluation and outcome expectancy. Hence, we predicted that the FN should be different between high trait-anxiety (HTA) and low trait-anxiety (LTA) individuals. To test our hypothesis, the ERPs were recorded during a simple monetary gambling task. The FN was measured as a difference wave created across conditions. We found that the amplitude of the FN indicating negative versus positive outcomes was significantly larger for LTA individuals compared to HTA individuals. However, there was no significant difference in the FN between groups in response to ambiguous versus positive outcomes. The results indicate that there is a relationship between the FN and individual differences in anxiety. We suggest that these results reflect the impact of anxiety on outcome expectation. Our results challenge the reinforcement learning theory of error-related negativity, which proposes that ERN and FN reflect the same cognitive process.

  1. Monsoon abrupt change and its dominant factors

    NASA Astrophysics Data System (ADS)

    Yao, Qiang; Fu, Conbin

    2010-05-01

    Abrupt changes of monsoon are apparent in the geological record of climate over various timescales. During Holocene and last glacial period, rainfall in India and China has undergone strong and abrupt changes. In this context, we regard monsoon as dissipative system, which has many characteristic times, to contrive various factors and corresponding mechanism dominated in monsoon's abrupt change. The abrupt change of monsoon over inter-decadal to century timescales may be resulting from different fluctuation's competition, which impose on the inner basic physic processes. In order to find out the key factors which control the monsoon's abrupt change, starting from the seminar works by Leith, who proposed to employ the Fluctuation-dissipation Response theory(FDR) to study the response of climatic systems to changes in the external forcing, many authors applied this relation to different geophysical problems, ranging from simplified models to general circulation models and to the covariance of satellite radiance spectra. The FDR has been originally developed in the framework of statistical mechanics of Hamiltonian systems, nevertheless a generalized FDR holds under rather general hypotheses, regardless of the Hamiltonian, or equilibrium nature of the system. Our work verify the FDR theory' applicability in monsoon systems, which demonstrates that it can reveal clear and fundamental factors that control monsoon's abrupt change. By making use of FDR theory, combined with observational data analysis, we have already seen how monsoon systems with many characteristics times, different correlation functions behave differently and a variety of timescales emerges, which correspond to the different decay times of the correlation functions. Via theoretical and data analysis, it is suggested that each monsoon system has experienced several significant abrupt changes in 20th century. The global main monsoon rainfall has undergone an obvious abrupt jump in the mid- and late 1970s

  2. Consumers, health insurance and dominated choices.

    PubMed

    Sinaiko, Anna D; Hirth, Richard A

    2011-03-01

    We analyze employee health plan choices when the choice set offered by their employer includes a dominated plan. During our study period, one-third of workers were enrolled in the dominated plan. Some may have selected the plan before it was dominated and then failed to switch out of it. However, a substantial number actively chose the dominated plan when they had an unambiguously better choice. These results suggest limitations in the ability of health reform based solely on consumer choice to achieve efficient outcomes and that implementation of health reform should anticipate, monitor and account for this consumer behavior. PMID:21300414

  3. Induction of plasticity in the dominant and non-dominant motor cortices of humans.

    PubMed

    Ridding, M C; Flavel, S C

    2006-06-01

    There are clear hemispheric differences in the human motor system. Studies using magnetic resonance morphometry have shown that representation of hand muscles is larger in the dominant hemisphere than the non-dominant hemisphere. There is some limited evidence of electrophysiological differences between hemispheres. For example, it has been reported recently that there is less intracortical inhibition in the dominant hemisphere than the non-dominant hemisphere, and it has been hypothesised that this reduction in inhibition may facilitate use-dependent plasticity in the dominant motor cortex. In the present study we examined this hypothesis in human subjects by examining plasticity induction in both dominant and non-dominant hemispheres using an experimental paradigm known to induce motor cortical plasticity, namely paired associative stimulation (PAS). Additionally, we investigated changes in dominant and non-dominant hand performance on a simple ballistic training task. Short-interval intracortical inhibition (SICI) was also measured for both dominant and non-dominant hands at a range of conditioning intensities. There was significantly less SICI in the dominant motor cortical hand area than in the non-dominant hand area. PAS induced a significant, and similar, increase in motor cortical excitability in both the dominant and non-dominant hemispheres. Motor training resulted in significant performance improvement in both dominant and non-dominant hands. However, there was significantly more improvement in the non-dominant hand. The results from these studies provide some further evidence of electrophysiological differences between the motor cortices of the two hemispheres. Additionally, these findings offer no support for the hypothesis that the dominant hemisphere is positioned more favourably, due to decreased inhibitory tone, than the non-dominant hemisphere for use-dependent plasticity. PMID:16501966

  4. Negative capacitance in multidomain ferroelectric superlattices.

    PubMed

    Zubko, Pavlo; Wojdeł, Jacek C; Hadjimichael, Marios; Fernandez-Pena, Stéphanie; Sené, Anaïs; Luk'yanchuk, Igor; Triscone, Jean-Marc; Íñiguez, Jorge

    2016-06-23

    The stability of spontaneous electrical polarization in ferroelectrics is fundamental to many of their current applications, which range from the simple electric cigarette lighter to non-volatile random access memories. Research on nanoscale ferroelectrics reveals that their behaviour is profoundly different from that in bulk ferroelectrics, which could lead to new phenomena with potential for future devices. As ferroelectrics become thinner, maintaining a stable polarization becomes increasingly challenging. On the other hand, intentionally destabilizing this polarization can cause the effective electric permittivity of a ferroelectric to become negative, enabling it to behave as a negative capacitance when integrated in a heterostructure. Negative capacitance has been proposed as a way of overcoming fundamental limitations on the power consumption of field-effect transistors. However, experimental demonstrations of this phenomenon remain contentious. The prevalent interpretations based on homogeneous polarization models are difficult to reconcile with the expected strong tendency for domain formation, but the effect of domains on negative capacitance has received little attention. Here we report negative capacitance in a model system of multidomain ferroelectric-dielectric superlattices across a wide range of temperatures, in both the ferroelectric and paraelectric phases. Using a phenomenological model, we show that domain-wall motion not only gives rise to negative permittivity, but can also enhance, rather than limit, its temperature range. Our first-principles-based atomistic simulations provide detailed microscopic insight into the origin of this phenomenon, identifying the dominant contribution of near-interface layers and paving the way for its future exploitation. PMID:27296225

  5. Negative capacitance in multidomain ferroelectric superlattices

    NASA Astrophysics Data System (ADS)

    Zubko, Pavlo; Wojdeł, Jacek C.; Hadjimichael, Marios; Fernandez-Pena, Stéphanie; Sené, Anaïs; Luk'Yanchuk, Igor; Triscone, Jean-Marc; Íñiguez, Jorge

    2016-06-01

    The stability of spontaneous electrical polarization in ferroelectrics is fundamental to many of their current applications, which range from the simple electric cigarette lighter to non-volatile random access memories. Research on nanoscale ferroelectrics reveals that their behaviour is profoundly different from that in bulk ferroelectrics, which could lead to new phenomena with potential for future devices. As ferroelectrics become thinner, maintaining a stable polarization becomes increasingly challenging. On the other hand, intentionally destabilizing this polarization can cause the effective electric permittivity of a ferroelectric to become negative, enabling it to behave as a negative capacitance when integrated in a heterostructure. Negative capacitance has been proposed as a way of overcoming fundamental limitations on the power consumption of field-effect transistors. However, experimental demonstrations of this phenomenon remain contentious. The prevalent interpretations based on homogeneous polarization models are difficult to reconcile with the expected strong tendency for domain formation, but the effect of domains on negative capacitance has received little attention. Here we report negative capacitance in a model system of multidomain ferroelectric-dielectric superlattices across a wide range of temperatures, in both the ferroelectric and paraelectric phases. Using a phenomenological model, we show that domain-wall motion not only gives rise to negative permittivity, but can also enhance, rather than limit, its temperature range. Our first-principles-based atomistic simulations provide detailed microscopic insight into the origin of this phenomenon, identifying the dominant contribution of near-interface layers and paving the way for its future exploitation.

  6. Negative ion kinetics in RF glow discharges

    SciTech Connect

    Gottscho, R.A.; Gacbe, C.E.

    1986-04-01

    Using temporally and spatially resolved laser spectroscopy, the authors have determined the identities, approximate concentrations, effects on the local field, and kinetics of formation and loss of negative ions in RF discharges. CI/sup -/ and BCI/sub 3//sup -/ are the dominant negative ions found in low-frequency discharges through CI/sub 2/ and BCI/sub 3/, respectively. The electron affinity for CI is measured to be 3.6118 +- 0.0005 eV. Negative ion kinetics are strongly affected by application of the RF field. Formation of negative ions by attachment of slow electrons in RF discharges is governed by the extent and duration of electron energy relaxation. Similarly, destruction of negative ions by collisional detachment and field extraction is dependent upon ion energy modulation. Thus, at low frequency, the anion density peaks at the beginning of the anodic and cathodic half-cycles after electrons have attached but before detachment and extraction have had time to occur. At higher frequencies, electrons have insufficient time to attach before they are reheated and the instantaneous anion density in the sheath is greatly reduced. When the negative ion density is comparable to the positive ion density, the plasma potential is observed to lie below the anode potential, double layers form between sheath and plasma, and anions and electrons are accelerated by large sheath fields to electrode surfaces.

  7. Negative capacitance in multidomain ferroelectric superlattices

    NASA Astrophysics Data System (ADS)

    Zubko, Pavlo; Wojdeł, Jacek C.; Hadjimichael, Marios; Fernandez-Pena, Stéphanie; Sené, Anaïs; Luk’Yanchuk, Igor; Triscone, Jean-Marc; Íñiguez, Jorge

    2016-06-01

    The stability of spontaneous electrical polarization in ferroelectrics is fundamental to many of their current applications, which range from the simple electric cigarette lighter to non-volatile random access memories. Research on nanoscale ferroelectrics reveals that their behaviour is profoundly different from that in bulk ferroelectrics, which could lead to new phenomena with potential for future devices. As ferroelectrics become thinner, maintaining a stable polarization becomes increasingly challenging. On the other hand, intentionally destabilizing this polarization can cause the effective electric permittivity of a ferroelectric to become negative, enabling it to behave as a negative capacitance when integrated in a heterostructure. Negative capacitance has been proposed as a way of overcoming fundamental limitations on the power consumption of field-effect transistors. However, experimental demonstrations of this phenomenon remain contentious. The prevalent interpretations based on homogeneous polarization models are difficult to reconcile with the expected strong tendency for domain formation, but the effect of domains on negative capacitance has received little attention. Here we report negative capacitance in a model system of multidomain ferroelectric–dielectric superlattices across a wide range of temperatures, in both the ferroelectric and paraelectric phases. Using a phenomenological model, we show that domain-wall motion not only gives rise to negative permittivity, but can also enhance, rather than limit, its temperature range. Our first-principles-based atomistic simulations provide detailed microscopic insight into the origin of this phenomenon, identifying the dominant contribution of near-interface layers and paving the way for its future exploitation.

  8. Negative capacitance in multidomain ferroelectric superlattices.

    PubMed

    Zubko, Pavlo; Wojdeł, Jacek C; Hadjimichael, Marios; Fernandez-Pena, Stéphanie; Sené, Anaïs; Luk'yanchuk, Igor; Triscone, Jean-Marc; Íñiguez, Jorge

    2016-06-23

    The stability of spontaneous electrical polarization in ferroelectrics is fundamental to many of their current applications, which range from the simple electric cigarette lighter to non-volatile random access memories. Research on nanoscale ferroelectrics reveals that their behaviour is profoundly different from that in bulk ferroelectrics, which could lead to new phenomena with potential for future devices. As ferroelectrics become thinner, maintaining a stable polarization becomes increasingly challenging. On the other hand, intentionally destabilizing this polarization can cause the effective electric permittivity of a ferroelectric to become negative, enabling it to behave as a negative capacitance when integrated in a heterostructure. Negative capacitance has been proposed as a way of overcoming fundamental limitations on the power consumption of field-effect transistors. However, experimental demonstrations of this phenomenon remain contentious. The prevalent interpretations based on homogeneous polarization models are difficult to reconcile with the expected strong tendency for domain formation, but the effect of domains on negative capacitance has received little attention. Here we report negative capacitance in a model system of multidomain ferroelectric-dielectric superlattices across a wide range of temperatures, in both the ferroelectric and paraelectric phases. Using a phenomenological model, we show that domain-wall motion not only gives rise to negative permittivity, but can also enhance, rather than limit, its temperature range. Our first-principles-based atomistic simulations provide detailed microscopic insight into the origin of this phenomenon, identifying the dominant contribution of near-interface layers and paving the way for its future exploitation.

  9. Basic Skills. NIACE Briefing Sheet.

    ERIC Educational Resources Information Center

    National Inst. of Adult Continuing Education, Leicester (England).

    Skills For Life, since 2001 the United Kingdom's national adult basic skills strategy, aims to improve literacy, numeracy, or English for speakers of other languages (ESOL) skills among people over the age of 16. Basic skills programs may be full- or part-time and are delivered in colleges, community venues, neighborhood learning centers, adult…

  10. Basic electronics for clinical neurophysiology.

    PubMed

    Misulis, K E

    1989-01-01

    This article reviews the basic electronics that are important to clinical neurophysiology. It is divided into six sections: basic principles of electronics; filters; transistors and amplifiers; displays; electrodes and the electrode-amplifier interface; and electrical safety. In addition, at the end of the review is a brief electronics glossary (Appendix A) and an annotated bibliography (Appendix B) to guide further reading.

