MLH1-Silenced and Non-Silenced Subgroups of Hypermutated Colorectal Carcinomas Have Distinct Mutational Landscapes

PubMed Central

Donehower, Lawrence A.; Creighton, Chad J.; Schultz, Nikolaus; Shinbrot, Eve; Chang, Kyle; Gunaratne, Preethi H.; Muzny, Donna; Sander, Chris; Hamilton, Stanley R.; Gibbs, Richard A.; Wheeler, David

2014-01-01

Approximately 15% of colorectal carcinomas (CRC) exhibit a hypermutated genotype accompanied by high levels of microsatellite instability (MSI-H) and defects in DNA mismatch repair. These tumors, unlike the majority of colorectal carcinomas, are often diploid, exhibit frequent epigenetic silencing of the MLH1 DNA mismatch repair gene, and have a better clinical prognosis. As an adjunct study to The Cancer Genome Atlas consortium that recently analyzed 224 colorectal cancers by whole exome sequencing, we compared the 35 CRC (15.6%) with a hypermutated genotype to those with a non-hypermutated genotype. We found that 22 (63%) of hypermutated CRC exhibited transcriptional silencing of the MLH1 gene, a high frequency of BRAF V600E gene mutations and infrequent APC and KRAS mutations, a mutational pattern significantly different from their non-hypermutated counterparts. However, the remaining 13 (37%) hypermutated CRC lacked MLH1 silencing, contained tumors with the highest mutation rates (“ultramutated” CRC), and exhibited higher incidences of APC and KRAS mutations, but infrequent BRAF mutations. These patterns were confirmed in an independent validation set of 250 exome-sequenced CRC. Analysis of mRNA and microRNA expression signatures revealed that hypermutated CRC with MLH1 silencing had greatly reduced levels of WNT signaling and increased BRAF signaling relative non-hypermutated CRC. Our findings suggest that hypermutated CRC include one subgroup with fundamentally different pathways to malignancy than the majority of CRC. Examination of MLH1 expression status and frequencies of APC, KRAS, and BRAF mutation in CRC may provide a useful diagnostic tool that could supplement the standard microsatellite instability assays and influence therapeutic decisions. PMID:22899370

Characterizing the Hypermutated Subtype of Advanced Prostate Cancer as a Predictive Biomarker for Precision Medicine

DTIC Science & Technology

2017-10-01

goal of this research is to characterize the mechanisms leading to hypermutated prostate cancer and to integrate tumor hypermutation status with... integrate tumor hypermutation status with clinical decision making and therapy to improve the care of men with advanced prostate cancer. Using Next-Gen...preparation of presentations that integrate prostate cancer patient clinical histories with genomic findings 1-36 Yes, see Prostate Precision Tumor

The Florida manatee (Trichechus manatus latirostris) immunoglobulin heavy chain suggests the importance of clan III variable segments in repertoire diversity

USGS Publications Warehouse

Breaux, Breanna; Deiss, Thaddeus C.; Chen, Patricia L.; Cruz-Schneider, Maria Paula; Sena, Leonardo; Hunter, Margaret E.; Bonde, Robert K.; Criscitiello, Michael F.

2017-01-01

Manatees are a vulnerable, charismatic sentinel species from the evolutionarily divergent Afrotheria. Manatee health and resistance to infectious disease is of great concern to conservation groups, but little is known about their immune system. To develop manatee-specific tools for monitoring health, we first must have a general knowledge of how the immunoglobulin heavy (IgH) chain locus is organized and transcriptionally expressed. Using the genomic scaffolds of the Florida manatee (Trichechus manatus latirostris), we characterized the potential IgH segmental diversity and constant region isotypic diversity and performed the first Afrotherian repertoire analysis. The Florida manatee has low V(D)J combinatorial diversity (3744 potential combinations) and few constant region isotypes. They also lack clan III V segments, which may have caused reduced VH segment numbers. However, we found productive somatic hypermutation concentrated in the complementarity determining regions. In conclusion, manatees have limited IGHV clan and combinatorial diversity. This suggests that clan III V segments are essential for maintaining IgH locus diversity.

DNA and RNA editing of retrotransposons accelerate mammalian genome evolution.

PubMed

Knisbacher, Binyamin A; Levanon, Erez Y

2015-04-01

Genome evolution is commonly viewed as a gradual process that is driven by random mutations that accumulate over time. However, DNA- and RNA-editing enzymes have been identified that can accelerate evolution by actively modifying the genomically encoded information. The apolipoprotein B mRNA editing enzymes, catalytic polypeptide-like (APOBECs) are potent restriction factors that can inhibit retroelements by cytosine-to-uridine editing of retroelement DNA after reverse transcription. In some cases, a retroelement may successfully integrate into the genome despite being hypermutated. Such events introduce unique sequences into the genome and are thus a source of genomic innovation. adenosine deaminases that act on RNA (ADARs) catalyze adenosine-to-inosine editing in double-stranded RNA, commonly formed by oppositely oriented retroelements. The RNA editing confers plasticity to the transcriptome by generating many transcript variants from a single genomic locus. If the editing produces a beneficial variant, the genome may maintain the locus that produces the RNA-edited transcript for its novel function. Here, we discuss how these two powerful editing mechanisms, which both target inserted retroelements, facilitate expedited genome evolution. © 2015 New York Academy of Sciences.

The Florida manatee (Trichechus manatus latirostris) immunoglobulin heavy chain suggests the importance of clan III variable segments in repertoire diversity.

PubMed

Breaux, Breanna; Deiss, Thaddeus C; Chen, Patricia L; Cruz-Schneider, Maria Paula; Sena, Leonardo; Hunter, Margaret E; Bonde, Robert K; Criscitiello, Michael F

2017-07-01

Manatees are a vulnerable, charismatic sentinel species from the evolutionarily divergent Afrotheria. Manatee health and resistance to infectious disease is of great concern to conservation groups, but little is known about their immune system. To develop manatee-specific tools for monitoring health, we first must have a general knowledge of how the immunoglobulin heavy (IgH) chain locus is organized and transcriptionally expressed. Using the genomic scaffolds of the Florida manatee (Trichechus manatus latirostris), we characterized the potential IgH segmental diversity and constant region isotypic diversity and performed the first Afrotherian repertoire analysis. The Florida manatee has low V(D)J combinatorial diversity (3744 potential combinations) and few constant region isotypes. They also lack clan III V segments, which may have caused reduced VH segment numbers. However, we found productive somatic hypermutation concentrated in the complementarity determining regions. In conclusion, manatees have limited IGHV clan and combinatorial diversity. This suggests that clan III V segments are essential for maintaining IgH locus diversity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Locus of control and peer relationships among Caucasian, Hispanic, Asian, and African American adolescents.

PubMed

Kang, Hannah Soo; Chang, Kyle Edward; Chen, Chuansheng; Greenberger, Ellen

2015-01-01

Past research has shown that locus of control plays an important role in a wide range of behaviors, such as academic achievement and positive social behaviors. However, little is known about whether locus of control plays the same role in minority adolescents' peer relationships. The current study examined ethnic differences in the associations between locus of control and peer relationships in early adolescence using samples from the Early Childhood Longitudinal Study (ECLS-K: 5,612 Caucasian, 1,562 Hispanic, 507 Asian, and 908 African-American adolescents) and the National Education Longitudinal Study (NELS: 8,484 Caucasian, 1,604 Hispanic, and 860 Asian, and 1,228 African American adolescents). Gender was approximately evenly split in both samples. The results from the two datasets were highly consistent. Significant interactions between ethnicity and locus of control indicated that having a more internal locus of control was particularly important for Caucasian students' peer relationships (ECLS-K) and social status (NELS), but less so for Asian, Hispanic, and African American students. Our findings suggest that the role of locus of control in peer relationship is contingent upon culture.

APOBEC3G-Induced Hypermutation of Human Immunodeficiency Virus Type-1 Is Typically a Discrete “All or Nothing” Phenomenon

PubMed Central

Armitage, Andrew E.; Deforche, Koen; Chang, Chih-hao; Wee, Edmund; Kramer, Beatrice; Welch, John J.; Gerstoft, Jan; Fugger, Lars; McMichael, Andrew; Rambaut, Andrew; Iversen, Astrid K. N.

2012-01-01

The rapid evolution of Human Immunodeficiency Virus (HIV-1) allows studies of ongoing host–pathogen interactions. One key selective host factor is APOBEC3G (hA3G) that can cause extensive and inactivating Guanosine-to-Adenosine (G-to-A) mutation on HIV plus-strand DNA (termed hypermutation). HIV can inhibit this innate anti-viral defense through binding of the viral protein Vif to hA3G, but binding efficiency varies and hypermutation frequencies fluctuate in patients. A pivotal question is whether hA3G-induced G-to-A mutation is always lethal to the virus or if it may occur at sub-lethal frequencies that could increase viral diversification. We show in vitro that limiting-levels of hA3G-activity (i.e. when only a single hA3G-unit is likely to act on HIV) produce hypermutation frequencies similar to those in patients and demonstrate in silico that potentially non-lethal G-to-A mutation rates are ∼10-fold lower than the lowest observed hypermutation levels in vitro and in vivo. Our results suggest that even a single incorporated hA3G-unit is likely to cause extensive and inactivating levels of HIV hypermutation and that hypermutation therefore is typically a discrete “all or nothing” phenomenon. Thus, therapeutic measures that inhibit the interaction between Vif and hA3G will likely not increase virus diversification but expand the fraction of hypermutated proviruses within the infected host. PMID:22457633

DOE Office of Scientific and Technical Information (OSTI.GOV)

Otani, Sanae; Department of Pediatrics, Graduate School of Medicine, Osaka City University, Osaka; Ayata, Minoru, E-mail: maverick@med.osaka-cu.ac.jp

Measles virus (MV) is the causative agent of measles and its neurological complications, subacute sclerosing panencephalitis (SSPE) and measles inclusion body encephalitis (MIBE). Biased hypermutation in the M gene is a characteristic feature of SSPE and MIBE. To determine whether the M gene is the preferred target of hypermutation, an additional transcriptional unit containing a humanized Renilla reniformis green fluorescent protein (hrGFP) gene was introduced into the IC323 MV genome, and nude mice were inoculated intracerebrally with the virus. Biased hypermutation occurred in the M gene and also in the hrGFP gene when it was inserted between the leader andmore » the N gene, but not between the H and L gene. These results indicate that biased hypermutation is usually found in a gene whose function is not essential for viral proliferation in the brain and that the location of a gene in the MV genome can affect its mutational frequency. - Highlights: • Wild-type MV can cause persistent infections in nude mice. • Biased hypermutation occurred in the M gene. • Biased hypermutation occurred in an inessential gene inserted between the leader and the N gene.« less

Perception of Contingency and Mental Retardation.

ERIC Educational Resources Information Center

DeVellis, Robert F.; McCauley, Charley

1979-01-01

It is argued that the general learning difficulties exhibited by mentally retarded persons are similar in many respects to the learning difficulties of nonretarded persons who are in a state of learned helplessness (M. Seligman, 1975) or who are external in locus of control orientation. (Author)

Preferrential rearrangement in normal rabbits of the 3' VHa allotype gene that is deleted in Alicia mutants; somatic hypermutation/conversion may play a major role in generating the heterogeneity of rabbit heavy chain variable region sequences.

PubMed

Allegrucci, M; Young-Cooper, G O; Alexander, C B; Newman, B A; Mage, R G

1991-02-01

The rabbit is unique in having well-defined allotypes in the variable region of the heavy chain. Products of the VHa locus, (with alleles a1, a2, and a3), account for the majority of the serum immunoglobulins. A small percentage of the serum immunoglobulins are a-negative. In 1986, Kelus and Weiss described a mutation that depressed the expression of the Ig VH a2 genes in an a1/a2 rabbit. From this animal the Alicia rabbit strain was developed and the mutation was termed ali. We previously showed, using Southern analysis and the transverse alternating field electrophoresis technique, that the difference between the ali rabbit and normal is a relatively small deletion including some of the most 3' VH genes. The most JH proximal 3' VH1 genes in DNA from normal rabbits of a1, a2 and a3 haplotypes encode a1, a2 and a3 molecules respectively, and it has been suggested that these genes are responsible for allelic inheritance of VHa allotypes. The present study suggests that the 3' end of the VH locus probably plays a key role in regulation of VH gene expression in rabbits because VH gene(s) in this region are the target(s) of preferential VDJ rearrangements. This raises the possibility that mechanisms such as somatic gene conversion and hypermutation are at work to generate the antibody repertoire in this species. Our data support the view that the 3' VH1 gene may be the preferred target for rearrangement in normal rabbits, and for the normal chromosome in heterozygous ali animals. However, homozygous ali rabbits with a deletion that removed the a2-encoding VH1 on both chromosomes do survive, rearrange other VH genes and produce normal levels of immunoglobulins as well as a significant percentage of B cells which bear the a2 allotype. This challenges the view that one VH gene, VH1, is solely responsible for the inheritance pattern of VHa allotypes.

Neurolinguistic programming training, trait anxiety, and locus of control.

PubMed

Konefal, J; Duncan, R C; Reese, M A

1992-06-01

Training in the neurolinguistic programming techniques of shifting perceptual position, visual-kinesthetic dissociation, timelines, and change-history, all based on experiential cognitive processing of remembered events, leads to an increased awareness of behavioral contingencies and a more sensitive recognition of environmental cues which could serve to lower trait anxiety and increase the sense of internal control. This study reports on within-person and between-group changes in trait anxiety and locus of control as measured on the Spielberger State-Trait Anxiety Inventory and Wallston, Wallston, and DeVallis' Multiple Health Locus of Control immediately following a 21-day residential training in neurolinguistic programming. Significant with-in-person decreases in trait-anxiety scores and increases in internal locus of control scores were observed as predicted. Chance and powerful other locus of control scores were unchanged. Significant differences were noted on trait anxiety and locus of control scores between European and U.S. participants, although change scores were similar for the two groups. These findings are consistent with the hypothesis that this training may lower trait-anxiety scores and increase internal locus of control scores. A matched control group was not available, and follow-up was unfortunately not possible.