  11. Children and Their Basic Needs.

    ERIC Educational Resources Information Center

    Prince, Debra Lindsey; Howard, Esther M.

    2002-01-01

    Describes obstacles presented by poverty in the fulfillment of the basic needs of children. Individually addresses Maslow's five basic needs with regard to children reared in poverty: (1) physiological needs; (2) safety needs; (3) belonging and love needs; (4) self-esteem needs; and (5) self-actualization needs. (Author/SD)

  12. Basic Skills: Dealing with Deficiencies.

    ERIC Educational Resources Information Center

    New Mexico State Univ., Las Cruces.

    Research findings on college instruction and basic skills deficiencies are discussed in 12 papers from the first Regional Conference on University Teaching. Titles and authors are as follows: "Basic Skills: Dealing with Deficiencies" (Susanne D. Roueche, with responses by Gary B. Donart, Betty Harris, and James Nordyke); "Is Higher Education an…

  13. Chinese-Cantonese Basic Course.

    ERIC Educational Resources Information Center

    Defense Language Inst., Washington, DC.

    This nine-volume basic course in Cantonese Chinese is designed for 47 weeks of intense audiolingual instruction. The first book of the series introduces the pronunciation, with emphasis on the tone system, and the basic aspects of the grammar. Also introduced in this volume is the romanization system used in this series (the U.S. Army Language…

  14. Creating Adult Basic Education Programs.

    ERIC Educational Resources Information Center

    Harris, Dolores M.

    Adult basic education programs must teach the "social living skills" disadvantaged adults need, as well as basic literacy skills. In creating an ABE program, one must first assess the needs of the target population--through surveys, group meetings, an advisory council of members of the target population, demographic studies, and consideration of…

  15. Basic electronics for the field technician

    SciTech Connect

    Perrodin, T.

    1995-12-01

    The field of electronics is considered by many to be the most exciting and complex of all fields of study. Although this may be true, electronics are a way of life for all, from the time we wake up, until the time we go to bed, and even as we sleep. Electronics surround us! Today`s industrial environment is filled with some of the most complex electronic devices ever designed. These systems have the capability to operate entire manufacturing processes, and even control operations of several facilities located hundreds of miles away from one another. However, when all is said and done, all of this complexity can be broken down into the very basic fundamentals of electronics: the resistor, the capacitor, the inductor, the diode, and the transistor. The only negative issue is that all of these devices are capable of failing, either from heat, overdriving, extended period of use, or even from manufacturing defects. It is possible to take each component and fully understand its purpose, its operating parameters, and its trouble-shooting characteristics. The following information is used to explain the basic operation of each component, how to determine its specific value, and the basics of troubleshooting the component.

  16. Basic emotions elicited by odors and pictures.

    PubMed

    Croy, Ilona; Olgun, Selda; Joraschky, Peter

    2011-12-01

    The sense of olfaction is often reported to have a special relationship with emotional processing. Memories triggered by olfactory cues often have a very emotional load. On the other hand, basic negative or positive emotional states should be sufficient to cover the most significant functions of the olfactory system including ingestion, hazard avoidance, and social communication. Thus, we investigated whether different basic emotions can be evoked in healthy people through the sense of olfaction. We asked 119 participants which odor evokes one of the six basic emotions (happiness, disgust, anger, anxiety, sadness, and surprise); another 97 participants were asked about pictures evoking those emotions. The results showed that almost every participant could name an olfactory elicitor for happiness or disgust. Olfactory elicitors of anxiety were reported less frequently, but they were still reported by three-quarters of the participants. However, for sadness and anger only about half of the participants reported an olfactory elicitor, whereas significantly more named a visual cue. Olfactory emotion elicitors were mainly related to the classes of culture, plants, and food, and visual emotion elicitors were largely related to humans. This data supports the hypothesis that in the vast majority of people, few differentiated emotions can be elicited through the olfactory channel. These emotions are happiness, disgust, and anxiety.

  17. Eating disorders: a basic emotion perspective.

    PubMed

    Fox, John R E; Froom, Kate

    2009-01-01

    Recent research and theory have started to highlight how eating disorder symptoms are often used to regulate painful emotions. However, there has not been one study that has looked at the contributory effect of all the basic emotions onto disordered eating patterns. This study was designed to address this gap within the literature with a detailed examination of the five basic emotions (anger, sadness, disgust, fear and happiness) in relation to disordered eating patterns. This study used the Basic Emotions Scale and the Hospital Anxiety and Depression Scale to explore levels of emotions within 53 female participants with disordered eating patterns who were recruited from the B-EAT research database. The results showed strong correlations between disordered eating and the four negative emotions, but only anger and sadness were left as significant contributors to disordered eating within the regression analysis. These findings were discussed in relation to the literature, with particular reference being made to the new Schematic Propositional Analogical Associative Representation System for Eating Disorders (SPAARS-ED) model.

  18. Basic sciences: an alternative career?

    PubMed

    Khatri, R

    2013-01-01

    Career selection is a crucial and a complex process which is also true for the medical profession. In the context of our country, due to the limited opportunity and proper guidance, migration of medical graduates to foreign countries is increasing. Though, clinical subjects have a huge attraction, basic science field has failed to impress our medical graduates. In current scenario, basic science field seems to be a dumping site for the incompetent as the candidates who have failed trying their luck elsewhere stumble upon basic science careers though it is not true for all. Moreover, a very few medical graduates are interested in developing their career as a basic scientist. Therefore, to motivate today's young medical graduates, there is a need of a good mentor along with a proper career guidance which can help them to understand the basic science field as an alternative career. PMID:23774420

  19. [Chemotherapies of negative schizophrenia].

    PubMed

    Petit, M; Dollfus, S

    1991-01-01

    Five years ago, Goldberg claimed that negative symptoms of schizophrenia do respond to neuroleptics. This apparent discovery is, in fact, a very common way of thinking for European schools of psychiatry, specially the French one guided by Delay and Deniker. Initially focused on reserpine and some alerting phenothiazines such as thioproperazine, this opinion has been extended to benzamides in the 1970s. The analysis of the publications devoted to this point indicates that several drugs are actually considered as potent disinhibitors (i.e. active on negative symptoms of schizophrenia): Phenothiazines: As shown in the controlled studies by Itil (1971), Poirier-Littré (1988), fluphenazine and pipotiazine improve the BPRS anergia factor and the SANS score. Butyrophenones: The first description of the "imipramine like" effect of trifluperidol by Janssen (1959) initiated the studies by Gallant (1960), Fox (1963). They compared trifluperidol at low doses versus haloperidol and chlorpromazine at medium and high doses, BPRS anergia factor improved only at low doses. Diphenylbutylpiperidines (DPBP): Meltzer's review (1986) concluded to the efficacy of such drugs on negative symptoms appearing as a specific biochemical relationship effect. A definite analysis about doses leads to a very different interpretation: DPBP low doses and only low doses improved negative symptoms as much as some low doses of phenothiazines. On the opposite, DPBP, phenothiazines and butyrophenones high doses are inefficient.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1683624

  20. The Negative Repetition Effect

    ERIC Educational Resources Information Center

    Mulligan, Neil W.; Peterson, Daniel J.

    2013-01-01

    A fundamental property of human memory is that repetition enhances memory. Peterson and Mulligan (2012) recently documented a surprising "negative repetition effect," in which participants who studied a list of cue-target pairs twice recalled fewer targets than a group who studied the pairs only once. Words within a pair rhymed, and…

  1. Interpersonal Dominance and Coronary-Prone Behavior.

    ERIC Educational Resources Information Center

    Yarnold, Paul R.; Grimm, Laurence G.

    Exploratory research has indicated that interpersonal dominance is one of the strongest correlates of Type A behavior, although little effort has been made to demonstrate a link between the behavioral manifestation of interpersonal dominance and Pattern A responding. To establish such a link two studies were conducted. In the first study, extreme…

  2. Computation of term dominance in text documents

    DOEpatents

    Bauer, Travis L.; Benz, Zachary O.; Verzi, Stephen J.

    2012-04-24

    An improved entropy-based term dominance metric useful for characterizing a corpus of text documents, and is useful for comparing the term dominance metrics of a first corpus of documents to a second corpus having a different number of documents.

  3. Aggression and Dominance Relations in Young Children.

    ERIC Educational Resources Information Center

    Missakian, Elizabeth; Hamer, Karen

    This study is an attempt to apply ethological tools of observation and analysis to the social behavior of 25 communally-reared children, ages 6 months to 4 years. The focus of this analysis is aggression and dominance relations. Findings indicate that: (1) agonistic behavior reveals stable and linear dominance hierarchies for children from 6…

  4. Dominance and Outcome: A Sequential Examination.

    ERIC Educational Resources Information Center

    Tracey, Terence J.

    1985-01-01

    Examined Haley's contention that successful counseling is characterized by counselor dominance or control. Interaction was rated for topic-initiating or topic-following responses in six counseling dyads. Results demonstrated that counselors were dominant in the successful dyads, whereas dependency was equal in the unsuccessful dyads. (BH)

  5. 38 CFR 4.69 - Dominant hand.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Dominant hand. 4.69 Section 4.69 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS SCHEDULE FOR RATING DISABILITIES Disability Ratings The Musculoskeletal System § 4.69 Dominant hand. Handedness for the purpose...

  6. Pareto-adaptive epsilon-dominance.

    PubMed

    Hernández-Díaz, Alfredo G; Santana-Quintero, Luis V; Coello Coello, Carlos A; Molina, Julián

    2007-01-01

    Efficiency has become one of the main concerns in evolutionary multiobjective optimization during recent years. One of the possible alternatives to achieve a faster convergence is to use a relaxed form of Pareto dominance that allows us to regulate the granularity of the approximation of the Pareto front that we wish to achieve. One such relaxed forms of Pareto dominance that has become popular in the last few years is epsilon-dominance, which has been mainly used as an archiving strategy in some multiobjective evolutionary algorithms. Despite its advantages, epsilon-dominance has some limitations. In this paper, we propose a mechanism that can be seen as a variant of epsilon-dominance, which we call Pareto-adaptive epsilon-dominance (paepsilon-dominance). Our proposed approach tries to overcome the main limitation of epsilon-dominance: the loss of several nondominated solutions from the hypergrid adopted in the archive because of the way in which solutions are selected within each box.

  7. Cryo-negative staining.

    PubMed

    Adrian, M; Dubochet, J; Fuller, S D; Harris, J R

    1998-01-01

    A procedure is presented for the preparation of thin layers of vitrified biological suspensions in the presence of ammonium molybdate, which we term cryo-negative staining. The direct blotting of sample plus stain solution on holey carbon supports produces thin aqueous films across the holes, which are routinely thinner than the aqueous film produced by conventional negative staining on a continuous carbon layer. Because of this, a higher than usual concentration of negative stain (ca. 16% rather than 2%) is required for cryo-negative staining in order to produce an optimal image contrast. The maintenance of the hydrated state, the absence of adsorption to a carbon film and associated sample flattening, together with reduced stain granularity, generates high contrast cryo-images of superior quality to conventional air-dry negative staining. Image features characteristic of unstained vitrified cryo-electron microscopic specimens are present, but with reverse contrast. Examples of cryo-negative staining of several particulate biological samples are shown, including bacteriophage T2, tobacco mosaic virus (TMV), bovine liver catalase crystals, tomato bushy stunt virus (TBSV), turnip yellow mosaic virus (TYMV), keyhole limpet hemocyanin (KLH) types 1 and 2, the 20S proteasome from moss and the E. coli chaperone GroEL. Densitometric quantitation of the mass-density of cryo-negatively stained bacteriophage T2 specimens before and after freeze-drying within the TEM indicates a water content of 30% in the vitreous specimen. Determination of the image resolution from cryo-negatively stained TMV rods and catalase crystals shows the presence of optical diffraction data to ca. 10 A and 11.5 A, respectively. For cryo-negatively stained vitrified catalase crystals, electron diffraction shows that atomic resolution is preserved (to better than 20 diffraction orders and less than 3 A). The electron diffraction resolution is reduced to ca. 10 A when catalase crystal specimens are

  8. Learning dominance relations in combinatorial search problems

    NASA Technical Reports Server (NTRS)

    Yu, Chee-Fen; Wah, Benjamin W.

    1988-01-01

    Dominance relations commonly are used to prune unnecessary nodes in search graphs, but they are problem-dependent and cannot be derived by a general procedure. The authors identify machine learning of dominance relations and the applicable learning mechanisms. A study of learning dominance relations using learning by experimentation is described. This system has been able to learn dominance relations for the 0/1-knapsack problem, an inventory problem, the reliability-by-replication problem, the two-machine flow shop problem, a number of single-machine scheduling problems, and a two-machine scheduling problem. It is considered that the same methodology can be extended to learn dominance relations in general.

  9. An algorithm for multivariate weak stochastic dominance

    SciTech Connect

    Mosler, K.

    1994-12-31

    The talk addresses the computational problem of comparing two given probability distributions in n-space with respect to several stochastic orderings. The orderings investigated are weak first degree stochastic dominance, weak second degree stochastic dominance, and their dual ordering relations. For each of the four dominance relations we present conditions which are necessary and sufficient for dominance of F over G when F and G have finite support in n-space. An algorithm is proposed which operates efficiently on the join-semilattice generated by their joint support. If F and G are empirical distribution functions, and {anti F} and {anti G}denote the underlying probability laws, significance tests can be performed on {anti F} = {anti G} against the alternative that {anti F} {ne} {anti G} and {anti F} dominates {anti G} in one of the four orderings. Other applications are found in decision theory, applied probability, operations research, and economics.

  10. Dominant-non-dominant asymmetry of kicking a stationary and rolling ball in a futsal context.

    PubMed

    Barbieri, Fabio Augusto; Gobbi, Lilian Teresa Bucken; Santiago, Paulo Roberto Pereira; Cunha, Sergio Augusto

    2015-01-01

    The aim of this study was to analyse the characteristics of the asymmetries in the dominant and non-dominant limbs when kicking stationary and rolling balls. Ten experienced Brazilian amateur futsal players participated in this study. Each participant performed kicks under two conditions (stationary ball vs. rolling ball) with the dominant and non-dominant limbs (five kicks per condition per limb). We analysed the kicking accuracy, ball and foot velocities, angular joint displacement and velocity. The asymmetry between the dominant and non-dominant limbs was analysed by symmetry index and two-way repeated measures ANOVA. The results did not reveal any interaction between the condition and limb for ball velocity, foot velocity and accuracy. However, kicking with the dominant limb in both kicks showed higher ball velocity (stationary ball: dominant - 24.27 ± 2.21 m · s(-1) and non-dominant - 21.62 ± 2.26 m · s(-1); rolling ball: dominant - 23.88 ± 2.71 m · s(-1) and non-dominant - 21.42 ± 2.25 m · s(-1)), foot velocity (stationary ball: dominant - 17.61 ± 1.87 m · s(-1) and non-dominant - 15.58 ± 2.69 m · s(-1); rolling ball: dominant - 17.25 ± 2.26 m · s(-1) and non-dominant - 14.77 ± 2.35 m · s(-1)) and accuracy (stationary ball: dominant - 1.17 ± 0.84 m and non-dominant - 1.56 ± 1.30 m; rolling ball: dominant - 1.31 ± 0.91 m and non-dominant - 1.97 ± 1.44 m). In addition, the angular joint adjustments were dependent on the limb in both kicks (the kicks with non-dominant limb showed lower hip external rotation than the kicks with the dominant limb), indicating that the hip joint is important in kick performance. In conclusion, the kicks with the non-dominant limb showed different angular adjustments in comparison to kicks with the dominant limb. In addition, kicking a rolling ball with the non-dominant limb showed higher asymmetry for accuracy, indicating that complex kicks are more asymmetric. PMID:25554927

  11. On wildebeests and humans: the preferential detection of negative stimuli.

    PubMed

    Dijksterhuis, Ap; Aarts, Henk

    2003-01-01

    On the basis of a functional perspective, we hypothesized that negative stimuli are detected faster than positive stimuli. In Experiment 1, participants were subliminally presented with positive and negative words or with no words at all. After each presentation, participants were asked whether they had seen a word. They detected negative words more accurately than positive words. In Experiment 2, participants were subliminally presented with negative or positive words. After each presentation, they were asked whether the presented word was positive or negative. Negative words were correctly categorized more often than positive words. Experiment 3 showed that although participants correctly categorized negative words more often than positive words. they could not guess the meaning of the words better than would be expected by chance. The results are discussed against the background of recent findings on basic affective processes. PMID:12564748

  12. Regulation of Arabidopsis Brassinosteroid Signaling by Atypical Basic Helix-Loop-Helix Proteins[C][W

    PubMed Central

    Wang, Hao; Zhu, Yongyou; Fujioka, Shozo; Asami, Tadao; Li, Jiayang; Li, Jianming

    2009-01-01

    Basic helix-loop-helix (bHLH) proteins are highly conserved transcription factors critical for cell proliferation and differentiation. Recent studies have implicated bHLH proteins in many plant signaling processes, including brassinosteroid (BR) signaling. Here, we report identification of two families of atypical bHLH proteins capable of modulating BR signaling. We found that activation-tagged bri1 suppressor 1-Dominant (atbs1-D), previously identified as a dominant suppressor of a weak BR receptor mutant bri1-301, was caused by overexpression of a 93–amino acid atypical bHLH protein lacking amino acids critical for DNA binding. Interestingly, atbs1-D only suppresses weak BR mutants, while overexpression of a truncated ATBS1 lacking the basic motif also rescues bri1-301, suggesting that ATBS1 likely stimulates BR signaling by sequestering negative BR signaling components. A yeast two-hybrid screen using ATBS1 as bait discovered four ATBS1-Interacting Factors (AIFs) that are members of another atypical bHLH protein subfamily. AIF1 exhibits an overlapping expression pattern with ATBS1 and its homologs and interacts with ATBS1 in vitro and in vivo. AIF1 overexpression nullifies the suppressive effect of atbs1-D on bri1-301 and results in dwarf transgenic plants resembling BR mutants. By contrast, silencing of AIF1 partially suppressed the bri1-301 phenotype. Our results suggested that plants use these atypical bHLH proteins to regulate BR signaling. PMID:20023194

  13. The basic aerodynamics of floatation

    SciTech Connect

    Davies, M.J.; Wood, D.H.

    1983-09-01

    The original derivation of the basic theory governing the aerodynamics of both hovercraft and modern floatation ovens, requires the validity of some extremely crude assumptions. However, the basic theory is surprisingly accurate. It is shown that this accuracy occurs because the final expression of the basic theory can be derived by approximating the full Navier-Stokes equations in a manner that clearly shows the limitations of the theory. These limitations are used in discussing the relatively small discrepancies between the theory and experiment, which may not be significant for practical purposes.

  14. Basic nitrogen in hydrocracked resids

    SciTech Connect

    Somogyvari, A.; Zanzotto, L. ); Jeffries, R. )

    1990-07-01

    No direct link has been established between the basic nitrogen components of hydrocracked residues and the increase in anti-stripping properties of distillation residues containing them. Thus, it is the intent of this report to show that a correlation exists between the basic nitrogen components of hydrocracked residues and the anti-stripping properties of asphalts containing them and that it is not only the quantity but also the type of basic nitrogen compounds found in the hydrocracked residues that account for the enhanced anti-stripping properties of these bitumens and blends containing them.

  15. Think (Gram) negative!

    PubMed Central

    2010-01-01

    The increasing prevalence of multiresistant Gram-negative bacteria of the Enterobacteriaceae family in Europe is a worrisome phenomenon. Extended spectrum betalactamase-producing Escherichia coli strains are widespread in the community and are frequently imported into the hospital. Of even more concern is the spread of carbapenem-resistant strains of Klebsiella spp. from regions where they are already endemic. Antibiotic use is a main driver of antibiotic resistance, which again increases broad spectrum antibiotic use, resulting in a vicious circle that is difficult to interrupt. The present commentary highlights important findings of a surveillance study of antimicrobial use and resistance in German ICUs over 8 years with a focus on Gram-negative resistance. PMID:20587087

  16. Negative refraction and superconductivity

    NASA Astrophysics Data System (ADS)

    Amariti, Antonio; Forcella, Davide; Mariotti, Alberto; Siani, Massimo

    2011-10-01

    We discuss exotic properties of charged hydrodynamical systems, in the broken superconducting phase, probed by electromagnetic waves. Motivated by general arguments from hydrodynamics, we observe that negative refraction, namely the propagation in opposite directions of the phase velocities and of the energy flux, is expected for low enough frequencies. We corroborate this general idea by analyzing a holographic superconductor in the AdS/CFT correspondence, where the response functions can be explicitly computed. We study the dual gravitational theory both in the probe and in the backreacted case. We find that, while in the first case the refractive index is positive at every frequency, in the second case there is negative refraction at low enough frequencies. This is in agreement with hydrodynamic considerations.

  17. The negative repetition effect.

    PubMed

    Mulligan, Neil W; Peterson, Daniel J

    2013-09-01

    A fundamental property of human memory is that repetition enhances memory. Peterson and Mulligan (2012) recently documented a surprising negative repetition effect, in which participants who studied a list of cue-target pairs twice recalled fewer targets than a group who studied the pairs only once. Words within a pair rhymed, and across pairs, the target words were drawn from a small set of categories. In the repetition condition, the pairs were initially presented in a random order and then presented a 2nd time blocked by the category of the target words. In the single presentation condition, the pairs were presented only in the blocked order. Participants in the former condition recalled fewer target words on a free recall test despite having seen the word pairs twice (the negative repetition effect). This phenomenon is explored in a series of 5 experiments assessing 3 theoretical accounts of the effect. The experiments demonstrate that the negative repetition effect generalizes over multiple encoding conditions (reading and generative encoding), over different memory tests (free and cued recall), and over delay (5 min and 2 days). The results argue against a retrieval account and a levels-of-processing account but are consistent with the item-specific-relational account, the account upon which the effect was initially predicated. PMID:23421508

  18. Predictors of dominance in male Betta splendens.

    PubMed

    Bronstein, P M

    1985-03-01

    The formation of dominance/subordinancy relations in pairs of male Siamese fighting fish was examined in six experiments. Dominant animals typically were those fish that built the largest nests and that attacked an image of a live, displaying male most intensely prior to combat. However, pretest performance on an operant task and reaction to an animal's own mirror image were not useful predictors of subsequent dominance. These findings are consistent with the suggestion that domesticated Bettas have a territorial social strategy that includes both nest-building and fighting behaviors.

  19. Female Dominance over Males in Primates: Self-Organisation and Sexual Dimorphism

    PubMed Central

    Hemelrijk, Charlotte K.; Wantia, Jan; Isler, Karin

    2008-01-01

    The processes that underlie the formation of the dominance hierarchy in a group are since long under debate. Models of self-organisation suggest that dominance hierarchies develop by the self-reinforcing effects of winning and losing fights (the so-called winner-loser effect), but according to ‘the prior attribute hypothesis’, dominance hierarchies develop from pre-existing individual differences, such as in body mass. In the present paper, we investigate the relevance of each of these two theories for the degree of female dominance over males. We investigate this in a correlative study in which we compare female dominance between groups of 22 species throughout the primate order. In our study female dominance may range from 0 (no female dominance) to 1 (complete female dominance). As regards ‘the prior attribute hypothesis’, we expected a negative correlation between female dominance over males and species-specific sexual dimorphism in body mass. However, to our surprise we found none (we use the method of independent contrasts). Instead, we confirm the self-organisation hypothesis: our model based on the winner-loser effect predicts that female dominance over males increases with the percentage of males in the group. We confirm this pattern at several levels in empirical data (among groups of a single species and between species of the same genus and of different ones). Since the winner-loser effect has been shown to work in many taxa including humans, these results may have broad implications. PMID:18628830

  20. Plants, Animals and Basic Skills.

    ERIC Educational Resources Information Center

    Pheasant, Robert

    2000-01-01

    Countrystart is a class in which students work with plants and animals, providing numerous opportunities to integrate basic skills teaching. The practical subject area becomes the vehicle to develop other skills needed by students. (JOW)

  1. French Basic Course. Grammatical Index.

    ERIC Educational Resources Information Center

    Defense Language Inst., Monterey, CA.

    This index is intended for use with Volumes 1 through 8 of the French Basic Course. It facilitates the finding of grammatical references in those volumes. The items are cross-referenced and arranged in alphabetical order. (Author/AMH)

  2. Brain Basics: Know Your Brain

    MedlinePlus

    ... fact sheet is a basic introduction to the human brain. It may help you understand how the healthy ... largest and most highly developed part of the human brain: it consists primarily of the cerebrum ( 2 ) and ...

  3. Finding dominant sets in microarray data.

    PubMed

    Fu, Xuping; Teng, Li; Li, Yao; Chen, Wenbin; Mao, Yumin; Shen, I-Fan; Xie, Yi

    2005-01-01

    Clustering allows us to extract groups of genes that are tightly coexpressed from Microarray data. In this paper, a new method DSF_Clust is developed to find dominant sets (clusters). We have preformed DSF_Clust on several gene expression datasets and given the evaluation with some criteria. The results showed that this approach could cluster dominant sets of good quality compared to kmeans method. DSF_Clust deals with three issues that have bedeviled clustering, some dominant sets being statistically determined in a significance level, predefining cluster structure being not required, and the quality of a dominant set being ensured. We have also applied this approach to analyze published data of yeast cell cycle gene expression and found some biologically meaningful gene groups to be dug out. Furthermore, DSF_Clust is a potentially good tool to search for putative regulatory signals.

  4. Testing the single-state dominance hypothesis

    SciTech Connect

    Álvarez-Rodríguez, R.; Moreno, O.; Moya de Guerra, E.; Sarriguren, P.; Šimkovic, F.; Faessler, A.

    2013-12-30

    We present a theoretical analysis of the single-state dominance hypothesis for the two-neutrino double-beta decay process. The theoretical framework is a proton-neutron QRPA based on a deformed Hartree-Fock mean field with BCS pairing correlations. We focus on the decays of {sup 100}Mo, {sup 116}Cd and {sup 128}Te. We do not find clear evidences for single-state dominance within the present approach.

  5. The relationship between basic need satisfaction and emotional eating.

    PubMed

    Timmerman, G M; Acton, G J

    2001-01-01

    Eating in response to emotions may lead to the consumption of excessive calories which typically leads to weight gain. This study examined the relationship between basic need satisfaction as identified by Maslow's hierarchy and emotional eating. According to Modeling and Role-Modeling theory, when lack of basic need satisfaction functions as a stressor, individuals may be more likely to engage in emotional eating as a substitute for fulfilling their needs in order to maintain homeostasis. The Basic Need Satisfaction Inventory (BNSI) had a strong, negative correlation (r = -.49; p < .001) to the Emotional Eating Scale (EES) indicating that the lower the level of basic need satisfaction, the more likely one engaged in emotional eating. In predicting EES score, 27.7% of the variance was explained by the self-esteem subscale of BNSI. This study supports looking at underlying issues contributing to weight gain in order to develop effective interventions for weight management.