Overlapping activation-induced cytidine deaminase hotspot motifs in Ig class-switch recombination

PubMed Central

Han, Li; Masani, Shahnaz; Yu, Kefei

2011-01-01

Ig class-switch recombination (CSR) is directed by the long and repetitive switch regions and requires activation-induced cytidine deaminase (AID). One of the conserved switch-region sequence motifs (AGCT) is a preferred site for AID-mediated DNA-cytosine deamination. By using somatic gene targeting and recombinase-mediated cassette exchange, we established a cell line-based CSR assay that allows manipulation of switch sequences at the endogenous locus. We show that AGCT is only one of a family of four WGCW motifs in the switch region that can facilitate CSR. We go on to show that it is the overlap of AID hotspots at WGCW sites on the top and bottom strands that is critical. This finding leads to a much clearer model for the difference between CSR and somatic hypermutation. PMID:21709240

Epigenetics of the antibody response

PubMed Central

Li, Guideng; Zan, Hong; Xu, Zhenming; Casali, Paolo

2013-01-01

Epigenetic marks, such as DNA methylation, histone posttranslational modifications and microRNAs, are induced in B cells by the same stimuli that drive the antibody response. They play major roles in regulating somatic hypermutation (SHM), class switch DNA recombination (CSR) and differentiation to plasma cells or long-lived memory B cells. Histone modifications target the CSR and, possibly, SHM machinery to the immunoglobulin locus; they together with DNA methylation and microRNAs modulate the expression of critical elements of that machinery, such as AID, as well as factors central to plasma cell differentiation, such as Blimp-1. These inducible B cell-intrinsic epigenetic marks instruct the maturation of antibody responses. Their dysregulation plays an important role in aberrant antibody responses to foreign antigens, such as those of microbial pathogens, and self-antigens, such those targeted in autoimmunity, and B cell neoplasias. PMID:23643790

Hypermutation in Burkholderia cepacia complex is mediated by DNA mismatch repair inactivation and is highly prevalent in cystic fibrosis chronic respiratory infection.

PubMed

Martina, Pablo; Feliziani, Sofía; Juan, Carlos; Bettiol, Marisa; Gatti, Blanca; Yantorno, Osvaldo; Smania, Andrea M; Oliver, Antonio; Bosch, Alejandra

2014-11-01

The Burkholderia cepacia complex (Bcc) represents an important group of pathogens involved in long-term lung infection in cystic fibrosis (CF) patients. A positive selection of hypermutators, linked to antimicrobial resistance development, has been previously reported for Pseudomonas aeruginosa in this chronic infection setting. Hypermutability, however, has not yet been systematically evaluated in Bcc species. A total of 125 well characterized Bcc isolates recovered from 48 CF patients, 10 non-CF patients and 15 environmental samples were analyzed. In order to determine the prevalence of mutators their spontaneous mutation rates to rifampicin resistance were determined. In addition, the genetic basis of the mutator phenotypes was investigated by sequencing the mutS and mutL genes, the main components of the mismatch repair system (MRS). The overall prevalence of hypermutators in the collection analyzed was 13.6%, with highest occurrence (40.7%) among the chronically infected CF patients, belonging mainly to B. cenocepacia, B. multivorans, B. cepacia, and B. contaminans -the most frequently recovered Bcc species from CF patients worldwide. Thirteen (76.5%) of the hypermutators were defective in mutS and/or mutL. Finally, searching for a possible association between antimicrobial resistance and hypermutability, the resistance-profiles to 17 antimicrobial agents was evaluated. High antimicrobial resistance rates were documented for all the Bcc species recovered from CF patients, but, except for ciprofloxacin, a significant association with hypermutation was not detected. In conclusion, in the present study we demonstrate for the first time that, MRS-deficient Bcc species mutators are highly prevalent and positively selected in CF chronic lung infections. Hypermutation therefore, might be playing a key role in increasing bacterial adaptability to the CF-airway environment, facilitating the persistence of chronic lung infections. Copyright © 2014 Elsevier GmbH. All rights reserved.

Mobile contingency locus controlling Escherichia coli K1 polysialic acid capsule acetylation.

PubMed

Vimr, Eric R; Steenbergen, Susan M

2006-05-01

Escherichia coli K1 is part of a reservoir of adherent, invasive facultative pathogens responsible for a wide range of human and animal disease including sepsis, meningitis, urinary tract infection and inflammatory bowel syndrome. A prominent virulence factor in these diseases is the polysialic acid capsular polysaccharide (K1 antigen), which is encoded by the kps/neu accretion domain inserted near pheV at 67 map units. Some E. coli K1 strains undergo form (phase) variation involving loss or gain of O-acetyl esters at carbon positions 7 or 9 of the individual sialic acid residues of the polysialic acid chains. Acetylation is catalysed by the receptor-modifying acetyl coenzyme-A-dependent O-acetyltransferase encoded by neuO, a phase variable locus mapping near the integrase gene of the K1-specific prophage, CUS-3, which is inserted in argW at 53.1 map units. As the first E. coli contingency locus shown to operate by a translational switch, further investigation of neuO should provide a better understanding of the invasive K1 pathotype. Minimal estimates of morbidity and economic costs associated with human infections caused by extraintestinal pathogenic E. coli strains such as K1 indicate at least 6.5 million cases with attendant medical costs exceeding 2.5 billion US dollars annually in the United States alone.

Reinforcement and the Overjustification Effect.

ERIC Educational Resources Information Center

Williams, Bruce W.

Reward contingencies and other extrinsic constraints on behavior can lead to reduced levels of interest in and/or decreased engagement in a target activity in a subsequent noncontingent situation. It has been hypothesized that this effect is caused by a change in the self-perceived locus of motivation from intrinsic to extrinsic. It follows from…

Communication with Children: Toward a Healthy Construction of Communicative Roles.

ERIC Educational Resources Information Center

Johnson, Fern L.

The family system--a primary locus in the formation of meaning for children--should encourage the healthy construction of communicative roles. What children learn about interaction is contingent on two processes, both central to the symbolic interaction perspective: role-taking and role-making. Role-taking is the ability to transcend an egocentric…

Characterizing the Hypermutated Subtype of Advanced Prostate Cancer as a Predictive Biomarker for Precision Medicine

DTIC Science & Technology

2015-10-01

a promising target for precision therapy , but the mechanisms leading to hypermutation, optimal methods to measure hypermutation status in the ...1 was largely completed in Year 1 and is summarized below. We published a manuscript in Nature Communications based on the work accomplished in Aim...multiplexing 24 samples per lane on a HiSeq2500. The BROCA assay uses the Agilent SureSelect enrichment system to capture the coding exons and

Biased hypermutation occurred frequently in a gene inserted into the IC323 recombinant measles virus during its persistence in the brains of nude mice.

PubMed

Otani, Sanae; Ayata, Minoru; Takeuchi, Kaoru; Takeda, Makoto; Shintaku, Haruo; Ogura, Hisashi

2014-08-01

Measles virus (MV) is the causative agent of measles and its neurological complications, subacute sclerosing panencephalitis (SSPE) and measles inclusion body encephalitis (MIBE). Biased hypermutation in the M gene is a characteristic feature of SSPE and MIBE. To determine whether the M gene is the preferred target of hypermutation, an additional transcriptional unit containing a humanized Renilla reniformis green fluorescent protein (hrGFP) gene was introduced into the IC323 MV genome, and nude mice were inoculated intracerebrally with the virus. Biased hypermutation occurred in the M gene and also in the hrGFP gene when it was inserted between the leader and the N gene, but not between the H and L gene. These results indicate that biased hypermutation is usually found in a gene whose function is not essential for viral proliferation in the brain and that the location of a gene in the MV genome can affect its mutational frequency. Copyright © 2014 Elsevier Inc. All rights reserved.

Comparison of identical and functional Igh alleles reveals a nonessential role for Eμ in somatic hypermutation and class-switch recombination.

PubMed

Li, Fubin; Yan, Yi; Pieretti, Joyce; Feldman, Danielle A; Eckhardt, Laurel A

2010-11-15

Somatic hypermutation (SHM), coupled with Ag selection, provides a mechanism for generating Abs with high affinity for invading pathogens. Class-switch recombination (CSR) ensures that these Abs attain pathogen-appropriate effector functions. Although the enzyme critical to both processes, activation-induced cytidine deaminase, has been identified, it remains unclear which cis-elements within the Ig loci are responsible for recruiting activation-induced cytidine deaminase and promoting its activity. Studies showed that Ig gene-transcription levels are positively correlated with the frequency of SHM and CSR, making the intronic, transcriptional enhancer Eμ a likely contributor to both processes. Tests of this hypothesis yielded mixed results arising, in part, from the difficulty in studying B cell function in mice devoid of Eμ. In Eμ's absence, V(H) gene assembly is dramatically impaired, arresting B cell development. The current study circumvented this problem by modifying the murine Igh locus through simultaneous insertion of a fully assembled V(H) gene and deletion of Eμ. The behavior of this allele was compared with that of a matched allele carrying the same V(H) gene but with Eμ intact. Although IgH transcription was as great or greater on the Eμ-deficient allele, CSR and SHM were consistently, but modestly, reduced relative to the allele in which Eμ remained intact. We conclude that Eμ contributes to, but is not essential for, these complex processes and that its contribution is not as a transcriptional enhancer but, rather, is at the level of recruitment and/or activation of the SHM/CSR machinery.

A non-sense mutation in the putative anti-mutator gene ada/alkA of Mycobacterium tuberculosis and M. bovis isolates suggests convergent evolution

PubMed Central

Nouvel, Laurent X; Vultos, Tiago Dos; Kassa-Kelembho, Eric; Rauzier, Jean; Gicquel, Brigitte

2007-01-01

Background Previous studies have suggested that variations in DNA repair genes of W-Beijing strains may have led to transient mutator phenotypes which in turn may have contributed to host adaptation of this strain family. Single nucleotide polymorphism (SNP) in the DNA repair gene mutT1 was identified in MDR-prone strains from the Central African Republic. A Mycobacteriumtuberculosis H37Rv mutant inactivated in two DNA repair genes, namely ada/alkA and ogt, was shown to display a hypermutator phenotype. We then looked for polymorphisms in these genes in Central African Republic strains (CAR). Results In this study, 55 MDR and 194 non-MDR strains were analyzed. Variations in DNA repair genes ada/alkA and ogt were identified. Among them, by comparison to M. tuberculosis published sequences, we found a non-sense variation in ada/alkA gene which was also observed in M. bovis AF2122 strain. SNPs that are present in the adjacent regions to the amber variation are different in M. bovis and in M. tuberculosis strain. Conclusion An Amber codon was found in the ada/alkA locus of clustered M. tuberculosis isolates and in M. bovis strain AF2122. This is likely due to convergent evolution because SNP differences between strains are incompatible with horizontal transfer of an entire gene. This suggests that such a variation may confer a selective advantage and be implicated in hypermutator phenotype expression, which in turn contributes to adaptation to environmental changes. PMID:17506895

DNA Editing of LTR Retrotransposons Reveals the Impact of APOBECs on Vertebrate Genomes

PubMed Central

Knisbacher, Binyamin A.; Levanon, Erez Y.

2016-01-01

Long terminal repeat retrotransposons (LTR) are widespread in vertebrates and their dynamism facilitates genome evolution. However, these endogenous retroviruses (ERVs) must be restricted to maintain genomic stability. The APOBECs, a protein family that can edit C-to-U in DNA, do so by interfering with reverse transcription and hypermutating retrotransposon DNA. In some cases, a retrotransposon may integrate into the genome despite being hypermutated. Such an event introduces a unique sequence into the genome, increasing retrotransposon diversity and the probability of developing new function at the locus of insertion. The prevalence of this phenomenon and its effects on vertebrate genomes are still unclear. In this study, we screened ERV sequences in the genomes of 123 diverse species and identified hundreds of thousands of edited sites in multiple vertebrate lineages, including placental mammals, marsupials, and birds. Numerous edited ERVs carry high mutation loads, some with greater than 350 edited sites, profoundly damaging their open-reading frames. For many of the species studied, this is the first evidence that APOBECs are active players in their innate immune system. Unexpectedly, some birds and especially zebra finch and medium ground-finch (one of Darwin’s finches) are exceptionally enriched in DNA editing. We demonstrate that edited retrotransposons may be preferentially retained in active genomic regions, as reflected from their enrichment in genes, exons, promoters, and transcription start sites, thereby raising the probability of their exaptation for novel function. In conclusion, DNA editing of retrotransposons by APOBECs has a substantial role in vertebrate innate immunity and may boost genome evolution. PMID:26541172

Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing

PubMed Central

Lohr, Jens G.; Stojanov, Petar; Lawrence, Michael S.; Auclair, Daniel; Chapuy, Bjoern; Sougnez, Carrie; Cruz-Gordillo, Peter; Knoechel, Birgit; Asmann, Yan W.; Slager, Susan L.; Novak, Anne J.; Dogan, Ahmet; Ansell, Stephen M.; Zou, Lihua; Gould, Joshua; Saksena, Gordon; Stransky, Nicolas; Rangel-Escareño, Claudia; Fernandez-Lopez, Juan Carlos; Hidalgo-Miranda, Alfredo; Melendez-Zajgla, Jorge; Hernández-Lemus, Enrique; Schwarz-Cruz y Celis, Angela; Imaz-Rosshandler, Ivan; Ojesina, Akinyemi I.; Jung, Joonil; Pedamallu, Chandra S.; Lander, Eric S.; Habermann, Thomas M.; Cerhan, James R.; Shipp, Margaret A.; Getz, Gad; Golub, Todd R.

2012-01-01

To gain insight into the genomic basis of diffuse large B-cell lymphoma (DLBCL), we performed massively parallel whole-exome sequencing of 55 primary tumor samples from patients with DLBCL and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, including MYD88, CARD11, EZH2, and CREBBP. We also identified somatic mutations in genes for which a functional role in DLBCL has not been previously suspected. These genes include MEF2B, MLL2, BTG1, GNA13, ACTB, P2RY8, PCLO, and TNFRSF14. Further, we show that BCL2 mutations commonly occur in patients with BCL2/IgH rearrangements as a result of somatic hypermutation normally occurring at the IgH locus. The BCL2 point mutations are primarily synonymous, and likely caused by activation-induced cytidine deaminase–mediated somatic hypermutation, as shown by comprehensive analysis of enrichment of mutations in WRCY target motifs. Those nonsynonymous mutations that are observed tend to be found outside of the functionally important BH domains of the protein, suggesting that strong negative selection against BCL2 loss-of-function mutations is at play. Last, by using an algorithm designed to identify likely functionally relevant but infrequent mutations, we identify KRAS, BRAF, and NOTCH1 as likely drivers of DLBCL pathogenesis in some patients. Our data provide an unbiased view of the landscape of mutations in DLBCL, and this in turn may point toward new therapeutic strategies for the disease. PMID:22343534

Overexpression of the DNA mismatch repair factor, PMS2, confers hypermutability and DNA damage tolerance.

PubMed

Gibson, Shannon L; Narayanan, Latha; Hegan, Denise Campisi; Buermeyer, Andrew B; Liskay, R Michael; Glazer, Peter M

2006-12-08

Inherited defects in genes associated with DNA mismatch repair (MMR) have been linked to familial colorectal cancer. Cells deficient in MMR are genetically unstable and demonstrate a tolerance phenotype in response to certain classes of DNA damage. Some sporadic human cancers also show abnormalities in MMR gene function, typically due to diminished expression of one of the MutL homologs, MLH1. Here, we report that overexpression of the MutL homolog, human PMS2, can also cause a disruption of the MMR pathway in mammalian cells, resulting in hypermutability and DNA damage tolerance. A mouse fibroblast cell line carrying a recoverable lambda phage shuttle vector for mutation detection was transfected with either a vector designed to express hPMS2 or with an empty vector control. Cells overexpressing hPMS2 were found to have elevated spontaneous mutation frequencies at the cII reporter gene locus. They also showed an increase in the level of mutations induced by the alkylating agent, methynitrosourea (MNU). Clonogenic survival assays demonstrated increased survival of the PMS2-overexpressing cells following exposure to MNU, consistent with the induction of a damage tolerance phenotype. Similar results were seen in cells expressing a mutant PMS2 gene, containing a premature stop codon at position 134 and representing a variant found in an individual with familial colon cancer. These results show that dysregulation of PMS2 gene expression can disrupt MMR function in mammalian cells and establish an additional carcinogenic mechanism by which cells can develop genetic instability and acquire resistance to cytotoxic cancer therapies.

TEAM: efficient two-locus epistasis tests in human genome-wide association study.

PubMed

Zhang, Xiang; Huang, Shunping; Zou, Fei; Wang, Wei

2010-06-15

As a promising tool for identifying genetic markers underlying phenotypic differences, genome-wide association study (GWAS) has been extensively investigated in recent years. In GWAS, detecting epistasis (or gene-gene interaction) is preferable over single locus study since many diseases are known to be complex traits. A brute force search is infeasible for epistasis detection in the genome-wide scale because of the intensive computational burden. Existing epistasis detection algorithms are designed for dataset consisting of homozygous markers and small sample size. In human study, however, the genotype may be heterozygous, and number of individuals can be up to thousands. Thus, existing methods are not readily applicable to human datasets. In this article, we propose an efficient algorithm, TEAM, which significantly speeds up epistasis detection for human GWAS. Our algorithm is exhaustive, i.e. it does not ignore any epistatic interaction. Utilizing the minimum spanning tree structure, the algorithm incrementally updates the contingency tables for epistatic tests without scanning all individuals. Our algorithm has broader applicability and is more efficient than existing methods for large sample study. It supports any statistical test that is based on contingency tables, and enables both family-wise error rate and false discovery rate controlling. Extensive experiments show that our algorithm only needs to examine a small portion of the individuals to update the contingency tables, and it achieves at least an order of magnitude speed up over the brute force approach.

Understanding the Different Realities, Experience, and Use of Self-Esteem between Black and White Adolescent Girls

ERIC Educational Resources Information Center

Adams, Portia E.

2010-01-01

African American adolescent females possess higher self-esteem than any other racial or ethnic adolescent female group. This article tests two popular empirically supported explanations for Black high self-esteem: "contingency of self-esteem theory" and the "locus of control model". This article builds on past research to illustrate the specific…

The somatic POLE P286R mutation defines a unique subclass of colorectal cancer featuring hypermutation, representing a potential genomic biomarker for immunotherapy

PubMed Central

Kim, Jihun; Kim, Deokhoon; Chun, Sung-Min; Kim, Jiyun; Kim, Tae Won; Park, Inja; Yu, Chang-Sik; Jang, Se Jin

2016-01-01

Early-onset colorectal cancers (EOCRCs) may have biological or genomic features distinct from late-onset CRCs (LOCRCs). Previous studies have mostly focused on the germline predisposition conditions of EOCRCs, but we hypothesized that EOCRCs may have distinct somatic aberrations that accelerate cancer development. To identify the somatic aberrations that accelerate cancer development at an early age, we conducted whole exome sequencing for 28 polyposis-unrelated, microsatellite stable (MSS) EOCRCs with no known germline predisposition conditions. Surprisingly, we found two distinct groups in the context of mutational burden: 6 hypermutated cases with 2325 to 10973 mutations and 22 nonhypermutated cases with 47 to 154 mutations. Further analysis revealed that four of the six hypermutated cases had the same POLE P286R mutation. We validated this finding in 83 MSS EOCRCs and 27 MSS LOCRCs, which revealed that 7.2% of EOCRCs (6/83) had the POLE P286R mutation, which was not found in LOCRCs. Clinicopathologically, EOCRCs with POLE mutations occurred far more frequently in the right colon than in the left colon, affecting men more frequently than women. In summary, we have identified a unique subclass of colon cancer characterized by a hypermutation associated with the POLE mutation. The acquisition of the POLE mutation leading to hypermutation can accelerate cancer development. Clinically, this subset with hypermutation may be susceptible to immune checkpoint blockade. PMID:27612425

AID Mediates Hypermutation by Deaminating Single Stranded DNA

PubMed Central

Dickerson, Sarah K.; Market, Eleonora; Besmer, Eva; Papavasiliou, F. Nina

2003-01-01

Activation-induced deaminase (AID) is a protein indispensable for the diversification of immunoglobulin (Ig) genes by somatic hypermutation (SHM), class switch recombination (CSR), and gene conversion. To date, the precise role of AID in these processes has not been determined. Here we demonstrate that purified, tetrameric AID can deaminate cytidine residues in DNA, but not in RNA. Furthermore, we show that AID will bind and deaminate only single-stranded DNA, which implies a direct, functional link between hypermutation and transcription. Finally, AID does not target mutational hotspots, thus mutational targeting to specific residues must be attributed to different factors. PMID:12756266

Overlapping hotspots in CDRs are critical sites for V region diversification.

PubMed

Wei, Lirong; Chahwan, Richard; Wang, Shanzhi; Wang, Xiaohua; Pham, Phuong T; Goodman, Myron F; Bergman, Aviv; Scharff, Matthew D; MacCarthy, Thomas

2015-02-17

Activation-induced deaminase (AID) mediates the somatic hypermutation (SHM) of Ig variable (V) regions that is required for the affinity maturation of the antibody response. An intensive analysis of a published database of somatic hypermutations that arose in the IGHV3-23*01 human V region expressed in vivo by human memory B cells revealed that the focus of mutations in complementary determining region (CDR)1 and CDR2 coincided with a combination of overlapping AGCT hotspots, the absence of AID cold spots, and an abundance of polymerase eta hotspots. If the overlapping hotspots in the CDR1 or CDR2 did not undergo mutation, the frequency of mutations throughout the V region was reduced. To model this result, we examined the mutation of the human IGHV3-23*01 biochemically and in the endogenous heavy chain locus of Ramos B cells. Deep sequencing revealed that IGHV3-23*01 in Ramos cells accumulates AID-induced mutations primarily in the AGCT in CDR2, which was also the most frequent site of mutation in vivo. Replacing the overlapping hotspots in CDR1 and CDR2 with neutral or cold motifs resulted in a reduction in mutations within the modified motifs and, to some degree, throughout the V region. In addition, some of the overlapping hotspots in the CDRs were at sites in which replacement mutations could change the structure of the CDR loops. Our analysis suggests that the local sequence environment of the V region, and especially of the CDR1 and CDR2, is highly evolved to recruit mutations to key residues in the CDRs of the IgV region.

Phosphatidylinositol 3-Kinase (PI3K) δ blockade increases genomic instability in B cells

PubMed Central

Compagno, Mara; Wang, Qi; Pighi, Chiara; Cheong, Taek-Chin; Meng, Fei-Long; Poggio, Teresa; Yeap, Leng-Siew; Karaca, Elif; Blasco, Rafael B.; Langellotto, Fernanda; Ambrogio, Chiara; Voena, Claudia; Wiestner, Adrian; Kasar, Siddha N.; Brown, Jennifer R.; Sun, Jing; Wu, Catherine J.; Gostissa, Monica; Alt, Frederick W.; Chiarle, Roberto

2017-01-01

Activation-induced cytidine deaminase (AID) is a B-cell specific enzyme that targets immunoglobulin (Ig) genes to initiate class switch recombination (CSR) and somatic hypermutation (SHM)1. Through off-target activity, however, AID has a much broader impact on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in lymphoma development and progression2. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation3. The phosphatidylinositol 3-kinase (PI3K) δ pathway plays a key role in AID regulation by suppressing its expression in B cells4. Novel drugs for leukemia or lymphoma therapy such as idelalisib, duvelisib or ibrutinib block PI3Kδ activity directly or indirectly5–8, potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation (SHM) and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both these effects were completely abrogated in AID deficient B cells. PI3Kδ inhibitors or ibrutinib increased the formation of AID-dependent tumors in pristane-treated mice. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IgH and AID off-target sites in human chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cell lines, and patients treated with idelalisib, but not ibrutinib, showed increased SHM in AID off-targets. In summary, we show that PI3Kδ or BTK inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism, an effect that should be carefully considered as such inhibitors are administered for years to patients. PMID:28199309

Analysis of Expressed and Non-Expressed IGK Locus Rearrangements in Chronic Lymphocytic Leukemia

PubMed Central

Belessi, Chrysoula; Stamatopoulos, Kostas; Hadzidimitriou, Anastasia; Hatzi, Katerina; Smilevska, Tatjana; Stavroyianni, Niki; Marantidou, Fotini; Paterakis, George; Fassas, Athanasios; Anagnostopoulos, Achilles; Laoutaris, Nikolaos

2005-01-01

Immunoglobulin κ (IGK) locus rearrangements were analyzed in parallel on cDNA/genomic DNA in 188 κ- and 103 λ-chronic lymphocytic leukemia (CLL) cases. IGKV-KDE and IGKJ-C-intron-KDE rearrangements were also analyzed on genomic DNA. In κ-CLL, only 3 of 188 cases carried double in-frame IGKV-J transcripts: in such cases, the possibility that leukemic cells expressed more than one κ chain cannot be excluded. Twenty-eight κ-CLL cases also carried nonexpressed (nontranscribed and/or out-of-frame) IGKV-J rearrangements. Taking IGKV-J, IGKV-KDE, and IGKJ-C-intron-KDE rearrangements together, 38% of κ-CLL cases carried biallelic IGK locus rearrangements. In λ-CLL, 69 IGKV-J rearrangements were detected in 64 of 103 cases (62%); 24 rearrangements (38.2%) were in-frame. Four cases carried in-frame IGKV-J transcripts but retained monotypic light-chain expression, suggesting posttranscriptional regulation of allelic exclusion. In all, taking IGKV-J, IGKV-KDE, and IGKJ-C-intron-KDE rearrangements together, 97% of λ-CLL cases had at least 1 rearranged IGK allele, in keeping with normal cells. IG repertoire comparisons in κ- versus λ-CLL revealed that CLL precursor cells tried many rearrangements on the same IGK allele before they became λ producers. Thirteen of 28 and 26 of 69 non-expressed sequences in, respectively, κ- or λ-CLL had < 100% homology to germline. This finding might be considered as evidence for secondary rearrangements occurring after the onset of somatic hypermutation, at least in some cases. The inactivation of potentially functional IGKV-J joints by secondary rearrangements indicates active receptor editing in CLL and provides further evidence for the role of antigen in CLL immunopathogenesis. PMID:16622520

Evidence for ADAR-induced hypermutation of the Drosophila sigma virus (Rhabdoviridae).

PubMed

Carpenter, Jennifer A; Keegan, Liam P; Wilfert, Lena; O'Connell, Mary A; Jiggins, Francis M

2009-11-26

ADARs are RNA editing enzymes that target double stranded RNA and convert adenosine to inosine, which is read by translation machinery as if it were guanosine. Aside from their role in generating protein diversity in the central nervous system, ADARs have been implicated in the hypermutation of some RNA viruses, although why this hypermutation occurs is not well understood. Here we describe the hypermutation of adenosines to guanosines in the genome of the sigma virus--a negative sense RNA virus that infects Drosophila melanogaster. The clustering of these mutations and the context in which they occur indicates that they have been caused by ADARs. However, ADAR-editing of viral RNA is either rare or edited viral RNA are rapidly degraded, as we only detected evidence for editing in two of the 104 viral isolates we studied. This is the first evidence for ADARs targeting viruses outside of mammals, and it raises the possibility that ADARs could play a role in the antiviral defences of insects.

Somatic hypermutation in MutS homologue (MSH)3-, MSH6-, and MSH3/MSH6-deficient mice reveals a role for the MSH2-MSH6 heterodimer in modulating the base substitution pattern.

PubMed

Wiesendanger, M; Kneitz, B; Edelmann, W; Scharff, M D

2000-02-07

Although the primary function of the DNA mismatch repair (MMR) system is to identify and correct base mismatches that have been erroneously introduced during DNA replication, recent studies have further implicated several MMR components in somatic hypermutation of immunoglobulin (Ig) genes. We studied the immune response in mice deficient in MutS homologue (MSH)3 and MSH6, two mutually exclusive partners of MSH2 that have not been examined previously for their role in Ig hypermutation. In Msh6(-)/- and Msh3(-)/-/Msh6(-)/- mice, base substitutions are preferentially targeted to G and C nucleotides and to an RGYW hot spot, as has been shown previously in Msh2(-)/- mice. In contrast, Msh3(-)/- mice show no differences from their littermate controls. These findings indicate that the MSH2-MSH6 heterodimer, but not the MSH2-MSH3 complex, is responsible for modulating Ig hypermutation.

Methods for engineering polypeptide variants via somatic hypermutation and polypeptide made thereby

DOEpatents

Tsien, Roger Y; Wang, Lei

2015-01-13

Methods using somatic hypermutation (SHM) for producing polypeptide and nucleic acid variants, and nucleic acids encoding such polypeptide variants are disclosed. Such variants may have desired properties. Also disclosed are novel polypeptides, such as improved fluorescent proteins, produced by the novel methods, and nucleic acids, vectors, and host cells comprising such vectors.

A Novel Hybrid Clonal Selection Algorithm with Combinatorial Recombination and Modified Hypermutation Operators for Global Optimization

PubMed Central

Lin, Jingjing; Jing, Honglei

2016-01-01

Artificial immune system is one of the most recently introduced intelligence methods which was inspired by biological immune system. Most immune system inspired algorithms are based on the clonal selection principle, known as clonal selection algorithms (CSAs). When coping with complex optimization problems with the characteristics of multimodality, high dimension, rotation, and composition, the traditional CSAs often suffer from the premature convergence and unsatisfied accuracy. To address these concerning issues, a recombination operator inspired by the biological combinatorial recombination is proposed at first. The recombination operator could generate the promising candidate solution to enhance search ability of the CSA by fusing the information from random chosen parents. Furthermore, a modified hypermutation operator is introduced to construct more promising and efficient candidate solutions. A set of 16 common used benchmark functions are adopted to test the effectiveness and efficiency of the recombination and hypermutation operators. The comparisons with classic CSA, CSA with recombination operator (RCSA), and CSA with recombination and modified hypermutation operator (RHCSA) demonstrate that the proposed algorithm significantly improves the performance of classic CSA. Moreover, comparison with the state-of-the-art algorithms shows that the proposed algorithm is quite competitive. PMID:27698662

Is Mutation Random or Targeted?: No Evidence for Hypermutability in Snail Toxin Genes.