  6. Automatic Detection of Dominance and Expected Interest

    NASA Astrophysics Data System (ADS)

    Escalera, Sergio; Pujol, Oriol; Radeva, Petia; Vitrià, Jordi; Anguera, M. Teresa

    2010-12-01

    Social Signal Processing is an emergent area of research that focuses on the analysis of social constructs. Dominance and interest are two of these social constructs. Dominance refers to the level of influence a person has in a conversation. Interest, when referred in terms of group interactions, can be defined as the degree of engagement that the members of a group collectively display during their interaction. In this paper, we argue that only using behavioral motion information, we are able to predict the interest of observers when looking at face-to-face interactions as well as the dominant people. First, we propose a simple set of movement-based features from body, face, and mouth activity in order to define a higher set of interaction indicators. The considered indicators are manually annotated by observers. Based on the opinions obtained, we define an automatic binary dominance detection problem and a multiclass interest quantification problem. Error-Correcting Output Codes framework is used to learn to rank the perceived observer's interest in face-to-face interactions meanwhile Adaboost is used to solve the dominant detection problem. The automatic system shows good correlation between the automatic categorization results and the manual ranking made by the observers in both dominance and interest detection problems.

  7. Hypothalamic digoxin, hemispheric chemical dominance, and spirituality.

    PubMed

    Kurup, Ravi Kumar; Kurup, Parameswara Achutha

    2003-03-01

    The isoprenoid pathway was assessed in atheistic and spiritually inclined individuals. The pathway was also assessed in individuals with differing hemispheric dominance to assess whether hemispheric dominance has a correlation with spiritual and atheistic tendency. HMG CoA reductase activity, serum digoxin, RBC membrane Na(+)-K+ ATPase activity, serum magnesium, and tyrosine/tryptophan catabolic patterns were assessed in spiritual/atheistic individuals and in those differing hemispheric dominance. In spiritually-inclined individuals, there was increased digoxin synthesis, decreased membrane Na(+)-K+ ATPase activity, increased tryptophan catabolites (serotonin, quinolinic acid, and nicotine), and decreased tyrosine catabolites (dopamine, noradrenaline, and morphine). The pattern in spiritually-inclined individuals correlated with right hemispheric chemical dominance. In atheistic individuals there was decreased digoxin synthesis, increased membrane Na(+)-K+ ATPase activity, decreased tryptophan catabolities (serotonin, quinolinic acid, and nicotine), and increased tyrosine catabolites (dopamine, noradrenaline, and morphine). This pattern in atheistic individuals correlated with that obtained in left hemispheric chemical dominance. Hemispheric chemical dominance and hypothalamic digoxin could regulate the predisposition to spirituality or atheism.

  8. Broadband negative optical constants in composite materials

    NASA Astrophysics Data System (ADS)

    Khosravi, S.; Rostami, A.; Rostami, G.; Dolatyari, M.

    2015-04-01

    Capability of flexible composite substrates, consisting of randomly distributed nanoparticles in polymeric host medium, to illustrate negative effective permittivity and permeability in the mid infrared wavelengths (3-5 μm) is investigated. To produce negative permittivity in the desired wavelength range, we proposed a structure in which plasmonic nanoparticles (doped semiconductors or metallic nanoparticles) are inserted inside polytetrafluoroethylene as the low refractive index polymeric medium. Also, the optical properties of the structures including core/shell nanoparticles in polytetrafluoroethylene host (with polytetrafluoroethylene as core material and dielectric shells possessing higher refractive index compared to refractive index of the host medium) are investigated. It is shown that, high refractive index dielectric shells result in negative μeff in these structures. As a basic idea, to obtain negative optical constants in broad wavelength range, superposition of the mentioned nanoparticles in the polymeric host is examined. The advantages and limitations of the proposed structure are carefully investigated. Moreover, based on the simulation results, we will introduce flexible media that simultaneously display negative permittivity and permeability in the wavelength range of interest. Capability of two types of composites (the first one contains mixture of plasmonic nanoparticles with polymer-dielectric core-shell nanoparticles and the second one includes metal-dielectric core-shell nanoparticles in the polymeric host) to produce both negative effective parameters in the desired wavelength range are investigated and compared together. Finally a polymeric medium with random distribution of core-shell (metal-dielectric) nanoparticles and plasmonic nanoparticles is introduced as an optimal medium to illustrate negative optical constants in mid infrared wavelengths. Clausius-Mossotti formula is used to calculate the effective parameters.

  9. Negative Casimir entropies

    NASA Astrophysics Data System (ADS)

    Li, Yang; Milton, Kimball

    In the last decade, various results on the entropy related to the Casimir interactions between two bodies have been obtained and the striking feature that negative values of Casimir entropy frequently appear. The origin of this effect lies in many factors, such as the dissipation of the materials, the geometry of the configuration and so on. We recently investigated the entropies of one body systems. Although the self-free energy of one body systems are always divergent, the self-entropy could be finite in many cases. These phenomenon may throw more light on thermal dynamical behavior of quantum field systems.

  10. Basics.

    ERIC Educational Resources Information Center

    Instructor, 1982

    1982-01-01

    Recommended activities include: (1) etymology exercises for elementary school students; (2) a search for information about Alexander the Great; (3) monthly inspections of the school yard to observe environmental changes; and (4) an art history unit on Cro-Magnon cave drawings. An interdisciplinary unit on transportation is included. (PP)

  11. Local dominance of exotic plants declines with residence time: a role for plant–soil feedback?

    PubMed Central

    Speek, Tanja A.A.; Schaminée, Joop H.J.; Stam, Jeltje M.; Lotz, Lambertus A.P.; Ozinga, Wim A.; van der Putten, Wim H.

    2015-01-01

    Recent studies have shown that introduced exotic plant species may be released from their native soil-borne pathogens, but that they become exposed to increased soil pathogen activity in the new range when time since introduction increases. Other studies have shown that introduced exotic plant species become less dominant when time since introduction increases, and that plant abundance may be controlled by soil-borne pathogens; however, no study yet has tested whether these soil effects might explain the decline in dominance of exotic plant species following their initial invasiveness. Here we determine plant–soil feedback of 20 plant species that have been introduced into The Netherlands. We tested the hypotheses that (i) exotic plant species with a longer residence time have a more negative soil feedback and (ii) greater local dominance of the introduced exotic plant species correlates with less negative, or more positive, plant–soil feedback. Although the local dominance of exotic plant species decreased with time since introduction, there was no relationship of local dominance with plant–soil feedback. Plant–soil feedback also did not become more negative with increasing time since introduction. We discuss why our results may deviate from some earlier published studies and why plant–soil feedback may not in all cases, or not in all comparisons, explain patterns of local dominance of introduced exotic plant species. PMID:25770013

  12. Classroom Management and Negative Reinforcement.

    ERIC Educational Resources Information Center

    Tauber, Robert T.

    Of the four simple consequences for behavior, none is more misunderstood than negative reinforcement. A Negative Reinforcement Quiz administered to 233 student teachers from two universities revealed that the vast majority of respondents mistakenly viewed negative reinforcement as a synonym for punishment, and believe that negative reinforcement…

  13. Polarized negative ions

    SciTech Connect

    Haeberli, W.

    1981-04-01

    This paper presents a survey of methods, commonly in use or under development, to produce beams of polarized negative ions for injection into accelerators. A short summary recalls how the hyperfine interaction is used to obtain nuclear polarization in beams of atoms. Atomic-beam sources for light ions are discussed. If the best presently known techniques are incorporated in all stages of the source, polarized H/sup -/ and D/sup -/ beams in excess of 10 ..mu..A can probably be achieved. Production of polarized ions from fast (keV) beams of polarized atoms is treated separately for atoms in the H(25) excited state (Lamb-Shift source) and atoms in the H(1S) ground state. The negative ion beam from Lamb-Shift sources has reached a plateau just above 1 ..mu..A, but this beam current is adequate for many applications and the somewhat lower beam current is compensated by other desirable characteristics. Sources using fast polarized ground state atoms are in a stage of intense development. The next sections summarize production of polarized heavy ions by the atomic beam method, which is well established, and by optical pumping, which has recently been demonstrated to yield very large nuclear polarization. A short discussion of proposed ion sources for polarized /sup 3/He/sup -/ ions is followed by some concluding remarks.

  14. Negative magnetoresistivity in holography

    NASA Astrophysics Data System (ADS)

    Sun, Ya-Wen; Yang, Qing

    2016-09-01

    Negative magnetoresistivity is a special magnetotransport property associated with chiral anomaly in four dimensional chiral anomalous systems, which refers to the transport behavior that the DC longitudinal magnetoresistivity decreases with increasing magnetic field. We calculate the longitudinal magnetoconductivity in the presence of back-reactions of the magnetic field to gravity in holographic zero charge and axial charge density systems with and without axial charge dissipation. In the absence of axial charge dissipation, we find that the quantum critical conductivity grows with increasing magnetic field when the backreaction strength is larger than a critical value, in contrast to the monotonically decreasing behavior of quantum critical conductivity in the probe limit. With axial charge dissipation, we find the negative magnetoresistivity behavior. The DC longitudinal magnetoconductivity scales as B in the large magnetic field limit, which deviates from the exact B 2 scaling of the probe limit result. In both cases, the small frequency longitudinal magnetoconductivity still agrees with the formula obtained from the hydrodynamic linear response theory, even in the large magnetic field limit.

  15. Underlying memory-dominant nature of hysteresis in piezoelectric materials

    NASA Astrophysics Data System (ADS)

    Bashash, Saeid; Jalili, Nader

    2006-07-01

    Although the existence of nonlocal memories in hysteresis behavior of piezoelectric materials has been demonstrated, their detailed and thorough properties have yet to be revealed. Along this line, we disclose and demonstrate the underlying memory-dominant nature of hysteresis, and characterize its important properties that must be considered for the accurate prediction of hysteresis trajectory in piezoelectric materials. More specifically, the concept of recording the turning points, targeting the previously recorded turning points, curve alignment, and wiping-out effects at these points are introduced as the basic intellectual properties of hysteresis nonlinearity. A constitutive memory-based mathematical modeling framework is then developed and trained for the precise prediction of a hysteresis path for arbitrarily assigned input profiles. Utilizing a piezoelectric-driven actuator, it is experimentally demonstrated that if the number of memory units is sufficiently selected, model response in the prediction of a hysteresis track is significantly improved.

  16. Resistance of mitochondrial p53 to dominant inhibition

    PubMed Central

    Heyne, Kristina; Schmitt, Katrin; Mueller, Daniel; Armbruester, Vivienne; Mestres, Pedro; Roemer, Klaus

    2008-01-01

    Background Mutation of a tumor suppressor allele leaves the second as backup. Not necessarily so with p53. This homo-tetrameric transcription factor can become contaminated with mutant p53 through hetero-tetramerization. In addition, it can be out-competed by the binding to p53 DNA recognition motifs of transactivation-incompetent isoforms (ΔN and ΔTA-isoforms) of the p53/p63/p73 family of proteins. Countermeasures against such dominant-negative or dominant-inhibitory action might include the evolutionary gain of novel, transactivation-independent tumor suppressor functions by the wild-type monomer. Results Here we have studied, mostly in human HCT116 colon adenocarcinoma cells with an intact p53 pathway, the effects of dominant-inhibitory p53 mutants and of Δex2/3p73, a tumor-associated ΔTA-competitor of wild-type p53, on the nuclear transactivation-dependent and extra-nuclear transactivation-independent functions of wild-type p53. We report that mutant p53 and Δex2/3p73, expressed from a single gene copy per cell, interfere with the stress-induced expression of p53-responsive genes but leave the extra-nuclear apoptosis by mitochondrial p53 largely unaffected, although both wild-type and mutant p53 associate with the mitochondria. In accord with these observations, we present evidence that in contrast to nuclear p53 the vast majority of mitochondrial p53, be it wild-type or mutant, is consisting of monomeric protein. Conclusion The extra-nuclear p53-dependent apoptosis may constitute a fail-safe mechanism against dominant inhibition. PMID:18547443

  17. The network motif architecture of dominance hierarchies.

    PubMed

    Shizuka, Daizaburo; McDonald, David B

    2015-04-01

    The widespread existence of dominance hierarchies has been a central puzzle in social evolution, yet we lack a framework for synthesizing the vast empirical data on hierarchy structure in animal groups. We applied network motif analysis to compare the structures of dominance networks from data published over the past 80 years. Overall patterns of dominance relations, including some aspects of non-interactions, were strikingly similar across disparate group types. For example, nearly all groups exhibited high frequencies of transitive triads, whereas cycles were very rare. Moreover, pass-along triads were rare, and double-dominant triads were common in most groups. These patterns did not vary in any systematic way across taxa, study settings (captive or wild) or group size. Two factors significantly affected network motif structure: the proportion of dyads that were observed to interact and the interaction rates of the top-ranked individuals. Thus, study design (i.e. how many interactions were observed) and the behaviour of key individuals in the group could explain much of the variations we see in social hierarchies across animals. Our findings confirm the ubiquity of dominance hierarchies across all animal systems, and demonstrate that network analysis provides new avenues for comparative analyses of social hierarchies. PMID:25762649

  18. The network motif architecture of dominance hierarchies.

    PubMed

    Shizuka, Daizaburo; McDonald, David B

    2015-04-01

    The widespread existence of dominance hierarchies has been a central puzzle in social evolution, yet we lack a framework for synthesizing the vast empirical data on hierarchy structure in animal groups. We applied network motif analysis to compare the structures of dominance networks from data published over the past 80 years. Overall patterns of dominance relations, including some aspects of non-interactions, were strikingly similar across disparate group types. For example, nearly all groups exhibited high frequencies of transitive triads, whereas cycles were very rare. Moreover, pass-along triads were rare, and double-dominant triads were common in most groups. These patterns did not vary in any systematic way across taxa, study settings (captive or wild) or group size. Two factors significantly affected network motif structure: the proportion of dyads that were observed to interact and the interaction rates of the top-ranked individuals. Thus, study design (i.e. how many interactions were observed) and the behaviour of key individuals in the group could explain much of the variations we see in social hierarchies across animals. Our findings confirm the ubiquity of dominance hierarchies across all animal systems, and demonstrate that network analysis provides new avenues for comparative analyses of social hierarchies.

  19. Anomalous dominance, immune parameters, and spatial ability.

    PubMed

    Hassler, M

    1993-02-01

    In a sample of male and female subjects in late adolescence, we investigated the relationship of spatial abilities to anomalous dominance and immune parameters as suggested by Geschwind's model of cerebral lateralization (Geschwind & Galaburda, 1985) In addition to the behavioral markers asthma/allergies, migraine, and myopia, we measured IgE and Ig total in blood serum. Atypical handedness, atypical language dominance, and atypical visuospatial dominance were found to be connected with spatial giftedness, and atypical handedness was related to immune vulnerability in males. This outcome provided some support for the Geschwind model in men. In women, spatial giftedness was related to immune vulnerability, but no indicator of anomalous dominance was connected with either giftedness, or immune parameters. Thus, the central thesis of the Geschwind model, i.e., elevated prenatal testosterone effects on the developing brain cause anomalous dominance and, as side effects, spatial giftedness and immune vulnerability, and all these consequences should be related to each other, was not confirmed by our data for females.

  20. Conditioned social dominance threat: observation of others' social dominance biases threat learning.

    PubMed

    Haaker, Jan; Molapour, Tanaz; Olsson, Andreas

    2016-10-01

    Social groups are organized along dominance hierarchies, which determine how we respond to threats posed by dominant and subordinate others. The persuasive impact of these dominance threats on mental and physical well-being has been well described but it is unknown how dominance rank of others bias our experience and learning in the first place. We introduce a model of conditioned social dominance threat in humans, where the presence of a dominant other is paired with an aversive event. Participants first learned about the dominance rank of others by observing their dyadic confrontations. During subsequent fear learning, the dominant and subordinate others were equally predictive of an aversive consequence (mild electric shock) to the participant. In three separate experiments, we show that participants' eye-blink startle responses and amygdala reactivity adaptively tracked dominance of others during observation of confrontation. Importantly, during fear learning dominant vs subordinate others elicited stronger and more persistent learned threat responses as measured by physiological arousal and amygdala activity. Our results characterize the neural basis of learning through observing conflicts between others, and how this affects subsequent learning through direct, personal experiences.

  1. Back to basics: hand hygiene and isolation

    PubMed Central

    Lin Huang, G. Khai; Stewardson, Andrew J.; Lindsay Grayson, M.

    2014-01-01

    Purpose of review Hand hygiene and isolation are basic, but very effective, means of preventing the spread of pathogens in healthcare. Although the principle may be straightforward, this review highlights some of the controversies regarding the implementation and efficacy of these interventions. Recent findings Hand hygiene compliance is an accepted measure of quality and safety in many countries. The evidence for the efficacy of hand hygiene in directly reducing rates of hospital-acquired infections has strengthened in recent years, particularly in terms of reduced rates of staphylococcal sepsis. Defining the key components of effective implementation strategies and the ideal method(s) of assessing hand hygiene compliance are dependent on a range of factors associated with the healthcare system. Although patient isolation continues to be an important strategy, particularly in outbreaks, it also has some limitations and can be associated with negative effects. Recent detailed molecular epidemiology studies of key healthcare-acquired pathogens have questioned the true efficacy of isolation, alone as an effective method for the routine prevention of disease transmission. Summary Hand hygiene and isolation are key components of basic infection control. Recent insights into the benefits, limitations and even adverse effects of these interventions are important for their optimal implementation. PMID:24945613

  2. E-Basics: Online Basic Training in Program Evaluation

    ERIC Educational Resources Information Center

    Silliman, Ben

    2016-01-01

    E-Basics is an online training in program evaluation concepts and skills designed for youth development professionals, especially those working in nonformal science education. Ten hours of online training in seven modules is designed to prepare participants for mentoring and applied practice, mastery, and/or team leadership in program evaluation.…

  3. The basic aerodynamics of floatation

    NASA Astrophysics Data System (ADS)

    Davies, M. J.; Wood, D. H.

    1983-09-01

    It is pointed out that the basic aerodynamics of modern floatation ovens, in which the continuous, freshly painted metal strip is floated, dried, and cured, is the two-dimensional analog of that of hovercraft. The basic theory for the static lift considered in connection with the study of hovercraft has had spectacular success in describing the experimental results. This appears surprising in view of the crudity of the theory. The present investigation represents an attempt to explore the reasons for this success. An outline of the basic theory is presented and an approach is shown for deriving the resulting expressions for the lift from the full Navier-Stokes equations in a manner that clearly indicates the limitations on the validity of the expressions. Attention is given to the generally good agreement between the theory and the axisymmetric (about the centerline) results reported by Jaumotte and Kiedrzynski (1965).

  4. Basic Operational Robotics Instructional System

    NASA Technical Reports Server (NTRS)

    Todd, Brian Keith; Fischer, James; Falgout, Jane; Schweers, John

    2013-01-01

    The Basic Operational Robotics Instructional System (BORIS) is a six-degree-of-freedom rotational robotic manipulator system simulation used for training of fundamental robotics concepts, with in-line shoulder, offset elbow, and offset wrist. BORIS is used to provide generic robotics training to aerospace professionals including flight crews, flight controllers, and robotics instructors. It uses forward kinematic and inverse kinematic algorithms to simulate joint and end-effector motion, combined with a multibody dynamics model, moving-object contact model, and X-Windows based graphical user interfaces, coordinated in the Trick Simulation modeling environment. The motivation for development of BORIS was the need for a generic system for basic robotics training. Before BORIS, introductory robotics training was done with either the SRMS (Shuttle Remote Manipulator System) or SSRMS (Space Station Remote Manipulator System) simulations. The unique construction of each of these systems required some specialized training that distracted students from the ideas and goals of the basic robotics instruction.

  5. Basic research for environmental restoration

    SciTech Connect

    Not Available

    1990-12-01

    The Department of Energy (DOE) is in the midst of a major environmental restoration effort to reduce the health and environmental risks resulting from past waste management and disposal practices at DOE sites. This report describes research needs in environmental restoration and complements a previously published document, DOE/ER-0419, Evaluation of Mid-to-Long Term Basic Research for Environmental Restoration. Basic research needs have been grouped into five major categories patterned after those identified in DOE/ER-0419: (1) environmental transport and transformations; (2) advanced sampling, characterization, and monitoring methods; (3) new remediation technologies; (4) performance assessment; and (5) health and environmental effects. In addition to basic research, this document deals with education and training needs for environmental restoration. 2 figs., 6 tabs.

  6. Negative ion source

    DOEpatents

    Leung, K.N.; Ehlers, K.W.

    1982-08-06

    An ionization vessel is divided into an ionizing zone and an extraction zone by a magnetic filter. The magnetic filter prevents high-energy electrons from crossing from the ionizing zone to the extraction zone. A small positive voltage impressed on a plasma grid, located adjacent an extraction grid, positively biases the plasma in the extraction zone to thereby prevent positive ions from migrating from the ionizing zone to the extraction zone. Low-energy electrons, which would ordinarily be dragged by the positive ions into the extraction zone, are thereby prevented from being present in the extraction zone and being extracted along with negative ions by the extraction grid. Additional electrons are suppressed from the output flux using ExB drift provided by permanent magnets and the extractor grid electrical field.

  7. Negative ion source

    DOEpatents

    Leung, Ka-Ngo; Ehlers, Kenneth W.

    1984-01-01

    An ionization vessel is divided into an ionizing zone and an extraction zone by a magnetic filter. The magnetic filter prevents high-energy electrons from crossing from the ionizing zone to the extraction zone. A small positive voltage impressed on a plasma grid, located adjacent an extraction grid, positively biases the plasma in the extraction zone to thereby prevent positive ions from migrating from the ionizing zone to the extraction zone. Low-energy electrons, which would ordinarily be dragged by the positive ions into the extraction zone, are thereby prevented from being present in the extraction zone and being extracted along with negative ions by the extraction grid. Additional electrons are suppressed from the output flux using ExB drift provided by permanent magnets and the extractor grid electrical field.

  8. Negative ion source

    DOEpatents

    Leung, K.N.; Ehlers, K.W.

    1984-12-04

    An ionization vessel is divided into an ionizing zone and an extraction zone by a magnetic filter. The magnetic filter prevents high-energy electrons from crossing from the ionizing zone to the extraction zone. A small positive voltage impressed on a plasma grid, located adjacent an extraction grid, positively biases the plasma in the extraction zone to thereby prevent positive ions from migrating from the ionizing zone to the extraction zone. Low-energy electrons, which would ordinarily be dragged by the positive ions into the extraction zone, are thereby prevented from being present in the extraction zone and being extracted along with negative ions by the extraction grid. Additional electrons are suppressed from the output flux using ExB drift provided by permanent magnets and the extractor grid electrical field. 14 figs.

  9. Do `negative' temperatures exist?

    NASA Astrophysics Data System (ADS)

    Lavenda, B. H.

    1999-06-01

    A modification of the second law is required for a system with a bounded density of states and not the introduction of a `negative' temperature scale. The ascending and descending branches of the entropy versus energy curve describe particle and hole states, having thermal equations of state that are given by the Fermi and logistic distributions, respectively. Conservation of energy requires isentropic states to be isothermal. The effect of adiabatically reversing the field is entirely mechanical because the only difference between the two states is their energies. The laws of large and small numbers, leading to the normal and Poisson approximations, characterize statistically the states of infinite and zero temperatures, respectively. Since the heat capacity also vanishes in the state of maximum disorder, the third law can be generalized in systems with a bounded density of states: the entropy tends to a constant as the temperature tends to either zero or infinity.

  10. Negative Optical Torque

    PubMed Central

    Chen, Jun; Ng, Jack; Ding, Kun; Fung, Kin Hung; Lin, Zhifang; Chan, C. T.

    2014-01-01

    Light carries angular momentum, and as such it can exert torques on material objects. Applications of these opto-mechanical effects were limited initially due to their smallness in magnitude, but later becomes powerful and versatile after the invention of laser. Novel and practical approaches for harvesting light for particle rotation have since been demonstrated, where the structure is always subjected to a positive optical torque along a certain axis if the incident angular momentum has a positive projection on the same axis. We report here an interesting phenomenon of “negative optical torque”, meaning that incoming photons carrying angular momentum rotate an object in the opposite sense. Surprisingly this can be realized quite straightforwardly in simple planar structures. Field retardation is a necessary condition and discrete rotational symmetry of material object plays an important role. The optimal conditions are explored and explained. PMID:25226863

  11. Negative Entropy of Life

    NASA Astrophysics Data System (ADS)

    Goradia, Shantilal

    2015-10-01

    We modify Newtonian gravity to probabilistic quantum mechanical gravity to derive strong coupling. If this approach is valid, we should be able to extend it to the physical body (life) as follows. Using Boltzmann equation, we get the entropy of the universe (137) as if its reciprocal, the fine structure constant (ALPHA), is the hidden candidate representing the negative entropy of the universe which is indicative of the binary information as its basis (http://www.arXiv.org/pdf/physics0210040v5). Since ALPHA relates to cosmology, it must relate to molecular biology too, with the binary system as the fundamental source of information for the nucleotides of the DNA as implicit in the book by the author: ``Quantum Consciousness - The Road to Reality.'' We debate claims of anthropic principle based on the negligible variation of ALPHA and throw light on thermodynamics. We question constancy of G in multiple ways.

  12. 48 CFR 16.702 - Basic agreements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Basic agreements. 16.702... AND CONTRACT TYPES TYPES OF CONTRACTS Agreements 16.702 Basic agreements. (a) Description. A basic... attachment the required and applicable clauses agreed upon in the basic agreement. A basic agreement is not...

  13. 48 CFR 16.702 - Basic agreements.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 1 2011-10-01 2011-10-01 false Basic agreements. 16.702... AND CONTRACT TYPES TYPES OF CONTRACTS Agreements 16.702 Basic agreements. (a) Description. A basic... attachment the required and applicable clauses agreed upon in the basic agreement. A basic agreement is not...

  14. 48 CFR 16.702 - Basic agreements.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 1 2012-10-01 2012-10-01 false Basic agreements. 16.702... AND CONTRACT TYPES TYPES OF CONTRACTS Agreements 16.702 Basic agreements. (a) Description. A basic... attachment the required and applicable clauses agreed upon in the basic agreement. A basic agreement is not...

  15. 48 CFR 16.702 - Basic agreements.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 1 2014-10-01 2014-10-01 false Basic agreements. 16.702... AND CONTRACT TYPES TYPES OF CONTRACTS Agreements 16.702 Basic agreements. (a) Description. A basic... attachment the required and applicable clauses agreed upon in the basic agreement. A basic agreement is not...