PubMed

Roy, Scott W

2016-10-01

Ever since Luria and Delbruck, the notion that mutation is random with respect to fitness has been foundational to modern biology. However, various studies have claimed striking exceptions to this rule. One influential case involves toxin-encoding genes in snails of the genus Conus, termed conotoxins, a large gene family that undergoes rapid diversification of their protein-coding sequences by positive selection. Previous reconstructions of the sequence evolution of conotoxin genes claimed striking patterns: (1) elevated synonymous change, interpreted as being due to targeted "hypermutation" in this region; (2) elevated transversion-to-transition ratios, interpreted as reflective of the particular mechanism of hypermutation; and (3) much lower rates of synonymous change in the codons encoding several highly conserved cysteine residues, interpreted as strong position-specific codon bias. This work has spawned a variety of studies on the potential mechanisms of hypermutation and on causes for cysteine codon bias, and has inspired hypermutation hypotheses for various other fast-evolving genes. Here, I show that all three findings are likely to be artifacts of statistical reconstruction. First, by simulating nonsynonymous change I show that high rates of dN can lead to overestimation of dS. Second, I show that there is no evidence for any of these three patterns in comparisons of closely related conotoxin sequences, suggesting that the reported findings are due to breakdown of statistical methods at high levels of sequence divergence. The current findings suggest that mutation and codon bias in conotoxin genes may not be atypical, and that random mutation and selection can explain the evolution of even these exceptional loci. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli.

PubMed

Bunnell, Bryan E; Escobar, Jillian F; Bair, Kirsten L; Sutton, Mark D; Crane, John K

2017-01-01

Zinc inhibits the virulence of diarrheagenic E. coli by inducing the envelope stress response and inhibiting the SOS response. The SOS response is triggered by damage to bacterial DNA. In Shiga-toxigenic E. coli, the SOS response strongly induces the production of Shiga toxins (Stx) and of the bacteriophages that encode the Stx genes. In E. coli, induction of the SOS response is accompanied by a higher mutation rate, called the mutator response, caused by a shift to error-prone DNA polymerases when DNA damage is too severe to be repaired by canonical DNA polymerases. Since zinc inhibited the other aspects of the SOS response, we hypothesized that zinc would also inhibit the mutator response, also known as hypermutation. We explored various different experimental paradigms to induce hypermutation triggered by the SOS response, and found that hypermutation was induced not just by classical inducers such as mitomycin C and the quinolone antibiotics, but also by antiviral drugs such as zidovudine and anti-cancer drugs such as 5-fluorouracil, 6-mercaptopurine, and azacytidine. Zinc salts inhibited the SOS response and the hypermutator phenomenon in E. coli as well as in Klebsiella pneumoniae, and was more effective in inhibiting the SOS response than other metals. We then attempted to determine the mechanism by which zinc, applied externally in the medium, inhibits hypermutation. Our results show that zinc interferes with the actions of RecA, and protects LexA from RecA-mediated cleavage, an early step in initiation of the SOS response. The SOS response may play a role in the development of antibiotic resistance and the effect of zinc suggests ways to prevent it.

Switch junction sequences in PMS2-deficient mice reveal a microhomology-mediated mechanism of Ig class switch recombination

PubMed Central

Ehrenstein, Michael R.; Rada, Cristina; Jones, Anne-Marie; Milstein, César; Neuberger, Michael S.

2001-01-01

Isotype switching involves a region-specific, nonhomologous recombinational deletion that has been suggested to occur by nonhomologous joining of broken DNA ends. Here, we find increased donor/acceptor homology at switch junctions from PMS2-deficient mice and propose that class switching can occur by microhomology-mediated end-joining. Interestingly, although isotype switching and somatic hypermutation show many parallels, we confirm that PMS2 deficiency has no major effect on the pattern of nucleotide substitutions generated during somatic hypermutation. This finding is in contrast to MSH2 deficiency. With MSH2, the altered pattern of switch recombination and hypermutation suggests parallels in the mechanics of the two processes, whereas the fact that PMS2 deficiency affects only switch recombination may reflect differences in the pathways of break resolution. PMID:11717399

Contracting with outpatient hemodialysis patients to improve adherence to treatment.

PubMed

Laidlaw, J K; Beeken, J E; Whitney, F W; Reyes, A A

1999-02-01

The purpose of this study was to examine the relationship between contingency contracting and adherence to prescribed therapy in outpatient chronic hemodialysis patients. A quasi-experimental, pretest/posttest design was used. The sample included 15 hemodialysis patients, 6 in the phosphorus group and 9 in the weight-gain group. The study was conducted at an outpatient hemodialysis center in a Midwestern rural state. Specific variables investigated were interdialytic weight gains and serum phosphorus levels that reflect adherence to fluid restrictions and to taking phosphate-binding medications. Weekly interviews were conducted with each patient and content analysis of interview data was completed to identify categories related to adherence and nonadherence. Pre- and postcontract weight gains and phosphorus levels were analyzed with a paired two sample t-test. The categories related to adherence and nonadherence included physiological, psychological, environmental, locus of control/self-control/self-praise, economical, medical, knowledge deficit, health benefits, family support, and social support. Adherence to taking phosphate-binding medication responded more favorably to contingency contracting than did adherence to fluid restrictions. Chronic outpatient hemodialysis patients in the sample responded to the use of contingency contracting and developed techniques to remember to take phosphate-binding medications in order to lower serum phosphorus medications.

In Vivo Hypermutation of Xenotropic Murine Leukemia Virus-Related Virus DNA in Peripheral Blood Mononuclear Cells of Rhesus Macaque by APOBEC3 Proteins

PubMed Central

Zhang, Ao; Bogerd, Hal; Villinger, Francois; Gupta, Jaydip Das; Dong, Beihua; Klein, Eric A.; Hackett, John; Schochetman, Gerald; Cullen, Bryan R.; Silverman, Robert H.

2011-01-01

The gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV), replicates to high titers in some human cell lines and is able to infect non-human primates. To determine whether APOBEC3 (A3) proteins restrict XMRV infections in a non-human primate model, we sequenced proviral DNA from peripheral blood mononuclear cells of XMRV-infected rhesus macaques. Hypermutation characteristic of A3DE, A3F and A3G activities was observed in the XMRV proviral sequences in vivo. Furthermore, expression of rhesus A3DE, A3F, or A3G in human cells inhibited XMRV infection and caused hypermutation of XMRV DNA. These studies show that some rhesus A3 isoforms are highly effective against XMRV in the blood of a non-human primate model of infection and in cultured human cells. PMID:21982221

Hypermutation by intersegmental transfer of APOBEC3G cytidine deaminase.

PubMed

Nowarski, Roni; Britan-Rosich, Elena; Shiloach, Tamar; Kotler, Moshe

2008-10-01

Deamination of cytidine residues in single-stranded DNA (ssDNA) is an important mechanism by which apolipoprotein B mRNA-editing, catalytic polypeptide-like (APOBEC) enzymes restrict endogenous and exogenous viruses. The dynamic process underlying APOBEC-induced hypermutation is not fully understood. Here we show that enzymatically active APOBEC3G can be detected in wild-type Vif(+) HIV-1 virions, albeit at low levels. In vitro studies showed that single enzyme-DNA encounters result in distributive deamination of adjacent cytidines. Nonlinear translocation of APOBEC3G, however, directed scattered deamination of numerous targets along the DNA. Increased ssDNA concentrations abolished enzyme processivity in the case of short, but not long, DNA substrates, emphasizing the key role of rapid intersegmental transfer in targeting the deaminase. Our data support a model by which APOBEC3G intersegmental transfer via monomeric binding to two ssDNA segments results in dispersed hypermutation of viral genomes.

Medical Drama Viewing and Healthy Lifestyle Behaviors: Understanding the Role of Health Locus of Control Beliefs and Education Level.

PubMed

Kim, Sungsu; Baek, Young Min

2017-11-22

The present study advances the understanding of how medical drama viewing influences healthy lifestyle behaviors (e.g., smoking, exercising, and consuming vegetables) by examining the role of the health locus of control (HLOC) beliefs and education level. An analysis of nationally representative data reveals that watching medical dramas is positively associated with chance and powerful others' HLOC beliefs. In addition, healthy lifestyle behaviors are positively associated with the internal HLOC belief and are negatively associated with the chance and powerful others' HLOC beliefs. Research findings demonstrate that there are indirect effects of medical drama viewing on these behaviors via chance and powerful others' HLOC beliefs. The indirect effect through the powerful others' HLOC belief is also contingent on the education level. The implications for the role of HLOC beliefs and education level in terms of the effects of medical dramas on health-promoting behaviors are discussed.

Somatic immunoglobulin hypermutation

PubMed Central

Diaz, Marilyn; Casali, Paolo

2015-01-01

Immunoglobulin hypermutation provides the structural correlate for the affinity maturation of the antibody response. Characteristic modalities of this mechanism include a preponderance of point-mutations with prevalence of transitions over transversions, and the mutational hotspot RGYW sequence. Recent evidence suggests a mechanism whereby DNA-breaks induce error-prone DNA synthesis in immunoglobulin V(D)J regions by error-prone DNA polymerases. The nature of the targeting mechanism and the trans-factors effecting such breaks and their repair remain to be determined. PMID:11869898

The population genetics of X-autosome synthetic lethals and steriles.

PubMed

Lachance, Joseph; Johnson, Norman A; True, John R

2011-11-01

Epistatic interactions are widespread, and many of these interactions involve combinations of alleles at different loci that are deleterious when present in the same individual. The average genetic environment of sex-linked genes differs from that of autosomal genes, suggesting that the population genetics of interacting X-linked and autosomal alleles may be complex. Using both analytical theory and computer simulations, we analyzed the evolutionary trajectories and mutation-selection balance conditions for X-autosome synthetic lethals and steriles. Allele frequencies follow a set of fundamental trajectories, and incompatible alleles are able to segregate at much higher frequencies than single-locus expectations. Equilibria exist, and they can involve fixation of either autosomal or X-linked alleles. The exact equilibrium depends on whether synthetic alleles are dominant or recessive and whether fitness effects are seen in males, females, or both sexes. When single-locus fitness effects and synthetic incompatibilities are both present, population dynamics depend on the dominance of alleles and historical contingency (i.e., whether X-linked or autosomal mutations occur first). Recessive synthetic lethality can result in high-frequency X-linked alleles, and dominant synthetic lethality can result in high-frequency autosomal alleles. Many X-autosome incompatibilities in natural populations may be cryptic, appearing to be single-locus effects because one locus is fixed. We also discuss the implications of these findings with respect to standing genetic variation and the origins of Haldane's rule.

Determining the Origin of Human Germinal Center B Cell-Derived Malignancies.

PubMed

Seifert, Marc; Küppers, Ralf

2017-01-01

Most human B cell lymphomas originate from germinal center (GC) B cells. This is partly caused by the high proliferative activity of GC B cells and the remodeling processes acting at the immunoglobulin (Ig) loci of these cells, i.e., somatic hypermutation and class-switching. Mistargeting of these processes can cause chromosomal translocations, and the hypermutation machinery may also target non-Ig genes. As somatic hypermutation is exclusively active in GC B cells, the presence of somatic mutations in rearranged IgV genes is a standard criterium for a GC or post-GC B cell origin of lymphomas. Beyond this, ongoing somatic hypermutation during lymphoma clone expansion indicates that the lymphoma has an active GC B cell differentiation program. The proto-oncogene BCL6 is specifically expressed in GC B cells and also acquires somatic mutations as a physiological by-product of the somatic hypermutation process, albeit at a lower level than IgV genes. Thus, detection of BCL6 mutations is a further genetic trait of a GC experience of a B cell lymphoma. Typically, B cell lymphomas retain key features of their specific cells of origin, including a differentiation stage-specific gene expression pattern. This is at least partly due to genetic lesions, which "freeze" the lymphoma cells at the differentiation stage at which the transformation occurred. Therefore, identification of the normal B cell subset with the most similar gene expression pattern to a particular type of B cell lymphoma has been instrumental to deduce the precise cell of origin of lymphomas.We present here protocols to analyze human B cell lymphomas for a potential origin from GC B cells by determining the presence of mutations in rearranged IgV genes and the BCL6 gene, and by comparing the gene expression pattern of lymphoma cells with those of normal B cell subsets by genechip or RNA-sequencing analysis.

Humanization of Antibodies Using Heavy Chain Complementarity-determining Region 3 Grafting Coupled with in Vitro Somatic Hypermutation*

PubMed Central

Bowers, Peter M.; Neben, Tamlyn Y.; Tomlinson, Geoffery L.; Dalton, Jennifer L.; Altobell, Larry; Zhang, Xue; Macomber, John L.; Wu, Betty F.; Toobian, Rachelle M.; McConnell, Audrey D.; Verdino, Petra; Chau, Betty; Horlick, Robert A.; King, David J.

2013-01-01

A method for simultaneous humanization and affinity maturation of monoclonal antibodies has been developed using heavy chain complementarity-determining region (CDR) 3 grafting combined with somatic hypermutation in vitro. To minimize the amount of murine antibody-derived antibody sequence used during humanization, only the CDR3 region from a murine antibody that recognizes the cytokine hβNGF was grafted into a nonhomologous human germ line V region. The resulting CDR3-grafted HC was paired with a CDR-grafted light chain, displayed on the surface of HEK293 cells, and matured using in vitro somatic hypermutation. A high affinity humanized antibody was derived that was considerably more potent than the parental antibody, possessed a low pm dissociation constant, and demonstrated potent inhibition of hβNGF activity in vitro. The resulting antibody contained half the heavy chain murine donor sequence compared with the same antibody humanized using traditional methods. PMID:23355464

Adaptive tuning of mutation rates allows fast response to lethal stress in Escherichia coli

PubMed Central

Swings, Toon; Van den Bergh, Bram; Wuyts, Sander; Oeyen, Eline; Voordeckers, Karin; Verstrepen, Kevin J; Fauvart, Maarten; Verstraeten, Natalie; Michiels, Jan

2017-01-01

While specific mutations allow organisms to adapt to stressful environments, most changes in an organism's DNA negatively impact fitness. The mutation rate is therefore strictly regulated and often considered a slowly-evolving parameter. In contrast, we demonstrate an unexpected flexibility in cellular mutation rates as a response to changes in selective pressure. We show that hypermutation independently evolves when different Escherichia coli cultures adapt to high ethanol stress. Furthermore, hypermutator states are transitory and repeatedly alternate with decreases in mutation rate. Specifically, population mutation rates rise when cells experience higher stress and decline again once cells are adapted. Interestingly, we identified cellular mortality as the major force driving the quick evolution of mutation rates. Together, these findings show how organisms balance robustness and evolvability and help explain the prevalence of hypermutation in various settings, ranging from emergence of antibiotic resistance in microbes to cancer relapses upon chemotherapy. DOI: http://dx.doi.org/10.7554/eLife.22939.001 PMID:28460660

Ultraviolet mutagenesis in a plasmid vector replicated in lymphoid cells from patient with the melanoma-prone disorder dysplastic nevus syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seetharam, S.; Waters, H.L.; Seidman, M.M.

The hereditary dysplastic nevus syndrome (DNS) is an autosomal dominant disorder in which affected individuals have increased numbers of dysplastic (premalignant) nevi and a greater than 100-fold increased risk of developing cutaneous melanoma. Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with hereditary DNS have been shown to be hypermutable to UV radiation. To examine the mechanism involved in this UV hypermutability, we used a shuttle vector plasmid, pZ189, which carries a 160-base pair marker gene, supF, and can replicate in human cells. pZ189 was treated with UV radiation and transfected into DNS6BE, a lymphoblastoid cell line from a patient withmore » hereditary DNS. Plasmid survival after UV was similar with the DNS6BE line and with a lymphoblastoid cell line from a normal donor. Plasmid mutation frequency was greater with the DNS line in accord with the DNS cellular hypermutability. Base sequence analysis was performed on 69 mutated plasmids recovered from the DNS line. There were significantly more plasmids with single base substitution mutations (P less than 0.01) in comparison to UV-treated plasmids passed through normal fibroblasts. pZ189 hypermutability and an increased frequency of single base substitutions was previously found with a cell line from a melanoma-prone xeroderma pigmentosum patient. These differences may be related to the increased melanoma susceptibility in both DNS and xeroderma pigmentosum.« less

The signature of somatic hypermutation appears to be written into the germline IgV segment repertoire.

PubMed

Blanden, R V; Rothenfluh, H S; Zylstra, P; Weiller, G F; Steele, E J

1998-04-01

We present here a unifying hypothesis for the molecular mechanism of somatic hypermutation and somatic gene conversion in IgV genes involving reverse transcription using RNA templates from the V-gene loci to produce cDNA which undergoes homologous recombination with chromosomal V(D)J DNA. Experimental evidence produced over the last 20 years is essentially consistent with this hypothesis. We also review evidence suggesting that somatically generated IgV sequences from B lymphocytes have been fed back to germline DNA over evolutionary time.

Tracking the location of visuospatial attention in a contingent capture paradigm.

PubMed

Leblanc, Emilie; Prime, David J; Jolicoeur, Pierre

2008-04-01

Currently, there is considerable controversy regarding the degree to which top-down control can affect attentional capture by salient events. According to the contingent capture hypothesis, attentional capture by a salient stimulus is contingent on a match between the properties of the stimulus and top-down attentional control settings. In contrast, bottom-up saliency accounts argue that the initial capture of attention is determined solely by the relative salience of the stimulus, and the effect of top-down attentional control is limited to effects on the duration of attentional engagement on the capturing stimulus. In the present study, we tested these competing accounts by utilizing the N2pc event-related potential component to track the locus of attention during an attentional capture task. The results were completely consistent with the contingent capture hypothesis: An N2pc wave was elicited only by distractors that possessed the target-defining attribute. In a second experiment, we expanded upon this finding by exploring the effect of target-distractor similarity on the duration that attention dwells at the distractor location. In this experiment, only distractors possessing the target-defining attribute (color) captured visuospatial attention to their location and the N2pc increased in duration and in magnitude when the capture distractor also shared a second target attribute (category membership). Finally, in three additional control experiments, we replicated the finding of an N2pc generated by distractors, only if they shared the target-defining attribute. Thus, our results demonstrate that attentional control settings influence both which stimuli attract attention and to what extent they are processed.

The evolution of multiple isotypic IgM heavy chain genes in the shark.

PubMed

Lee, Victor; Huang, Jing Li; Lui, Ming Fai; Malecek, Karolina; Ohta, Yuko; Mooers, Arne; Hsu, Ellen

2008-06-01

The IgM H chain gene organization of cartilaginous fishes consists of 15-200 miniloci, each with a few gene segments (V(H)-D1-D2-J(H)) and one C gene. This is a gene arrangement ancestral to the complex IgH locus that exists in all other vertebrate classes. To understand the molecular evolution of this system, we studied the nurse shark, which has relatively fewer loci, and characterized the IgH isotypes for organization, functionality, and the somatic diversification mechanisms that act upon them. Gene numbers differ slightly between individuals ( approximately 15), but five active IgM subclasses are always present. Each gene undergoes rearrangement that is strictly confined within the minilocus; in B cells there is no interaction between adjacent loci located > or =120 kb apart. Without combinatorial events, the shark IgM H chain repertoire is based on junctional diversity and, subsequently, somatic hypermutation. We suggest that the significant contribution by junctional diversification reflects the selected novelty introduced by RAG in the early vertebrate ancestor, whereas combinatorial diversity coevolved with the complex translocon organization. Moreover, unlike other cartilaginous fishes, there are no germline-joined VDJ at any nurse shark mu locus, and we suggest that such genes, when functional, are species-specific and may have specialized roles. With an entire complement of IgM genes available for the first time, phylogenetic analyses were performed to examine how the multiple Ig loci evolved. We found that all domains changed at comparable rates, but V(H) appears to be under strong positive selection for increased amino acid sequence diversity, and surprisingly, so does Cmicro2.

Class-Switch Recombination in the Absence of the IgH 3' Regulatory Region.

PubMed

Kim, Ahrom; Han, Li; Santiago, Gabriel E; Verdun, Ramiro E; Yu, Kefei

2016-10-01

The ∼28-kb 3' regulatory region (3'RR), which is located at the most distal 3' region of the Ig H chain locus, has multiple regulatory functions that control IgH expression, class-switch recombination (CSR), and somatic hypermutation. In this article, we report that deletion of the entire 3'RR in a mouse B cell line that is capable of robust cytokine-dependent CSR to IgA results in reduced, but not abolished, CSR. These data suggest that 3'RR is not absolutely required for CSR and, thus, is not essential for targeting activation-induced cytidine deaminase to S regions, as was suggested. Moreover, replacing 3'RR with a DNA fragment including only its four DNase I hypersensitive sites (lacking the large spacer regions) restores CSR to a level equivalent to or even higher than in wild-type cells, suggesting that the four hypersensitive sites contain most of the CSR-promoting functions of 3'RR. Stimulated cells express abundant germline transcripts, with the presence or absence of 3'RR, providing evidence that 3'RR has a role in promoting CSR that is unique from enhancing S region transcription. Copyright © 2016 by The American Association of Immunologists, Inc.

Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse

PubMed Central

Bashford-Rogers, R J M; Nicolaou, K A; Bartram, J; Goulden, N J; Loizou, L; Koumas, L; Chi, J; Hubank, M; Kellam, P; Costeas, P A; Vassiliou, G S

2016-01-01

The strongest predictor of relapse in B-cell acute lymphoblastic leukemia (B-ALL) is the level of persistence of tumor cells after initial therapy. The high mutation rate of the B-cell receptor (BCR) locus allows high-resolution tracking of the architecture, evolution and clonal dynamics of B-ALL. Using longitudinal BCR repertoire sequencing, we find that the BCR undergoes an unexpectedly high level of clonal diversification in B-ALL cells through both somatic hypermutation and secondary rearrangements, which can be used for tracking the subclonal composition of the disease and detect minimal residual disease with unprecedented sensitivity. We go on to investigate clonal dynamics of B-ALL using BCR phylogenetic analyses of paired diagnosis-relapse samples and find that large numbers of small leukemic subclones present at diagnosis re-emerge at relapse alongside a dominant clone. Our findings suggest that in all informative relapsed patients, the survival of large numbers of clonogenic cells beyond initial chemotherapy is a surrogate for inherent partial chemoresistance or inadequate therapy, providing an increased opportunity for subsequent emergence of fully resistant clones. These results frame early cytoreduction as an important determinant of long-term outcome. PMID:27211266

Somatic hypermutation of the new antigen receptor gene (NAR) in the nurse shark does not generate the repertoire: possible role in antigen-driven reactions in the absence of germinal centers.

PubMed

Diaz, M; Greenberg, A S; Flajnik, M F

1998-11-24

The new antigen receptor (NAR) gene in the nurse shark diversifies extensively by somatic hypermutation. It is not known, however, whether NAR somatic hypermutation generates the primary repertoire (like in the sheep) or rather is used in antigen-driven immune responses. To address this issue, the sequences of NAR transmembrane (Tm) and secretory (Sec) forms, presumed to represent the primary and secondary repertoires, respectively, were examined from the peripheral blood lymphocytes of three adult nurse sharks. More than 40% of the Sec clones but fewer than 11% of Tm clones contained five mutations or more. Furthermore, more than 75% of the Tm clones had few or no mutations. Mutations in the Sec clones occurred mostly in the complementarity-determining regions (CDR) with a significant bias toward replacement substitutions in CDR1; in Tm clones there was no significant bias toward replacements and only a low level of targeting to the CDRs. Unlike the Tm clones where the replacement mutational pattern was similar to that seen for synonymous changes, Sec replacements displayed a distinct pattern of mutations. The types of mutations in NAR were similar to those found in mouse Ig genes rather than to the unusual pattern reported for shark and Xenopus Ig. Finally, an oligoclonal family of Sec clones revealed a striking trend toward acquisition of glutamic/aspartic acid, suggesting some degree of selection. These data strongly suggest that hypermutation of NAR does not generate the repertoire, but instead is involved in antigen-driven immune responses.

Genetic population structure of the recently introduced Asian clam, Potamocorbula amurensis, in San Francisco Bay

USGS Publications Warehouse

Duda, T. F.

1994-01-01

The genetic population structure of the recently introduced Asian clam, Potamocorbula amurensis, in San Francisco Bay was described using starch gel electrophoresis at eight presumptive loci. Specimens were taken from five environmentally distinct sites located throughout the bay. The population maintains a high degree of genetic variation, with a mean heterozygosity of 0.295, a mean polymorphism of 0.75, and an average of 3.70 alleles per locus. The population is genetically homogeneous, as evidenced from genetic distance values and F-statistics. However, heterogeneity of populations was indicated from a contingency chi-square test. Significant deviations from Hardy-Weinberg equilibrium and heterozygote deficiencies were found at the Lap-1 locus for all populations and at the Lap-2 locus for a single population. High levels of variability could represent a universal characteristic of invading species, the levels of variability in the source population(s), and/or the dynamics of the introduction. Lack of differentiation between subpopulations may be due to the immaturity of the San Francisco Bay population, the “general purpose” phenotype genetic strategy of the species, high rates of gene flow in the population, and/or the selective neutrality of the loci investigated.

Lck is a relevant target in chronic lymphocytic leukaemia cells whose expression variance is unrelated to disease outcome.

PubMed

Till, Kathleen J; Allen, John C; Talab, Fatima; Lin, Ke; Allsup, David; Cawkwell, Lynn; Bentley, Alison; Ringshausen, Ingo; Duckworth, Andrew D; Pettitt, Andrew R; Kalakonda, Nagesh; Slupsky, Joseph R

2017-12-01

Pathogenesis of chronic lymphocytic leukaemia (CLL) is contingent upon antigen receptor (BCR) expressed by malignant cells of this disease. Studies on somatic hypermutation of the antigen binding region, receptor expression levels and signal capacity have all linked BCR on CLL cells to disease prognosis. Our previous work showed that the src-family kinase Lck is a targetable mediator of BCR signalling in CLL cells, and that variance in Lck expression associated with ability of BCR to induce signal upon engagement. This latter finding makes Lck similar to ZAP70, another T-cell kinase whose aberrant expression in CLL cells also associates with BCR signalling capacity, but also different because ZAP70 is not easily pharmacologically targetable. Here we describe a robust method of measuring Lck expression in CLL cells using flow cytometry. However, unlike ZAP70 whose expression in CLL cells predicts prognosis, we find Lck expression and disease outcome in CLL are unrelated despite observations that its inhibition produces effects that biologically resemble the egress phenotype taken on by CLL cells treated with idelalisib. Taken together, our findings provide insight into the pathobiology of CLL to suggest a more complex relationship between expression of molecules within the BCR signalling pathway and disease outcome.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Du, Jiansen; Xue, Hailing; Ma, Jing

HIV CRF07 B′/C is a strain circulating mainly in northwest region of China. The gp41 region of CRF07 is derived from a clade C virus. In order to compare the difference of CRF07 gp41 with that of typical clade B virus, we solved the crystal structure of the core region of CRF07 gp41. Compared with clade B gp41, CRF07 gp41 evolved more basic and hydrophilic residues on its helix bundle surface. Based on sequence alignment, a hyper-mutant cluster located in the middle of HR2 heptads repeat was identified. The mutational study of these residues revealed that this site is importantmore » in HIV mediated cell–cell fusion and plays critical roles in conformational changes during viral invasion. - Highlights: • We solved the crystal structure of HIV CRF07 gp41 core region. • A hyper-mutant cluster in the middle of HR2 heptads repeat was identified. • The hyper-mutant site is important in HIV-cell fusion. • The model will help to understand the HIV fusion process.« less

Crowding, visual awareness, and their respective neural loci

PubMed Central

Shin, Kilho; Chung, Susana T. L.; Tjan, Bosco S.

2017-01-01

In peripheral vision, object identification can be impeded when a target object is flanked by other objects. This phenomenon of crowding has been attributed to basic processes associated with image encoding by the visual system, but the neural origin of crowding is not known. Determining whether crowding depends on subjective awareness of the flankers can provide information on the neural origin of crowding. However, recent studies that manipulated flanker awareness have yielded conflicting results. In the current study, we suppressed flanker awareness with two methods: interocular suppression (IOS) and adaptation-induced blindness (AIB). We tested two different types of stimuli: gratings and letters. With IOS, we found that the magnitude of crowding increased as the number of physical flankers increased, even when the observers did not report seeing any of the flankers. In contrast, when flanker awareness was manipulated with AIB, the magnitude of crowding increased with the number of perceived flankers. Our results show that whether crowding is contingent on awareness of the flankers depends on the method used to suppress awareness. In addition, our results imply that the locus of crowding is upstream from the neural locus of IOS and close to or downstream from that of AIB. Neurophysiology and neuroimaging studies jointly implicate mid-to-high level visual processing stages for IOS, while direct evidence regarding the neural locus of AIB is limited. The most consistent interpretation of our empirical findings is to place the neural locus of crowding at an early cortical site, such as V1 or V2. PMID:28549353

Defect in IgV gene somatic hypermutation in common variable immuno-deficiency syndrome.