  16. 48 CFR 16.702 - Basic agreements.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 1 2013-10-01 2013-10-01 false Basic agreements. 16.702... AND CONTRACT TYPES TYPES OF CONTRACTS Agreements 16.702 Basic agreements. (a) Description. A basic... attachment the required and applicable clauses agreed upon in the basic agreement. A basic agreement is not...

  17. Basic Communication Course Annual. Volume 5.

    ERIC Educational Resources Information Center

    Hugenberg, Lawrence W., Ed.

    This volume of an annual collection of essays relating to instruction in the basic communication course presents 1992 Speech Communication Association Basic Course Committee award winning papers, articles on teaching assistants in the basic course, approaches to teaching in the basic course, research on the basic course, and a commentary. Essays…

  18. Basic Communication Course Annual. Volume 2.

    ERIC Educational Resources Information Center

    Hugenberg, Lawrence W., Ed.

    This annual collection contains essays relating to instruction in the basic communication course, grading in the basic communication course, evaluating the basic communication course, and the "state" of the basic communication course. Papers in the collection include: "The Future of the Basic Course" (Judy C. Pearson and Paul Nelson);…

  19. An exploitation-competition system with negative effect of prey on its predator.

    PubMed

    Wang, Yuanshi

    2015-05-01

    This paper considers an exploitation-competition system in which exploitation is the dominant interaction when the prey is at low density, while competition is dominant when the prey is at high density due to its negative effect on the predator. The two-species system is characterized by differential equations, which are the combination of Lotka-Volterra competitive and predator-prey models. Global dynamics of the model demonstrate some basic properties of exploitation-competition systems: (i) When the growth rate of prey is extremely small, the prey cannot promote the growth of predator. (ii) When the growth rate is small, an obligate predator can survive by preying on the prey, while a facultative predator can approach a high density by the predation. (iii) When the growth rate is intermediate, the predator can approach the maximal density by an intermediate predation. (iv) When the growth rate is large, the predator can persist only if it has a large density and its predation on the prey is big. (v) Intermediate predation is beneficial to the predator under certain parameter range, while over- or under-predation is not good. Extremely big/small predation would lead to extinction of species. Numerical simulations confirm and extend our results.

  20. An exploitation-competition system with negative effect of prey on its predator.

    PubMed

    Wang, Yuanshi

    2015-05-01

    This paper considers an exploitation-competition system in which exploitation is the dominant interaction when the prey is at low density, while competition is dominant when the prey is at high density due to its negative effect on the predator. The two-species system is characterized by differential equations, which are the combination of Lotka-Volterra competitive and predator-prey models. Global dynamics of the model demonstrate some basic properties of exploitation-competition systems: (i) When the growth rate of prey is extremely small, the prey cannot promote the growth of predator. (ii) When the growth rate is small, an obligate predator can survive by preying on the prey, while a facultative predator can approach a high density by the predation. (iii) When the growth rate is intermediate, the predator can approach the maximal density by an intermediate predation. (iv) When the growth rate is large, the predator can persist only if it has a large density and its predation on the prey is big. (v) Intermediate predation is beneficial to the predator under certain parameter range, while over- or under-predation is not good. Extremely big/small predation would lead to extinction of species. Numerical simulations confirm and extend our results. PMID:25707917

  1. Toward the next generation of negative symptom assessments: the collaboration to advance negative symptom assessment in schizophrenia.

    PubMed

    Blanchard, Jack J; Kring, Ann M; Horan, William P; Gur, Raquel

    2011-03-01

    Negative symptoms in schizophrenia are related to poor functional outcome, persistent over time, a source of burden for caregivers, and only minimally responsive to currently available medications. A major challenge to developing efficacious interventions concerns the valid and reliable assessment of negative symptoms. In a recent consensus statement on negative symptoms, a central recommendation was the need to develop new assessment approaches that address the limitations of existing instruments. In the current report, we summarize the background and rationale for the Collaboration to Advance Negative Symptom Assessment in Schizophrenia (CANSAS). The CANSAS project is an National Institute of Mental Health-funded multisite study that is constructing a next-generation negative symptom scale, the Clinical Assessment Interview for Negative Symptoms (CAINS). The CAINS is being developed within a data-driven iterative process that seeks to ensure the measure's reliability, validity, and utility for both basic psychopathology and treatment development research. PMID:20861151

  2. EXTRASOLAR REFRACTORY-DOMINATED PLANETESIMALS: AN ASSESSMENT

    SciTech Connect

    Jura, M.; Xu, S. E-mail: sxu@astro.ucla.edu

    2013-02-01

    Previously published observations of 60 externally polluted white dwarfs show that none of the stars have accreted from intact refractory-dominated parent bodies composed mainly of Al, Ca, and O, although planetesimals with such a distinctive composition have been predicted to form. We propose that such remarkable objects are not detected by themselves because, unless they are scattered outward from their initial orbit, they are engulfed and destroyed during the star's asymptotic giant branch evolution. As yet, there is at most only weak evidence supporting a scenario where the composition of any extrasolar minor planet can be explained by blending of an outwardly scattered refractory-dominated planetesimal with an ambient asteroid.

  3. 19. Print from copy negative (original glass plate negative in ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    19. Print from copy negative (original glass plate negative in Tippecanoe County Historical Society.) Original photo dated May 7, 1893. View north, south side. - Big Four Depot, 10 South Second Street, Lafayette, Tippecanoe County, IN

  4. The Electrophysiology of Basic Phrase Building

    PubMed Central

    Lapinskaya, Natalia; Heffner, Christopher C.; Malko, Anton; Lau, Ellen F.

    2016-01-01

    A defining trait of linguistic competence is the ability to combine elements into increasingly complex structures to denote, and to comprehend, a potentially infinite number of meanings. Recent magnetoencephalography (MEG) work has investigated these processes by comparing the response to nouns in combinatorial (blue car) and non-combinatorial (rnsh car) contexts. In the current study we extended this paradigm using electroencephalography (EEG) to dissociate the role of semantic content from phonological well-formedness (yerl car). We used event-related potential (ERP) recordings in order to better relate the observed neurophysiological correlates of basic combinatorial operations to prior ERP work on comprehension. We found that nouns in combinatorial contexts (blue car) elicited a greater centro-parietal negativity between 180-400ms, independent of the phonological well-formedness of the context word. We discuss the potential relationship between this ‘combinatorial’ effect and classic N400 effects. We also report preliminary evidence for an early anterior negative deflection immediately preceding the critical noun in combinatorial contexts, which we tentatively interpret as an electrophysiological reflex of syntactic structure initialization. PMID:27711111

  5. Basics of Resonance Chiral Theory

    SciTech Connect

    Portoles, J.

    2010-12-28

    We review the main components that have to be considered, within Resonance Chiral Theory, in the study of processes whose dynamics is dominated by hadron resonances. We show its application in the study of the {tau}{yields}{pi}{pi}{pi}{nu}{sub {tau}} decay.

  6. Basic Program Plan. Condensed Version.

    ERIC Educational Resources Information Center

    Stanford Univ., CA. Stanford Center for Research and Development in Teaching.

    This condensed version of the Basic Program Plan for the Stanford Center for Research and Development in Teaching (SCDRT) outlines the proposed plans of substantive programs over the next several years (beginning December 1, 1972). Information on projected costs and the Center's institutional capabilities for administering, reviewing, and…

  7. The Audit Committee. Board Basics

    ERIC Educational Resources Information Center

    Ostrom, John S.

    2004-01-01

    The Effective Committees set of booklets comprises publications on the following committees: investment, buildings and grounds, academic affairs, student affairs, finance, development, trustees, audit, compensation, and executive. It is part of the AGB Board Basics Series. This report describes the primary role of an audit committee. The primary…

  8. Adult Basic Education; Operations Manual.

    ERIC Educational Resources Information Center

    Missouri State Dept. of Education, Jefferson City.

    This publication is an administrative guide for Missouri school administrators and local adult basic education supervisors. First, general information is given as to legislative authority, standards for approval, procedures for implementation, expenditures and reimbursement, teacher qualifications, program administration, student eligibility and…

  9. Play Therapy: Basics and Beyond.

    ERIC Educational Resources Information Center

    Kottman, Terry

    This book provides an atheoretical orientation to basic concepts involved in play therapy and an introduction to different skills used in play therapy. The demand for mental professionals and school counselors who have training and expertise in using play as a therapeutic tool when working with children has increased tremendously. In response to…

  10. Basic Mechanisms of the Epilepsies.

    ERIC Educational Resources Information Center

    Jasper, Herbert H., Ed.; And Others

    A collection of highly technical scientific articles by international basic and clinical neuroscientists constitutes a review of their knowledge of the brain and nervous system, particularly the aspects related to loss of brain function control and its explosive discharges which cause epileptic seizures. Anatomy, biophysics, biochemistry, and…

  11. The Future of Basic Writing

    ERIC Educational Resources Information Center

    Otte, George; Mlynarczyk, Rebecca Williams

    2010-01-01

    In this article, we assess the status of basic writing early in the twenty-first century. Beginning with a discussion of the attacks on BW that intensified during the 1990s and early 2000s--attacks that originated from such diverse sources as state legislatures, university officials, and BW scholars themselves--we go on to summarize the responses…

  12. Emergency medicine: beyond the basics.

    PubMed

    Malamed, S F

    1997-07-01

    Medical emergencies can arise in the dental office. Preparedness for these emergencies is predicated on an ability to rapidly recognize a problem and to effectively institute prompt and proper management. In all emergency situations, management is based on implementation of basic life support, as needed. The author describes the appropriate management of two common emergency situations: allergy and chest pain.

  13. Basic Education in International Perspective.

    ERIC Educational Resources Information Center

    Cain, Edmund J.; And Others

    These papers, delivered at the 1981 World Assembly of the International Council on Education for Teaching, reflect the theme of the conference: provision of basic education for all persons, focusing particularly on policies and situations in developing nations. The 14 presentations were from nine nations: (1) "Curriculum Materials for Basic…

  14. Core Competencies for Basic Drafting.

    ERIC Educational Resources Information Center

    Werner, Claire; Calderon, Ray

    These competencies for drafting are designed to cover basic principles and practices for beginning drafters. Each competency appears in a one-page format. It is presented as a goal statement followed by one or more "indicator" statements, which are performance objectives describing an ability that, upon attainment, will establish competency for…

  15. Basic Objects in Natural Categories

    ERIC Educational Resources Information Center

    Rosch, Eleanor; And Others

    1976-01-01

    Results show that basic objects are shown to be the most inclusive categories for which a concrete image of the category as a whole can be formed, to be the first categorizations made during perception of the environment and to be the categories most codable, most coded, and most necessary in language. (Author/DEP)

  16. Getting Back to Basics (& Acidics)

    ERIC Educational Resources Information Center

    Rhodes, Sam

    2006-01-01

    This article describes a few novel acid-base experiments intended to introduce students to the basic concepts of acid-base chemistry and provide practical examples that apply directly to the study of biology and the human body. Important concepts such as the reaction between carbon dioxide and water, buffers and protein denaturation, are covered.…

  17. Basic Considerations in Interviewing Children.

    ERIC Educational Resources Information Center

    Jennings, Rick L.

    This manual summarizes and highlights basic considerations in interviewing children. The relationship between interviewing for data collection and interviewing within the counseling or psychotherapeutic context is discussed. The Interviewer's Functional Checklist is presented to provide a method for self-evaluating interviewer behavior, and for…

  18. Guarani Basic Course, Part I.

    ERIC Educational Resources Information Center

    Blair, Robert W.; And Others

    This is the first in a two-volume basic course in Guarani, the indigenous language of Paraguay. The volume consists of an introduction to the Guarani language, some general principles for adult language-learning, and ten instructional units. Because the goal of the course is to encourage and lead the learner to communicate in Guarani in class and…

  19. Guarani Basic Course, Part II.

    ERIC Educational Resources Information Center

    Blair, Robert W.; And Others

    This volume of the basic course in Guarani (the indigenous language of Paraguay) contains the core stage, or class-instructional phase, of the ten units presented in Volume One. These units contain explanations, exercises, dialogues, various types of pattern drills, suggestions for games and communication activities, and various types of…

  20. Basic Instructional Technology Staff Guide.

    ERIC Educational Resources Information Center

    Horton, Debbie

    As part of the overall goal of the Environmental Protection Agency (EPA) to help provide environmental professionals with the skills required to plan and deliver training programs, this staff guide, and its related participant reference manual have been developed for conducting a workshop in basic instructional technology. The workshop consists of…

  1. Response to "Back to Basics"

    ERIC Educational Resources Information Center

    Jacques, Doug

    2007-01-01

    In this article, the author provides a response to Andrew McMartin's article "Back to Basics: Meditations on Quality vs. Quantity in Outdoor Education." In considering quality vs. quantity in outdoor education it is still important from the author's perspective to be conscious of one's viewpoint. He has taught and run trips from a survival…

  2. Science versus Basic Educational Research

    ERIC Educational Resources Information Center

    Engelmann, Siegfried

    2008-01-01

    One goal of basic research in education is to identify the variables of effective instruction. As this pursuit has been conceived, however, its theoretical problems make it unlikely that the effort will provide a clear picture of instructional variables, their interactions, or the kind of teacher training that is implied by instructional variables.

  3. Adult Basic Education Annotated Bibliography.

    ERIC Educational Resources Information Center

    Carter, Nancy B.