PubMed

Levy, Y; Gupta, N; Le Deist, F; Garcia, C; Fischer, A; Weill, J C; Reynaud, C A

1998-10-27

Common Variable Immuno-Deficiency (CVID) is the most common symptomatic primary antibody-deficiency syndrome, but the basic immunologic defects underlying this syndrome are not well defined. We report here that among eight patients studied (six CVID and two hypogammaglobulinemic patients with recurrent infections), there is in two CVID patients a dramatic reduction in Ig V gene somatic hypermutation with 40-75% of IgG transcripts totally devoid of mutations in the circulating memory B cell compartment. Functional assays of the T cell compartment point to an intrinsic B cell defect in the process of antibody affinity maturation in these two cases.

Hypermutation In Pancreatic Cancer.

PubMed

Humphris, Jeremy L; Patch, Ann-Marie; Nones, Katia; Bailey, Peter J; Johns, Amber L; McKay, Skye; Chang, David K; Miller, David K; Pajic, Marina; Kassahn, Karin S; Quinn, Michael C J; Bruxner, Timothy J C; Christ, Angelika N; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourse, Craig; Nourbakhsh, Ehsan; Stone, Andrew; Wilson, Peter J; Anderson, Matthew; Fink, J Lynn; Holmes, Oliver; Kazakoff, Stephen; Leonard, Conrad; Newell, Felicity; Waddell, Nick; Wood, Scott; Mead, Ronald S; Xu, Qinying; Wu, Jianmin; Pinese, Mark; Cowley, Mark J; Jones, Marc D; Nagrial, Adnan M; Chin, Venessa T; Chantrill, Lorraine A; Mawson, Amanda; Chou, Angela; Scarlett, Christopher J; Pinho, Andreia V; Rooman, Ilse; Giry-Laterriere, Marc; Samra, Jaswinder S; Kench, James G; Merrett, Neil D; Toon, Christopher W; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Jamieson, Nigel B; McKay, Colin J; Carter, C Ross; Dickson, Euan J; Graham, Janet S; Duthie, Fraser; Oien, Karin; Hair, Jane; Morton, Jennifer P; Sansom, Owen J; Grützmann, Robert; Hruban, Ralph H; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Schulick, Richard D; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Rusev, Borislav; Corbo, Vincenzo; Salvia, Roberto; Cataldo, Ivana; Tortora, Giampaolo; Tempero, Margaret A; Hofmann, Oliver; Eshleman, James R; Pilarsky, Christian; Scarpa, Aldo; Musgrove, Elizabeth A; Gill, Anthony J; Pearson, John V; Grimmond, Sean M; Waddell, Nicola; Biankin, Andrew V

2017-01-01

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Transcription factor YY1 can control AID-mediated mutagenesis in mice.

PubMed

Zaprazna, Kristina; Basu, Arindam; Tom, Nikola; Jha, Vibha; Hodawadekar, Suchita; Radova, Lenka; Malcikova, Jitka; Tichy, Boris; Pospisilova, Sarka; Atchison, Michael L

2018-02-01

Activation-induced cytidine deminase (AID) is crucial for controlling the immunoglobulin (Ig) diversification processes of somatic hypermutation (SHM) and class switch recombination (CSR). AID initiates these processes by deamination of cytosine, ultimately resulting in mutations or double strand DNA breaks needed for SHM and CSR. Levels of AID control mutation rates, and off-target non-Ig gene mutations can contribute to lymphomagenesis. Therefore, factors that control AID levels in the nucleus can regulate SHM and CSR, and may contribute to disease. We previously showed that transcription factor YY1 can regulate the level of AID in the nucleus and Ig CSR. Therefore, we hypothesized that conditional knock-out of YY1 would lead to reduction in AID localization at the Ig locus, and reduced AID-mediated mutations. Using mice that overexpress AID (IgκAID yy1 f/f ) or that express normal AID levels (yy1 f/f ), we found that conditional knock-out of YY1 results in reduced AID nuclear levels, reduced localization of AID to the Sμ switch region, and reduced AID-mediated mutations. We find that the mechanism of YY1 control of AID nuclear accumulation is likely due to YY1-AID physical interaction which blocks AID ubiquitination. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Generalized Least-Squares Estimate for the Origin of Sporophytic Self-Incompatibility

PubMed Central

Uyenoyama, M. K.

1995-01-01

Analysis of nucleotide sequences that regulate the expression of self-incompatibility in flowering plants affords a direct means of examining classical hypotheses for the origin and evolution of this major feature of mating systems. Departing from the classical view of monophyly of all forms of self-incompatibility, the current paradigm for the origin of self-incompatibility postulates multiple episodes of recruitment and modification of preexisting genes. In Brassica, the S locus, which regulates sporophytic self-incompatibility, shows homology to a multigene family present both in self-compatible congeners and in groups for which this form of self-incompatibility is atypical. A phylogenetic analysis of S-allele sequences together with homologous sequences that do not cosegregate with self-incompatibility permits dating the change of function that marked the origin of self-incompatibility. A generalized least-squares method is introduced that provides closed-form expressions for estimates and standard errors for function-specific divergence rates and times of divergence among sequences. This analysis suggests that the age of the sporophytic self-incompatibility system expressed in Brassica exceeds species divergence within the genus by four- to fivefold. The extraordinarily high levels of sequence diversity exhibited by S alleles appears to reflect their ancient derivation, with the alternative hypothesis of hypermutability rejected by the analysis. PMID:7713446

Timing matters: error-prone gap filling and translesion synthesis in immunoglobulin gene hypermutation

PubMed Central

Sale, Julian E.; Batters, Christopher; Edmunds, Charlotte E.; Phillips, Lara G.; Simpson, Laura J.; Szüts, Dávid

2008-01-01

By temporarily deferring the repair of DNA lesions encountered during replication, the bypass of DNA damage is critical to the ability of cells to withstand genomic insults. Damage bypass can be achieved either by recombinational mechanisms that are generally accurate or by a process called translesion synthesis. Translesion synthesis involves replacing the stalled replicative polymerase with one of a number of specialized DNA polymerases whose active sites are able to tolerate a distorted or damaged DNA template. While this property allows the translesion polymerases to synthesize across damaged bases, it does so with the trade-off of an increased mutation rate. The deployment of these enzymes must therefore be carefully regulated. In addition to their important role in general DNA damage tolerance and mutagenesis, the translesion polymerases play a crucial role in converting the products of activation induced deaminase-catalysed cytidine deamination to mutations during immunoglobulin gene somatic hypermutation. In this paper, we specifically consider the control of translesion synthesis in the context of the timing of lesion bypass relative to replication fork progression and arrest at sites of DNA damage. We then examine how recent observations concerning the control of translesion synthesis might help refine our view of the mechanisms of immunoglobulin gene somatic hypermutation. PMID:19008194

Hypermutation in shark immunoglobulin light chain genes results in contiguous substitutions.

PubMed

Lee, Susan S; Tranchina, Daniel; Ohta, Yuko; Flajnik, Martin F; Hsu, Ellen

2002-04-01

Among 631 substitutions present in 90 nurse shark immunoglobulin light chain somatic mutants, 338 constitute 2-4 bp stretches of adjacent changes. An absence of mutations in perinatal sequences and the bias for one mutating V gene in adults suggest that the diversification is antigen dependent. The substitutions shared no patterns, and the absence of donor sequences, including from family members, supports the idea that most changes arose from nontemplated mutation. The tandem mutations as a group are distinguished by consistently fewer transition changes and an A bias. We suggest this is one of several pathways of hypermutation diversifying shark antigen-receptor genes--point mutations, tandem mutations, and mutations with a G-C preference--that coevolved with or preceded gene rearrangement.

Mammalian cell display technology coupling with AID induced SHM in vitro: an ideal approach to the production of therapeutic antibodies.

PubMed

Qin, Chang-Fei; Li, Guan-Cheng

2014-12-01

Traditional antibody production technology within non-mammalian cell expression systems has shown many unsatisfactory properties for the development of therapeutic antibodies. Nevertheless, mammalian cell display technology reaps the benefits of producing full-length all human antibodies. Together with the developed cytidine deaminase induced in vitro somatic hypermutation technology, mammalian cell display technology provides the opportunity to produce high affinity antibodies that might be ideal for therapeutic application. This review was concentrated on the development of the mammalian cell display technology as well as the activation-induced cytidine deaminase induced in vitro somatic hypermutation technology and their applications for the production of therapeutic antibodies. Copyright © 2014 Elsevier B.V. All rights reserved.

Parallel Evolution of High-Level Aminoglycoside Resistance in Escherichia coli Under Low and High Mutation Supply Rates.

PubMed

Ibacache-Quiroga, Claudia; Oliveros, Juan C; Couce, Alejandro; Blázquez, Jesus

2018-01-01

Antibiotic resistance is a major concern in public health worldwide, thus there is much interest in characterizing the mutational pathways through which susceptible bacteria evolve resistance. Here we use experimental evolution to explore the mutational pathways toward aminoglycoside resistance, using gentamicin as a model, under low and high mutation supply rates. Our results show that both normo and hypermutable strains of Escherichia coli are able to develop resistance to drug dosages > 1,000-fold higher than the minimal inhibitory concentration for their ancestors. Interestingly, such level of resistance was often associated with changes in susceptibility to other antibiotics, most prominently with increased resistance to fosfomycin. Whole-genome sequencing revealed that all resistant derivatives presented diverse mutations in five common genetic elements: fhuA, fusA and the atpIBEFHAGDC, cyoABCDE , and potABCD operons. Despite the large number of mutations acquired, hypermutable strains did not pay, apparently, fitness cost. In contrast to recent studies, we found that the mutation supply rate mainly affected the speed (tempo) but not the pattern (mode) of evolution: both backgrounds acquired the mutations in the same order, although the hypermutator strain did it faster. This observation is compatible with the adaptive landscape for high-level gentamicin resistance being relatively smooth, with few local maxima; which might be a common feature among antibiotics for which resistance involves multiple loci.

Parallel Evolution of High-Level Aminoglycoside Resistance in Escherichia coli Under Low and High Mutation Supply Rates

PubMed Central

Ibacache-Quiroga, Claudia; Oliveros, Juan C.; Couce, Alejandro; Blázquez, Jesus

2018-01-01

Antibiotic resistance is a major concern in public health worldwide, thus there is much interest in characterizing the mutational pathways through which susceptible bacteria evolve resistance. Here we use experimental evolution to explore the mutational pathways toward aminoglycoside resistance, using gentamicin as a model, under low and high mutation supply rates. Our results show that both normo and hypermutable strains of Escherichia coli are able to develop resistance to drug dosages > 1,000-fold higher than the minimal inhibitory concentration for their ancestors. Interestingly, such level of resistance was often associated with changes in susceptibility to other antibiotics, most prominently with increased resistance to fosfomycin. Whole-genome sequencing revealed that all resistant derivatives presented diverse mutations in five common genetic elements: fhuA, fusA and the atpIBEFHAGDC, cyoABCDE, and potABCD operons. Despite the large number of mutations acquired, hypermutable strains did not pay, apparently, fitness cost. In contrast to recent studies, we found that the mutation supply rate mainly affected the speed (tempo) but not the pattern (mode) of evolution: both backgrounds acquired the mutations in the same order, although the hypermutator strain did it faster. This observation is compatible with the adaptive landscape for high-level gentamicin resistance being relatively smooth, with few local maxima; which might be a common feature among antibiotics for which resistance involves multiple loci. PMID:29615988

DNA polymerase θ contributes to the generation of C/G mutations during somatic hypermutation of Ig genes

PubMed Central

Masuda, Keiji; Ouchida, Rika; Takeuchi, Arata; Saito, Takashi; Koseki, Haruhiko; Kawamura, Kiyoko; Tagawa, Masatoshi; Tokuhisa, Takeshi; Azuma, Takachika; O-Wang, Jiyang

2005-01-01

Somatic hypermutation of Ig variable region genes is initiated by activation-induced cytidine deaminase; however, the activity of multiple DNA polymerases is required to ultimately introduce mutations. DNA polymerase η (Polη) has been implicated in mutations at A/T, but polymerases involved in C/G mutations have not been identified. We have generated mutant mice expressing DNA polymerase (Polθ) specifically devoid of polymerase activity. Compared with WT mice, Polq-inactive (Polq, the gene encoding Polθ) mice exhibited a reduced level of serum IgM and IgG1. The mutant mice mounted relatively normal primary and secondary immune responses to a T-dependent antigen, but the production of high-affinity specific antibodies was partially impaired. Analysis of the JH4 intronic sequences revealed a slight reduction in the overall mutation frequency in Polq-inactive mice. Remarkably, although mutations at A/T were unaffected, mutations at C/G were significantly decreased, indicating an important, albeit not exclusive, role for Polθ activity. The reduction of C/G mutations was particularly focused on the intrinsic somatic hypermutation hotspots and both transitions and transversions were similarly reduced. These findings, together with the recent observation that Polθ efficiently catalyzes the bypass of abasic sites, lead us to propose that Polθ introduces mutations at C/G by replicating over abasic sites generated via uracil-DNA glycosylase. PMID:16172387

Epstein-Barr virus-infected B cells expanding in germinal centers of infectious mononucleosis patients do not participate in the germinal center reaction.

PubMed

Kurth, Julia; Hansmann, Martin-Leo; Rajewsky, Klaus; Küppers, Ralf

2003-04-15

To assess the impact of the germinal center (GC) reaction on viral spread in Epstein-Barr virus (EBV) infection, we isolated EBV(+) GC B cells from the tonsils of two infectious mononucleosis patients, sequenced their rearranged V genes, and determined expression of the EBV latency genes EBV nuclear antigen 2 and latent membrane protein 1. Most EBV(+) GC B cells belonged to clones of cells harboring somatically mutated V gene rearrangements. Ongoing somatic hypermutation, the hallmark of the GC reaction, was seen only in uninfected GC B cell clones, not in EBV(+) B cell clones. Thus, in infectious mononucleosis, GC and/or memory B cells are directly infected by EBV and expand without somatic hypermutation, whereas the GC passage of EBV-infected naive B cells does not contribute detectably to the generation of infected memory B cells, the main reservoir of EBV during persistence. Most, if not all, EBV-infected cells in GCs exhibited an unusual EBV gene expression pattern in that they were positive for EBV nuclear antigen 2 but negative for latent membrane protein 1. Although the three main types of EBV-associated B cell lymphomas (Burkitt's, Hodgkin's, and posttransplant lymphomas) presumably are derived from GC B cells, EBV(+) GC B cells resembling these EBV(+) GC B cell lymphomas in terms of EBV gene expression and somatic hypermutation pattern could not be identified.