    This annotated bibliography contains sections divided according to area of study, and within each category materials are listed alphabetically by publisher. Publishers and mailing addresses are listed at the end of the bibliography. Throughout the annotations, whenever specific grade level divisions are not named, the regular Adult Basic Education…

  4. Unions: Bread, Butter & Basic Skills.

    ERIC Educational Resources Information Center

    BCEL Newsletter for the Business Community, 1987

    1987-01-01

    Unions are natural providers of basic skills instruction. They are in daily workplace contact with their membership, are trusted to work on members' behalf, and speak the language of the worker. Unions are trying to address the needs of illiterate workers through collective bargaining arrangements in which employers contribute a percentage of…

  5. Attention Deficit Hyperactivity Disorder Basics

    MedlinePlus

    ... us to find out more about ADHD. Share Attention Deficit Hyperactivity Disorder Basics Download PDF Download ePub Order a free ... attention deficit/hyperactivity disorder , or ADHD . What is attention deficit/hyperactivity disorder, or ADHD? ADHD is a common mental disorder ...

  6. Basic HIV/AIDS Statistics

    MedlinePlus

    ... Abroad Treatment Basic Statistics Get Tested Find an HIV testing site near you. Enter ZIP code or city Follow HIV/AIDS CDC HIV CDC HIV/AIDS See RSS | ... Collapse All How many people are diagnosed with HIV each year in the United States? In 2014, ...

  7. The Measurement of Basic Stuff.

    ERIC Educational Resources Information Center

    Disch, James G., Ed.; And Others

    1983-01-01

    Seven articles contain information about measurement and evaluation in physical education and sport and complement the "Basic Stuff" series. They focus on (1) student self-assessment for exercise physiology; (2) monitoring motor development; (3) biomechanical analysis; and (4) measurements of aesthetic qualities, psychosocial characteristics, and…

  8. Carpentry. Performance Objectives. Basic Course.

    ERIC Educational Resources Information Center

    Downing, C. L.; Adcox, John W., Jr.

    Several intermediate performance objectives and corresponding criterion measures are listed for each of 12 terminal objectives in this course guide in basic carpentry. The guide is designed to prepare persons for initial employment, or to upgrade or retrain persons already employed, or to provide the apprenticeship related course work necessary to…

  9. Women in Adult Basic Education

    ERIC Educational Resources Information Center

    Park, Rosemarie J.

    1977-01-01

    A survey of adult basic education (ABE) program directors in five states revealed that most ABE teachers are women and work part-time without benefits while most ABE administrators are men who are employed full-time. Concludes that women employed in ABE are victims of discrimination. (EM)

  10. Basic Skills in Asian Studies.

    ERIC Educational Resources Information Center

    Hantula, James

    This publication contains field tested learning activities which will help secondary students develop basic skills while learning about Asian history, culture, and geography. The activities can be used or easily adapted by teachers in any Asian studies course. The publication is organized by the skills taught. These are: reading; applying…

  11. JSC interactive basic accounting system

    NASA Technical Reports Server (NTRS)

    Spitzer, J. F.

    1978-01-01

    Design concepts for an interactive basic accounting system (IBAS) are considered in terms of selecting the design option which provides the best response at the lowest cost. Modeling the IBAS workload and applying this workload to a U1108 EXEC 8 based system using both a simulation model and the real system is discussed.

  12. Welding. Performance Objectives. Basic Course.

    ERIC Educational Resources Information Center

    Vincent, Kenneth

    Several intermediate performance objectives and corresponding criterion measures are listed for each of eight terminal objectives for a basic welding course. The materials were developed for a 36-week (2 hours daily) course developed to teach the fundamentals of welding shop work, to become familiar with the operation of the welding shop…

  13. French Basic Course. Area Studies.

    ERIC Educational Resources Information Center

    Defense Language Inst., Monterey, CA.

    This volume provides the prescribed cultural background that is part of the final phase of the Basic Course in French. The texts provide the basis for discussions and personal research through which students become acquainted with various aspects of the French-speaking world and learn the referential meaning of words and expressions as they are…

  14. Re-Modeling Basic Writing

    ERIC Educational Resources Information Center

    Rigolino, Rachel; Freel, Penny

    2007-01-01

    In 1996, the State University of New York at New Paltz developed the Supplemental Writing Workshop Program for its basic writing students in response to public pressure to discontinue the offering of so-called remedial writing courses at four-year institutions. Our primary purpose in this article is to describe the design of the SWW Program, which…

  15. Susu Basic Course. Final Report.

    ERIC Educational Resources Information Center

    Sangster, Linda; Faber, Emmanuel

    The introductory section of this basic course in Susu presents the phonology of the language--vowels, consonants, intonation, vowel contractions and conditioning, and tones. Examples of equivalent or similar sounds in English and French are provided, as well as listening and transcribing exercises. (The material is designed to be used with a…

  16. Drafting. Performance Objectives. Basic Course.

    ERIC Educational Resources Information Center

    Allen, Charles

    Several intermediate performance objectives and corresponding criterion measures are listed for each of 12 terminal objectives for a basic drafting course. The materials were developed for a two-semester course (2 hours daily). The organized classroom and shop experiences are designed to enable the student to develop general competencies in the…

  17. Negative Expertise: Comparing Differently Tenured Elder Care Nurses' Negative Knowledge

    ERIC Educational Resources Information Center

    Gartmeier, Martin; Lehtinen, Erno; Gruber, Hans; Heid, Helmut

    2011-01-01

    Negative expertise is conceptualised as the professional's ability to avoid errors during practice due to certain cognitive agencies. In this study, negative knowledge (i.e. knowledge about what is wrong in a certain context and situation) is conceptualised as one such agency. This study compares and investigates the negative knowledge of elder…

  18. Brain Dominance Patterns of Tennessee School Leaders.

    ERIC Educational Resources Information Center

    Norris, Cynthia J.

    This exploratory study investigated the leadership styles of selected administrators in Tennessee's public schools. Styles of leadership were viewed against a backdrop of current brain research, and the subjects' underlying patterns of cognitive processing were identified by means of a self-report measurement of brain dominance--the Herrmann Brain…

  19. Injectivity Testing for Vapour Dominated Feed Zones

    SciTech Connect

    Clotworthy, A.W.; Hingoyon, C.S.

    1995-01-01

    Wells with vapor dominated feed zones yield abnormal pressure data. This is caused by the condensation of vapor during water injection. A revised injectivity test procedure currently applied by PNOC at the Leyte Geothermal Power Project has improved the injectivity test results.

  20. Measuring Cerebral Dominance: Implications for Education.

    ERIC Educational Resources Information Center

    Yachimowicz, David J.; And Others

    The psychometric properties of a paper-and-pencil instrument for assessing individual differences in cerebral dominance are explored. The instrument, Your Style of Learning and Thinking (SOLAT), contains 50 multiple-choice questions. The study subjects consisted of three groups: 235 undergraduate and graduate students, 124 undergraduate and…

  1. Role of dominant visibles in mutagenicity testing

    SciTech Connect

    Searle, A.G.; Beechey, C.

    1986-01-01

    Our results suggest that inclusion of growth retardation as one of the components of the dominant visible category will make this a useful end-point for mutational studies in which it is important to gauge the extent to which transmissible genetic damage of a particularly relevant kind is induced in mammals. These visibles are easily scored and the use of an automated weighing device would lessen subjectivity. In the present experiment with 5Gy + 5Gy spermatogonial X-irradiation (24h interval) 7309 offspring have been examined at weaning age and 23 heritable dominant visibles identified. These included 12 with growth retardation, one of which was mutant at the steel (S1) locus, as were 3-4 others of normal size. However, only 46 out of 112 offspring recorded as small were actually kept for genetic tests, while only 30 (65%) of these could be fully tested because of death or infertility in the others. Thus this experiment throws some light on the induction of presumptive dominant sub-lethals which survive until weaning age, a little-studied category. Twelve out of the 30 fully tested small mice (40%) proved to carry dominant visible mutations. If this proportion is applied to the total recorded as small then we can derive an overall total of about 45 mutations for growth retardation. It is hoped to determine the actual rate of induction of these by further work.

  2. Space and Domination -- A Marxist Approach

    ERIC Educational Resources Information Center

    Santos, Milton

    1975-01-01

    From a Marxist standpoint the author deals with the subject of economic and social domination in space. Topics discussed include agricultural spaces, spatial specialization and alienation, urban-rural relations in developing countries, and the disalienation of space and man. For address of journal see SO 504 028. (Author/RM)

  3. Genetics Home Reference: autosomal dominant vitreoretinochoroidopathy

    MedlinePlus

    ... autosomal dominant vitreoretinochoroidopathy: a degenerative disease with a range of developmental ocular anomalies. Eye (Lond). 2011 Jan;25(1):113-8. doi: 10.1038/eye.2010.165. Epub 2010 Nov 12. Citation on PubMed or Free article on PubMed Central Yardley J, Leroy BP, ...

  4. Stochastic dominance and medical decision making.

    PubMed

    Leshno, Moshe; Levy, Haim

    2004-08-01

    Stochastic Dominance (SD) criteria are decision making tools which allow us to choose among various strategies with only partial information on the decision makers' preferences. The notion of Stochastic Dominance has been extensively employed and developed in the area of economics, finance, agriculture, statistics, marketing and operation research since the late 1960s. For example, it may tell us which of two medical treatments with uncertain outcomes is preferred in the absence of full information on the patients' preferences. This paper presents a short review of the SD paradigm and demonstrates how the SD criteria may be employed in medical decision making, using the case of small abdominal aortic aneurysms as an illustration. Thus, for instance by assuming risk aversion one can employ second-degree stochastic dominance to divide the set of all possible treatments into the efficient set, from which the decision makers should always choose, and the inefficient (inferior) set. By employing Prospect Stochastic Dominance (PSD) a similar division can be conducted corresponding to all S-shaped utility functions.

  5. Dominant Teaching Practices of FCS College Faculty

    ERIC Educational Resources Information Center

    Banerjee, Madhumita; Hausafus, Cheryl O.

    2009-01-01

    This study examines characteristics of family and consumer sciences (FCS) collegiate faculty who do and do not incorporate service-learning in their teaching and determines their dominant mode of teaching practice. Survey results from 368 faculty members in institutions of higher education across the United States demonstrate that FCS faculty…

  6. Language and Sex: Difference and Dominance.

    ERIC Educational Resources Information Center

    Thorne, Barrie, Ed.; Henley, Nancy, Ed.

    The twelve papers in this volume, which concerns the interrelationship of language and sex, include: (1) "Difference and Dominance: An Overview of Language, Gender, and Society," by Barrie Thorne and Nancy Henley; (2) "Women's Speech: Separate But Unequal?" by Cheris Kramer; (3) "The Making of a Nonsexist Dictionary," by Alma Graham; (4) "The…

  7. Stochastic dominance and medical decision making.

    PubMed

    Leshno, Moshe; Levy, Haim

    2004-08-01

    Stochastic Dominance (SD) criteria are decision making tools which allow us to choose among various strategies with only partial information on the decision makers' preferences. The notion of Stochastic Dominance has been extensively employed and developed in the area of economics, finance, agriculture, statistics, marketing and operation research since the late 1960s. For example, it may tell us which of two medical treatments with uncertain outcomes is preferred in the absence of full information on the patients' preferences. This paper presents a short review of the SD paradigm and demonstrates how the SD criteria may be employed in medical decision making, using the case of small abdominal aortic aneurysms as an illustration. Thus, for instance by assuming risk aversion one can employ second-degree stochastic dominance to divide the set of all possible treatments into the efficient set, from which the decision makers should always choose, and the inefficient (inferior) set. By employing Prospect Stochastic Dominance (PSD) a similar division can be conducted corresponding to all S-shaped utility functions. PMID:15648563

  8. Wave propagation in negative index materials

    NASA Astrophysics Data System (ADS)

    Aylo, Rola

    Properties of electromagnetic propagation in materials with negative permittivities and permeabilities were first studied in 1968. In such metamaterials, the electric field vector, the magnetic field vector, and the propagation vector form a left hand triad, thus the name left hand materials. Research in this area was practically non-existent, until about 10 years ago, a composite material consisting of periodic metallic rods and split-ring resonators showed left-handed properties. Because the dimension of the constituents of the metamaterial are small compared to the operating wavelength, it is possible to describe the electromagnetic properties of the composite using the concept of effective permittivity and permeability. In this dissertation, the basic properties of electromagnetic propagation through homogenous left hand materials are first studied. Many of the basic properties of left hand materials are in contrast to those in right hand materials, viz., negative refraction, perfect lensing, and the inverse Doppler effect. Dispersion relations are used to study wave propagation in negative index materials. For the first time to the best of our knowledge, we show that a reduced dispersion relation, obtained from the frequency dependence of the propagation constant by neglecting a linear frequency dependent term, obeys causality. Causality of the propagation constant enables us to use a novel and simple operator formalism approach to derive the underlying partial differential equations for baseband and envelope wave propagation. Various tools for understanding and characterizing left-handed materials are thereafter presented. The transfer matrix method is used to analyze periodic and random structures composed of positive and negative index materials. By random structures we mean randomness in layer position, index of refraction, and thickness. As an application of alternating periodic negative index and positive index structures, we propose a novel sensor using

  9. Coagulase-Negative Staphylococci

    PubMed Central

    Heilmann, Christine; Peters, Georg

    2014-01-01

    SUMMARY The definition of the heterogeneous group of coagulase-negative staphylococci (CoNS) is still based on diagnostic procedures that fulfill the clinical need to differentiate between Staphylococcus aureus and those staphylococci classified historically as being less or nonpathogenic. Due to patient- and procedure-related changes, CoNS now represent one of the major nosocomial pathogens, with S. epidermidis and S. haemolyticus being the most significant species. They account substantially for foreign body-related infections and infections in preterm newborns. While S. saprophyticus has been associated with acute urethritis, S. lugdunensis has a unique status, in some aspects resembling S. aureus in causing infectious endocarditis. In addition to CoNS found as food-associated saprophytes, many other CoNS species colonize the skin and mucous membranes of humans and animals and are less frequently involved in clinically manifested infections. This blurred gradation in terms of pathogenicity is reflected by species- and strain-specific virulence factors and the development of different host-defending strategies. Clearly, CoNS possess fewer virulence properties than S. aureus, with a respectively different disease spectrum. In this regard, host susceptibility is much more important. Therapeutically, CoNS are challenging due to the large proportion of methicillin-resistant strains and increasing numbers of isolates with less susceptibility to glycopeptides. PMID:25278577

  10. Negative ion source

    DOEpatents

    Delmore, James E.