Conditional control of selectin ligand expression and global fucosylation events in mice with a targeted mutation at the FX locus.

PubMed

Smith, Peter L; Myers, Jay T; Rogers, Clare E; Zhou, Lan; Petryniak, Bronia; Becker, Daniel J; Homeister, Jonathon W; Lowe, John B

2002-08-19

Glycoprotein fucosylation enables fringe-dependent modulation of signal transduction by Notch transmembrane receptors, contributes to selectin-dependent leukocyte trafficking, and is faulty in leukocyte adhesion deficiency (LAD) type II, also known as congenital disorder of glycosylation (CDG)-IIc, a rare human disorder characterized by psychomotor defects, developmental abnormalities, and leukocyte adhesion defects. We report here that mice with an induced null mutation in the FX locus, which encodes an enzyme in the de novo pathway for GDP-fucose synthesis, exhibit a virtually complete deficiency of cellular fucosylation, and variable frequency of intrauterine demise determined by parental FX genotype. Live-born FX(-/-) mice exhibit postnatal failure to thrive that is suppressed with a fucose-supplemented diet. FX(-/-) adults suffer from an extreme neutrophilia, myeloproliferation, and absence of leukocyte selectin ligand expression reminiscent of LAD-II/CDG-IIc. Contingent restoration of leukocyte and endothelial selectin ligand expression, general cellular fucosylation, and normal postnatal physiology is achieved by modulating dietary fucose to supply a salvage pathway for GDP-fucose synthesis. Conditional control of fucosylation in FX(-/-) mice identifies cellular fucosylation events as essential concomitants to fertility, early growth and development, and leukocyte adhesion.

A double-strand break can trigger immunoglobulin gene conversion

PubMed Central

Bastianello, Giulia; Arakawa, Hiroshi

2017-01-01

All three B cell-specific activities of the immunoglobulin (Ig) gene re-modeling system—gene conversion, somatic hypermutation and class switch recombination—require activation-induced deaminase (AID). AID-induced DNA lesions must be further processed and dissected into different DNA recombination pathways. In order to characterize potential intermediates for Ig gene conversion, we inserted an I-SceI recognition site into the complementarity determining region 1 (CDR1) of the Ig light chain locus of the AID knockout DT40 cell line, and conditionally expressed I-SceI endonuclease. Here, we show that a double-strand break (DSB) in CDR1 is sufficient to trigger Ig gene conversion in the absence of AID. The pattern and pseudogene usage of DSB-induced gene conversion were comparable to those of AID-induced gene conversion; surprisingly, sometimes a single DSB induced multiple gene conversion events. These constitute direct evidence that a DSB in the V region can be an intermediate for gene conversion. The fate of the DNA lesion downstream of a DSB had more flexibility than that of AID, suggesting two alternative models: (i) DSBs during the physiological gene conversion are in the minority compared to single-strand breaks (SSBs), which are frequently generated following DNA deamination, or (ii) the physiological gene conversion is mediated by a tightly regulated DSB that is locally protected from non-homologous end joining (NHEJ) or other non-homologous DNA recombination machineries. PMID:27701075

Hyper-IgM syndrome type 4 with a B lymphocyte–intrinsic selective deficiency in Ig class-switch recombination

PubMed Central

Imai, Kohsuke; Catalan, Nadia; Plebani, Alessandro; Maródi, László; Sanal, Özden; Kumaki, Satoru; Nagendran, Vasantha; Wood, Philip; Glastre, Catherine; Sarrot-Reynauld, Françoise; Hermine, Olivier; Forveille, Monique; Revy, Patrick; Fischer, Alain; Durandy, Anne

2003-01-01

Hyper-IgM syndrome (HIGM) is a heterogeneous condition characterized by impaired Ig class-switch recombination (CSR). The molecular defects that have so far been associated with this syndrome — which affect the CD40 ligand in HIGM type 1 (HIGM1), CD40 in HIGM3, and activation-induced cytidine deaminase (AID) in HIGM2 — do not account for all cases. We investigated the clinical and immunological characteristics of 15 patients with an unidentified form of HIGM. Although the clinical manifestations were similar to those observed in HIGM2, these patients exhibited a slightly milder HIGM syndrome with residual IgG production. We found that B cell CSR was intrinsically impaired. However, the generation of somatic hypermutations was observed in the variable region of the Ig heavy chain gene, as in control B lymphocytes. In vitro studies showed that the molecular defect responsible for this new HIGM entity (HIGM4) occurs downstream of the AID activity, as the AID gene was induced normally and AID-induced DNA double-strand breaks in the switch μ region of the Ig heavy chain locus were detected during CSR as normal. Thus, HIGM4 is probably the consequence of a selective defect either in a CSR-specific factor of the DNA repair machinery or in survival signals delivered to switched B cells. PMID:12840068

The Transcription Elongation Complex Directs Activation-Induced Cytidine Deaminase-Mediated DNA Deamination†

PubMed Central

Besmer, Eva; Market, Eleonora; Papavasiliou, F. Nina

2006-01-01

Activation-induced cytidine deaminase (AID) is a single-stranded DNA deaminase required for somatic hypermutation of immunoglobulin (Ig) genes, a key process in the development of adaptive immunity. Transcription provides a single-stranded DNA substrate for AID, both in vivo and in vitro. We present here an assay which can faithfully replicate all of the molecular features of the initiation of hypermutation of Ig genes in vivo. In this assay, which detects AID-mediated deamination in the context of transcription by Escherichia coli RNA polymerase, deamination targets either strand and declines in efficiency as the distance from the promoter increases. We show that AID binds DNA exposed by the transcribing polymerase, implicating the polymerase itself as the vehicle which distributes AID on DNA as it moves away from the promoter. PMID:16705187

A role for Msh6 but not Msh3 in somatic hypermutation and class switch recombination.

PubMed

Martomo, Stella A; Yang, William W; Gearhart, Patricia J

2004-07-05

Somatic hypermutation is initiated by activation-induced cytidine deaminase (AID), and occurs in several kilobases of DNA around rearranged immunoglobulin variable (V) genes and switch (S) sites before constant genes. AID deaminates cytosine to uracil, which can produce mutations of C:G nucleotide pairs, and the mismatch repair protein Msh2 participates in generating substitutions of downstream A:T pairs. Msh2 is always found as a heterodimer with either Msh3 or Msh6, so it is important to know which one is involved. Therefore, we sequenced V and S regions from Msh3- and Msh6-deficient mice and compared mutations to those from wild-type mice. Msh6-deficient mice had fewer substitutions of A and T bases in both regions and reduced heavy chain class switching, whereas Msh3-deficient mice had normal antibody responses. This establishes a role for the Msh2-Msh6 heterodimer in hypermutation and switch recombination. When the positions of mutation were mapped, several focused peaks were found in Msh6(-/-) clones, whereas mutations were dispersed in Msh3(-/-) and wild-type clones. The peaks occurred at either G or C in WGCW motifs (W = A or T), indicating that C was mutated on both DNA strands. This suggests that AID has limited entry points into V and S regions in vivo, and subsequent mutation requires Msh2-Msh6 and DNA polymerase.

Secondary immunization generates clonally related antigen-specific plasma cells and memory B cells.

PubMed

Frölich, Daniela; Giesecke, Claudia; Mei, Henrik E; Reiter, Karin; Daridon, Capucine; Lipsky, Peter E; Dörner, Thomas

2010-09-01

Rechallenge with T cell-dependent Ags induces memory B cells to re-enter germinal centers (GCs) and undergo further expansion and differentiation into plasma cells (PCs) and secondary memory B cells. It is currently not known whether the expanded population of memory B cells and PCs generated in secondary GCs are clonally related, nor has the extent of proliferation and somatic hypermutation of their precursors been delineated. In this study, after secondary tetanus toxoid (TT) immunization, TT-specific PCs increased 17- to 80-fold on days 6-7, whereas TT-specific memory B cells peaked (delayed) on day 14 with a 2- to 22-fold increase. Molecular analyses of V(H)DJ(H) rearrangements of individual cells revealed no major differences of gene usage and CDR3 length between TT-specific PCs and memory B cells, and both contained extensive evidence of somatic hypermutation with a pattern consistent with GC reactions. This analysis identified clonally related TT-specific memory B cells and PCs. Within clusters of clonally related cells, sequences shared a number of mutations but also could contain additional base pair changes. The data indicate that although following secondary immunization PCs can derive from memory B cells without further somatic hypermutation, in some circumstances, likely within GC reactions, asymmetric mutation can occur. These results suggest that after the fate decision to differentiate into secondary memory B cells or PCs, some committed precursors continue to proliferate and mutate their V(H) genes.

Evolutionary immunology. A boost to immunity from nurse sharks.

PubMed

Parham, P

1995-07-01

A study of the nurse shark has revealed a type of rearranging gene that has yet to be seen in mammals; it encodes a secreted 'new antigen receptor' which, unlike shark immunoglobulin, revels in somatic hypermutation.

Natural mismatch repair mutations mediate phenotypic diversity and drug resistance in Cryptococcus deuterogattii.

PubMed

Billmyre, R Blake; Clancey, Shelly Applen; Heitman, Joseph

2017-09-26

Pathogenic microbes confront an evolutionary conflict between the pressure to maintain genome stability and the need to adapt to mounting external stresses. Bacteria often respond with elevated mutation rates, but little evidence exists of stable eukaryotic hypermutators in nature. Whole genome resequencing of the human fungal pathogen Cryptococcus deuterogattii identified an outbreak lineage characterized by a nonsense mutation in the mismatch repair component MSH2. This defect results in a moderate mutation rate increase in typical genes, and a larger increase in genes containing homopolymer runs. This allows facile inactivation of genes with coding homopolymer runs including FRR1 , which encodes the target of the immunosuppresive antifungal drugs FK506 and rapamycin. Our study identifies a eukaryotic hypermutator lineage spread over two continents and suggests that pathogenic eukaryotic microbes may experience similar selection pressures on mutation rate as bacterial pathogens, particularly during long periods of clonal growth or while expanding into new environments.

Life state response to environmental crisis: the case of the Love Canal, Niagara Falls, New York

DOE Office of Scientific and Technical Information (OSTI.GOV)

Masters, S.K.

1986-01-01

This thesis explored the differences between two life stages - young and old - in perceiving and responding to man-made environmental disaster, as well as the support resources utilized to cope with disaster - personal, familial/friendship, and organizational. Because of the characteristics of man-made environmental disaster, and because of the different conditions of life and constructions of reality of older and younger families, it was expected that definitions of the situation would vary by life stage and locus of control - authoritative and personal. The research took place in the Love Canal neighborhood of Niagara Falls, New York. Fifty-eight familiesmore » were interviewed in the fall of 1978, and thirty-nine of these families were reinterviewed in the spring of 1979. Interviews were tape recorded, transcribed, and coded. The data were presented in contingency tables and interview excerpts. The interview schedules elicited information of perception of impact, responses to impact, and the utilization of support resources. In an authoritative locus of control situation, the major findings were that both older and younger families perceived impact, that older families were slightly less disrupted, that younger families relied on organizational and familial/friendship support resources, and that older families relied on familial/friendship support resources.« less

An analog of camptothecin inactive against Topoisomerase I is broadly neutralizing of HIV-1 through inhibition of Vif-dependent APOBEC3G degradation.

PubMed

Bennett, Ryan P; Stewart, Ryan A; Hogan, Priscilla A; Ptak, Roger G; Mankowski, Marie K; Hartman, Tracy L; Buckheit, Robert W; Snyder, Beth A; Salter, Jason D; Morales, Guillermo A; Smith, Harold C

2016-12-01

Camptothecin (CPT) is a natural product discovered to be active against various cancers through its ability to inhibit Topoisomerase I (TOP1). CPT analogs also have anti-HIV-1 (HIV) activity that was previously shown to be independent of TOP1 inhibition. We show that a cancer inactive CPT analog (O2-16) inhibits HIV infection by disrupting multimerization of the HIV protein Vif. Antiviral activity depended on the expression of the cellular viral restriction factor APOBEC3G (A3G) that, in the absence of functional Vif, has the ability to hypermutate HIV proviral DNA during reverse transcription. Our studies demonstrate that O2-16 has low cytotoxicity and inhibits Vif-dependent A3G degradation, enabling A3G packaging into HIV viral particles that results in A3G signature hypermutations in viral genomes. This antiviral activity was A3G-dependent and broadly neutralizing against sixteen HIV clinical isolates from groups M (subtypes A-G), N, and O as well as seven single and multi-drug resistant strains of HIV. Molecular modeling predicted binding near the PPLP motif crucial for Vif multimerization and activity. O2-16 also was active in blocking Vif degradation of APOBEC3F (A3F). We propose that CPT analogs not active against TOP1 have novel therapeutic potential as Vif antagonists that enable A3G-dependent hypermutation of HIV. Copyright © 2016 Elsevier B.V. All rights reserved.

Somatic hypermutation at A/T-rich oligonucleotide substrates shows different strand polarities in Ung-deficient or -proficient backgrounds.

PubMed

Zivojnovic, Marija; Delbos, Frédéric; Girelli Zubani, Giulia; Julé, Amélie; Alcais, Alexandre; Weill, Jean-Claude; Reynaud, Claude-Agnès; Storck, Sébastien

2014-06-01

A/T mutations at immunoglobulin loci are introduced by DNA polymerase η (Polη) during an Msh2/6-dependent repair process which results in A's being mutated 2-fold more often than T's. This patch synthesis is initiated by a DNA incision event whose origin is still obscure. We report here the analysis of A/T oligonucleotide mutation substrates inserted at the heavy chain locus, including or not including internal C's or G's. Surprisingly, the template composed of only A's and T's was highly mutated over its entire 90-bp length, with a 2-fold decrease in mutation from the 5' to the 3' end and a constant A/T ratio of 4. These results imply that Polη synthesis was initiated from a break in the 5'-flanking region of the substrate and proceeded over its entire length. The A/T bias was strikingly altered in an Ung(-/-) background, which provides the first experimental evidence supporting a concerted action of Ung and Msh2/6 pathways to generate mutations at A/T bases. New analysis of Pms2(-/-) animals provided a complementary picture, revealing an A/T mutation ratio of 4. We therefore propose that Ung and Pms2 may exert a mutual backup function for the DNA incision that promotes synthesis by Polη, each with a distinct strand bias. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Somatic Hypermutation at A/T-Rich Oligonucleotide Substrates Shows Different Strand Polarities in Ung-Deficient or -Proficient Backgrounds

PubMed Central

Zivojnovic, Marija; Delbos, Frédéric; Girelli Zubani, Giulia; Julé, Amélie; Alcais, Alexandre; Storck, Sébastien

2014-01-01

A/T mutations at immunoglobulin loci are introduced by DNA polymerase η (Polη) during an Msh2/6-dependent repair process which results in A's being mutated 2-fold more often than T's. This patch synthesis is initiated by a DNA incision event whose origin is still obscure. We report here the analysis of A/T oligonucleotide mutation substrates inserted at the heavy chain locus, including or not including internal C's or G's. Surprisingly, the template composed of only A's and T's was highly mutated over its entire 90-bp length, with a 2-fold decrease in mutation from the 5′ to the 3′ end and a constant A/T ratio of 4. These results imply that Polη synthesis was initiated from a break in the 5′-flanking region of the substrate and proceeded over its entire length. The A/T bias was strikingly altered in an Ung−/− background, which provides the first experimental evidence supporting a concerted action of Ung and Msh2/6 pathways to generate mutations at A/T bases. New analysis of Pms2−/− animals provided a complementary picture, revealing an A/T mutation ratio of 4. We therefore propose that Ung and Pms2 may exert a mutual backup function for the DNA incision that promotes synthesis by Polη, each with a distinct strand bias. PMID:24710273

Phenotypic and genetic characteristics of fluoroquinolone- and methicillin-resistant Staphylococcus aureus.