    1987-01-01

    A method and apparatus for providing a negative ion source accelerates electrons away from a hot filament electron emitter into a region of crossed electric and magnetic fields arranged in a magnetron configuration. During a portion of the resulting cycloidal path, the electron velocity is reduced below its initial value. The electron accelerates as it leaves the surface at a rate of only slightly less than if there were no magnetic field, thereby preventing a charge buildup at the surface of the emitter. As the electron traverses the cycloid, it is decelerated during the second, third, and fourth quadrants, then reeccelerated as it approaches the end of the fourth quadrant to regain its original velocity. The minimum velocity occurs during the fourth quadrant, and corresponds to an electron temperature of 200.degree. to 500.degree. for the electric and magnetic fields commonly encountered in the ion sources of magnetic sector mass spectrometers. An ion source using the above-described thermalized electrons is also disclosed.

  11. Plasmonics without negative dielectrics

    NASA Astrophysics Data System (ADS)

    Della Giovampaola, Cristian; Engheta, Nader

    2016-05-01

    Plasmonic phenomena are exhibited in light-matter interaction involving materials whose real parts of permittivity functions attain negative values at operating wavelengths. However, such materials usually suffer from dissipative losses, thus limiting the performance of plasmon-based optical devices. Here, we utilize an alternative methodology that mimics a variety of plasmonic phenomena by exploiting the well-known structural dispersion of electromagnetic modes in bounded guided-wave structures filled with only materials with positive permittivity. A key issue in the design of such structures is prevention of mode coupling, which can be achieved by implementing thin metallic wires at proper interfaces. This method, which is more suitable for lower frequencies, allows designers to employ conventional dielectrics and highly conductive metals for which the loss is low at these frequencies, while achieving plasmonic features. We demonstrate, numerically and analytically, that this platform can provide surface plasmon polaritons, local plasmonic resonance, plasmonic cloaking, and epsilon-near-zero-based tunneling using conventional positive-dielectric materials.

  12. Coagulase-negative staphylococci.

    PubMed

    Becker, Karsten; Heilmann, Christine; Peters, Georg

    2014-10-01

    The definition of the heterogeneous group of coagulase-negative staphylococci (CoNS) is still based on diagnostic procedures that fulfill the clinical need to differentiate between Staphylococcus aureus and those staphylococci classified historically as being less or nonpathogenic. Due to patient- and procedure-related changes, CoNS now represent one of the major nosocomial pathogens, with S. epidermidis and S. haemolyticus being the most significant species. They account substantially for foreign body-related infections and infections in preterm newborns. While S. saprophyticus has been associated with acute urethritis, S. lugdunensis has a unique status, in some aspects resembling S. aureus in causing infectious endocarditis. In addition to CoNS found as food-associated saprophytes, many other CoNS species colonize the skin and mucous membranes of humans and animals and are less frequently involved in clinically manifested infections. This blurred gradation in terms of pathogenicity is reflected by species- and strain-specific virulence factors and the development of different host-defending strategies. Clearly, CoNS possess fewer virulence properties than S. aureus, with a respectively different disease spectrum. In this regard, host susceptibility is much more important. Therapeutically, CoNS are challenging due to the large proportion of methicillin-resistant strains and increasing numbers of isolates with less susceptibility to glycopeptides. PMID:25278577

  13. The genetic and environmental roots of variance in negativity toward foreign nationals.

    PubMed

    Kandler, Christian; Lewis, Gary J; Feldhaus, Lea Henrike; Riemann, Rainer

    2015-03-01

    This study quantified genetic and environmental roots of variance in prejudice and discriminatory intent toward foreign nationals and examined potential mediators of these genetic influences: right-wing authoritarianism (RWA), social dominance orientation (SDO), and narrow-sense xenophobia (NSX). In line with the dual process motivational (DPM) model, we predicted that the two basic attitudinal and motivational orientations-RWA and SDO-would account for variance in out-group prejudice and discrimination. In line with other theories, we expected that NSX as an affective component would explain additional variance in out-group prejudice and discriminatory intent. Data from 1,397 individuals (incl. twins as well as their spouses) were analyzed. Univariate analyses of twins' and spouses' data yielded genetic (incl. contributions of assortative mating) and multiple environmental sources (i.e., social homogamy, spouse-specific, and individual-specific effects) of variance in negativity toward strangers. Multivariate analyses suggested an extension to the DPM model by including NSX in addition to RWA and SDO as predictor of prejudice and discrimination. RWA and NSX primarily mediated the genetic influences on the variance in prejudice and discriminatory intent toward foreign nationals. In sum, the findings provide the basis of a behavioral genetic framework integrating different scientific disciplines for the study of negativity toward out-groups.

  14. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression

    NASA Astrophysics Data System (ADS)

    Makino, Yuichi; Cao, Renhai; Svensson, Kristian; Bertilsson, Göran; Asman, Mikael; Tanaka, Hirotoshi; Cao, Yihai; Berkenstam, Anders; Poellinger, Lorenz

    2001-11-01

    Alteration of gene expression is a crucial component of adaptive responses to hypoxia. These responses are mediated by hypoxia-inducible transcription factors (HIFs). Here we describe an inhibitory PAS (Per/Arnt/Sim) domain protein, IPAS, which is a basic helix-loop-helix (bHLH)/PAS protein structurally related to HIFs. IPAS contains no endogenous transactivation function but demonstrates dominant negative regulation of HIF-mediated control of gene expression. Ectopic expression of IPAS in hepatoma cells selectively impairs induction of genes involved in adaptation to a hypoxic environment, notably the vascular endothelial growth factor (VEGF) gene, and results in retarded tumour growth and tumour vascular density in vivo. In mice, IPAS was predominantly expressed in Purkinje cells of the cerebellum and in corneal epithelium of the eye. Expression of IPAS in the cornea correlates with low levels of expression of the VEGF gene under hypoxic conditions. Application of an IPAS antisense oligonucleotide to the mouse cornea induced angiogenesis under normal oxygen conditions, and demonstrated hypoxia-dependent induction of VEGF gene expression in hypoxic corneal cells. These results indicate a previously unknown mechanism for negative regulation of angiogenesis and maintenance of an avascular phenotype.

  15. Age and group residence but not maternal dominance affect dominance rank in young domestic horses.

    PubMed

    Komárková, M; Bartošová, J; Dubcová, J

    2014-11-01

    We present a study focused on those factors influencing dominance position in young horses, with emphasis on the role of the mother. Horses, as other group-living polygynous mammals, form stable linear dominance hierarchies based on agonistic interactions. Higher dominance positions are believed to be connected, in both sexes, to better condition and higher reproductive success. Many variables play a role in forming the dominant-submissive relationships between horses; however, the maternal effect on the dominance position of the offspring still remains unclear, as do the possible mechanisms of transference ("inheritance"). We hypothesized that the maternal dominance position, plus differences in suckling parameters or maternal style, may be responsible for later outcome of the offspring's dominance position, characterized by 2 variables: index of fighting success (CB); and rate of winning encounters (RW). Our study animals were 8 groups of Kladruby horses, loose-housed lactating mares with foals (n = 66 mare-foal pairs); and subsequently 4 groups of the same foals at 3 yr of age. Our results revealed the impact of age on the dominance position of the young horses (P < 0.001 for CB, and P < 0.01 for RW), and residence in the group (P < 0.01, P < 0.01, respectively); not the maternal dominance position. Older foals reached higher dominance positions, independent of the dominance position, age, or experience of the mother; therefore, we did not find support for direct inheritance of maternal rank. Nevertheless, the foals born to the same mare in 2 consecutive seasons (n = 16 mares) revealed fair repeatability in the dominance position they obtained at 3 yr of age (intraclass correlation coefficient = 0.46). This suggests an important constant effect of the mother on the social success of her progeny; however, we did not find a significant effect of any of the tested variables describing maternal characteristics or maternal care. Dominance position depended

  16. Age and group residence but not maternal dominance affect dominance rank in young domestic horses.

    PubMed

    Komárková, M; Bartošová, J; Dubcová, J

    2014-11-01

    We present a study focused on those factors influencing dominance position in young horses, with emphasis on the role of the mother. Horses, as other group-living polygynous mammals, form stable linear dominance hierarchies based on agonistic interactions. Higher dominance positions are believed to be connected, in both sexes, to better condition and higher reproductive success. Many variables play a role in forming the dominant-submissive relationships between horses; however, the maternal effect on the dominance position of the offspring still remains unclear, as do the possible mechanisms of transference ("inheritance"). We hypothesized that the maternal dominance position, plus differences in suckling parameters or maternal style, may be responsible for later outcome of the offspring's dominance position, characterized by 2 variables: index of fighting success (CB); and rate of winning encounters (RW). Our study animals were 8 groups of Kladruby horses, loose-housed lactating mares with foals (n = 66 mare-foal pairs); and subsequently 4 groups of the same foals at 3 yr of age. Our results revealed the impact of age on the dominance position of the young horses (P < 0.001 for CB, and P < 0.01 for RW), and residence in the group (P < 0.01, P < 0.01, respectively); not the maternal dominance position. Older foals reached higher dominance positions, independent of the dominance position, age, or experience of the mother; therefore, we did not find support for direct inheritance of maternal rank. Nevertheless, the foals born to the same mare in 2 consecutive seasons (n = 16 mares) revealed fair repeatability in the dominance position they obtained at 3 yr of age (intraclass correlation coefficient = 0.46). This suggests an important constant effect of the mother on the social success of her progeny; however, we did not find a significant effect of any of the tested variables describing maternal characteristics or maternal care. Dominance position depended

  17. Liberals and conservatives can show similarities in negativity bias.

    PubMed

    Brandt, Mark J; Wetherell, Geoffrey; Reyna, Christine

    2014-06-01

    Negativity bias may underlie the development of political ideologies, but liberals and conservatives are likely to respond to threats similarly. We review evidence from research on intolerance, motivated reasoning, and basic psychological threats that suggest liberals and conservatives are more similar than different when confronting threatening groups, situations, and information. PMID:24970429

  18. Negative Effects of Learning Spreadsheet Management on Learning Database Management

    ERIC Educational Resources Information Center

    Vágner, Anikó; Zsakó, László

    2015-01-01

    A lot of students learn spreadsheet management before database management. Their similarities can cause a lot of negative effects when learning database management. In this article, we consider these similarities and explain what can cause problems. First, we analyse the basic concepts such as table, database, row, cell, reference, etc. Then, we…

  19. Anodes - Materials for negative electrodes in electrochemical energy technology

    NASA Astrophysics Data System (ADS)

    Holze, Rudolf

    2014-06-01

    The basic concepts of electrodes and electrochemical cells (including both galvanic and electrolytic ones) are introduced and illustrated with practical examples. Particular attention is paid to negative electrodes in primary and secondary cells, fuel cell electrodes and electrodes in redox flow batteries. General features and arguments pertaining to selection, optimization and further development are highlighted.

  20. Radiative torques: analytical model and basic properties

    NASA Astrophysics Data System (ADS)

    Lazarian, A.; Hoang, Thiem

    2007-07-01

    We attempt to get a physical insight into grain alignment processes by studying basic properties of radiative torques (RATs). For this purpose we consider a simple toy model of a helical grain that reproduces well the basic features of RATs. The model grain consists of a spheroidal body with a mirror attached at an angle to it. Being very simple, the model allows analytical description of RATs that act upon it. We show a good correspondence of RATs obtained for this model and those of irregular grains calculated by DDSCAT. Our analysis of the role of different torque components for grain alignment reveals that one of the three RAT components does not affect the alignment, but induces only for grain precession. The other two components provide a generic alignment with grain long axes perpendicular to the radiation direction, if the radiation dominates the grain precession, and perpendicular to magnetic field, otherwise. The latter coincides with the famous predictions of the Davis-Greenstein process, but our model does not invoke paramagnetic relaxation. In fact, we identify a narrow range of angles between the radiation beam and the magnetic field, for which the alignment is opposite to the Davis-Greenstein predictions. This range is likely to vanish, however, in the presence of thermal wobbling of grains. In addition, we find that a substantial part of grains subjected to RATs gets aligned with low angular momentum, which testifies that most of the grains in diffuse interstellar medium do not rotate fast, that is, rotate with thermal or even subthermal velocities. This tendency of RATs to decrease grain angular velocity as a result of the RAT alignment decreases the degree of polarization, by decreasing the degree of internal alignment, that is, the alignment of angular momentum with the grain axes. For the radiation-dominated environments, we find that the alignment can take place on the time-scale much shorter than the time of gaseous damping of grain rotation