PubMed

Moreno-Flores, Antonio; Potel-Alvarellos, Carmen; Otero-Fernández, Susana; Álvarez-Fernández, Maximiliano

2017-07-20

Fluoroquinolone resistance in methicillin-resistant Staphylococcus aureus (MRSA) has increased in recent years. The objective of this study was to characterise two MRSA populations, one susceptible to fluoroquinolones and other resistant identifying the clonal types and the differential characteristics of both MRSA populations. Molecular typing using PFGE, MLST, spa and SSCmec was performed on 192 MRSA strains isolated from 2009 to 2011, 49 only oxacillin-resistant (OX-R) and 143 oxacillin and levofloxacin-resistant (OX-R-LEV-R). Mutations that conferred resistance to fluoroquinolones, hypermutable phenotypes and the presence of eight microbial surface components recognising adhesive matrix molecules (MSCRAMMs) were also studied. A statistically significant increase in the OX-R-LEV-R phenotype was observed (p<0.05). The most common clone of the OX-R isolates was sequence type (ST) 8 (32.6%), followed by ST72 (26.5%) and ST5 (26.5%). In the OX-R-LEV-R phenotype, the ST5 clone was the most common (65.7%), followed by ST72 (15.4%), and ST125 (12.6%). All isolates except the ST398 clone carried the SCCmecIVc. Clones ST5, ST72, ST125, and ST30 had hypermutable phenotypes. The ST72 clone and the ST30 clone in the OX-R phenotype harboured the highest number of MSCRAMMs. ST5 and ST72 clones were the most frequent clones identified in OX-R-LEV-R phenotype. Both clones showed a hypermutable phenotype that favours their selection as the fluoroquinolone resistant clones. The genetic relationships identified indicate that OX-R-LEV-R clones have evolved from OX-R MRSA clones. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

E2A-positive gastric MALT lymphoma has weaker plasmacytoid infiltrates and stronger expression of the memory B-cell-associated miR-223: possible correlation with stage and treatment response.

PubMed

Liu, Ting-Yun; Chen, Shee-Uan; Kuo, Sung-Hsin; Cheng, Ann-Lii; Lin, Chung-Wu

2010-11-01

Extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue of the stomach (gastric MALT lymphoma) is derived from memory B cells of the marginal zone. Normal memory B cells do not express markers of germinal-center B cells, such as E2A (immunoglobulin enhancer-binding factor E12/E47), B-cell chronic lymphocytic leukemia/lymphoma 6 (BCL6), or activation-induced cytidine deaminase (AID). E2A is a transcription factor that induces somatic hypermutations and blocks plasma cell differentiation. In 50 stage-I(E)/II(E1) gastric MALT lymphomas, we confirmed that all cases were BCL6(-)/AID(-), but a subset (50%, 25/50) was E2A(+). As E2A(-) and E2A(+) gastric MALT lymphomas had similar numbers of somatic hypermutations without intraclonal variations, which implied an origin from memory B cells, the expression of E2A was best regarded as a marker of aberrant follicular differentiation. Although the status of somatic hypermutation was not affected by E2A, E2A(+) gastric MALT lymphoma showed less plasmacytoid infiltrates and higher expressions of miRNA-223, a microRNA associated with memory B cells. Clinically, E2A(+) gastric MALT lymphomas were more likely to spread to perigastric lymph nodes and were less responsive to Helicobacter eradication therapy than were E2A(-) gastric MALT lymphomas. Taken together, aberrant E2A expression is a diagnostic feature of a subtype of gastric MALT lymphoma with weaker plasmacytoid infiltrates and stronger miR-223 expression. A prospective study would be necessary to verify the association between E2A expression and a poor response to Helicobacter eradication therapy.

Dynamics of long-term colonization of respiratory tract by Haemophilus influenzae in cystic fibrosis patients shows a marked increase in hypermutable strains.

PubMed

Román, Federico; Cantón, Rafael; Pérez-Vázquez, María; Baquero, Fernando; Campos, José

2004-04-01

The persistence and variability of 188 Haemophilus influenzae isolates in respiratory tract of 30 cystic fibrosis (CF) patients over the course of 7 years was studied. Antibiotic susceptibility testing, DNA fingerprinting, and analysis of outer membrane protein profiles were performed on all isolates. A total of 115 distinct pulsed-field gel electrophoresis profiles were identified. Ninety percent of patients were cocolonized with two or more clones over the studied period. A third of the patients were cross-colonized with one or two H. influenzae strains; 11% of the clones persisted for 3 or more months. Biotype, outer membrane protein profiles, and resistance profiles showed variation along the studied period, even in persisting clones. Four isolates (2.1%) recovered from 3 patients were type f capsulate, with three of them belonging to the same clone. beta-Lactamase production was detected in 23.9% of isolates while 7% of the beta-lactamase-negative isolates presented diminished susceptibility to ampicillin (beta-lactamase-negative ampicillin resistance phenotype). Remarkably, 21.3% of the H. influenzae isolates presented decreased susceptibility to ciprofloxacin, which was mainly observed in persisting clones. Of the H. influenzae isolates from CF patients, 18 (14.5%) were found to be hypermutable in comparison with 1 (1.4%) from non-CF patients (P < 0.0001). Ten patients (33.3%) were colonized by hypermutable strains over the study period. A multiresistance phenotype and long-term clonal persistence were significantly associated in some cases for up to 7 years. These results suggest that H. influenzae bronchial colonization in CF patients is a dynamic process, but better-adapted clones can persist for long periods of time.

Dynamics of Long-Term Colonization of Respiratory Tract by Haemophilus influenzae in Cystic Fibrosis Patients Shows a Marked Increase in Hypermutable Strains

PubMed Central

Román, Federico; Cantón, Rafael; Pérez-Vázquez, María; Baquero, Fernando; Campos, José

2004-01-01

The persistence and variability of 188 Haemophilus influenzae isolates in respiratory tract of 30 cystic fibrosis (CF) patients over the course of 7 years was studied. Antibiotic susceptibility testing, DNA fingerprinting, and analysis of outer membrane protein profiles were performed on all isolates. A total of 115 distinct pulsed-field gel electrophoresis profiles were identified. Ninety percent of patients were cocolonized with two or more clones over the studied period. A third of the patients were cross-colonized with one or two H. influenzae strains; 11% of the clones persisted for 3 or more months. Biotype, outer membrane protein profiles, and resistance profiles showed variation along the studied period, even in persisting clones. Four isolates (2.1%) recovered from 3 patients were type f capsulate, with three of them belonging to the same clone. β-Lactamase production was detected in 23.9% of isolates while 7% of the β-lactamase-negative isolates presented diminished susceptibility to ampicillin (β-lactamase-negative ampicillin resistance phenotype). Remarkably, 21.3% of the H. influenzae isolates presented decreased susceptibility to ciprofloxacin, which was mainly observed in persisting clones. Of the H. influenzae isolates from CF patients, 18 (14.5%) were found to be hypermutable in comparison with 1 (1.4%) from non-CF patients (P < 0.0001). Ten patients (33.3%) were colonized by hypermutable strains over the study period. A multiresistance phenotype and long-term clonal persistence were significantly associated in some cases for up to 7 years. These results suggest that H. influenzae bronchial colonization in CF patients is a dynamic process, but better-adapted clones can persist for long periods of time. PMID:15070988

High level of APOBEC3F/3G editing in HIV-2 DNA vif and pol sequences from antiretroviral-naive patients.

PubMed

Bertine, Mélanie; Charpentier, Charlotte; Visseaux, Benoit; Storto, Alexandre; Collin, Gilles; Larrouy, Lucile; Damond, Florence; Matheron, Sophie; Brun-Vézinet, Françoise; Descamps, Diane

2015-04-24

In HIV-1, hypermutation introduced by APOBEC3F/3G cytidine deaminase activity leads to defective viruses. In-vivo impact of APOBEC3F/3G editing on HIV-2 sequences remains unknown. The objective of this study was to assess the level of APOBEC3F/3G editing in HIV-2-infected antiretroviral-naive patients. Direct sequencing of vif and pol regions was performed on HIV-2 proviral DNA from antiretroviral-naive patients included in the French Agence Nationale de Recherches sur le SIDA et les hépatites virales CO5 HIV-2 cohort. Hypermutated sequences were identified using Hypermut2.0 program. HIV-1 proviral sequences from Genbank were also assessed. Among 82 antiretroviral-naive HIV-2-infected patients assessed, 15 (28.8%) and five (16.7%) displayed Vif proviral defective sequences in HIV-2 groups A and B, respectively. A lower proportion of defective sequences was observed in protease-reverse transcriptase region. A higher median number of G-to-A mutations was observed in HIV-2 group B than in group A, both in Vif and protease-reverse transcriptase regions (P = 0.02 and P = 0.006, respectively). Compared with HIV-1 Vif sequences, a higher number of Vif defective sequences was observed in HIV-2 group A (P = 0.00001) and group B sequences (P = 0.013). We showed for the first time a high level of APOBEC3F/3G editing in HIV-2 sequences from antiretroviral-naive patients. Our study reported a group effect with a significantly higher level of APOBEC3F/3G editing in HIV-2 group B than in group A sequences.

DNA polymerase η mutational signatures are found in a variety of different types of cancer.

PubMed

Rogozin, Igor B; Goncearenco, Alexander; Lada, Artem G; De, Subhajyoti; Yurchenko, Vyacheslav; Nudelman, German; Panchenko, Anna R; Cooper, David N; Pavlov, Youri I

2018-01-01

DNA polymerase (pol) η is a specialized error-prone polymerase with at least two quite different and contrasting cellular roles: to mitigate the genetic consequences of solar UV irradiation, and promote somatic hypermutation in the variable regions of immunoglobulin genes. Misregulation and mistargeting of pol η can compromise genome integrity. We explored whether the mutational signature of pol η could be found in datasets of human somatic mutations derived from normal and cancer cells. A substantial excess of single and tandem somatic mutations within known pol η mutable motifs was noted in skin cancer as well as in many other types of human cancer, suggesting that somatic mutations in A:T bases generated by DNA polymerase η are a common feature of tumorigenesis. Another peculiarity of pol ηmutational signatures, mutations in YCG motifs, led us to speculate that error-prone DNA synthesis opposite methylated CpG dinucleotides by misregulated pol η in tumors might constitute an additional mechanism of cytosine demethylation in this hypermutable dinucleotide.

Analysis of immunoglobulin transcripts and hypermutation following SHIV(AD8) infection and protein-plus-adjuvant immunization.

PubMed

Francica, Joseph R; Sheng, Zizhang; Zhang, Zhenhai; Nishimura, Yoshiaki; Shingai, Masashi; Ramesh, Akshaya; Keele, Brandon F; Schmidt, Stephen D; Flynn, Barbara J; Darko, Sam; Lynch, Rebecca M; Yamamoto, Takuya; Matus-Nicodemos, Rodrigo; Wolinsky, David; Nason, Martha; Valiante, Nicholas M; Malyala, Padma; De Gregorio, Ennio; Barnett, Susan W; Singh, Manmohan; O'Hagan, Derek T; Koup, Richard A; Mascola, John R; Martin, Malcolm A; Kepler, Thomas B; Douek, Daniel C; Shapiro, Lawrence; Seder, Robert A

2015-04-10

Developing predictive animal models to assess how candidate vaccines and infection influence the ontogenies of Envelope (Env)-specific antibodies is critical for the development of an HIV vaccine. Here we use two nonhuman primate models to compare the roles of antigen persistence, diversity and innate immunity. We perform longitudinal analyses of HIV Env-specific B-cell receptor responses to SHIV(AD8) infection and Env protein vaccination with eight different adjuvants. A subset of the SHIV(AD8)-infected animals with higher viral loads and greater Env diversity show increased neutralization associated with increasing somatic hypermutation (SHM) levels over time. The use of adjuvants results in increased ELISA titres but does not affect the mean SHM levels or CDR H3 lengths. Our study shows how the ontogeny of Env-specific B cells can be tracked, and provides insights into the requirements for developing neutralizing antibodies that should facilitate translation to human vaccine studies.

Cytidine deamination induced HIV-1 drug resistance

PubMed Central

Mulder, Lubbertus C. F.; Harari, Ariana; Simon, Viviana

2008-01-01

The HIV-1 Vif protein is essential for overcoming the antiviral activity of DNA-editing apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3) cytidine deaminases. We show that naturally occurring HIV-1 Vif point mutants with suboptimal anti-APOBEC3G activity induce the appearance of proviruses with lamivudine (3TC) drug resistance-associated mutations before any drug exposure. These mutations, ensuing from cytidine deamination events, were detected in >40% of proviruses with partially defective Vif mutants. Transfer of drug resistance from hypermutated proviruses via recombination allowed for 3TC escape under culture conditions prohibitive for any WT viral growth. These results demonstrate that defective hypermutated genomes can shape the phenotype of the circulating viral population. Partially active Vif alleles resulting in incomplete neutralization of cytoplasmic APOBEC3 molecules are directly responsible for the generation of a highly diverse, yet G-to-A biased, proviral reservoir, which can be exploited by HIV-1 to generate viable and drug-resistant progenies. PMID:18391217

Projection specificity in heterogeneous locus coeruleus cell populations: implications for learning and memory

PubMed Central

Uematsu, Akira; Tan, Bao Zhen

2015-01-01

Noradrenergic neurons in the locus coeruleus (LC) play a critical role in many functions including learning and memory. This relatively small population of cells sends widespread projections throughout the brain including to a number of regions such as the amygdala which is involved in emotional associative learning and the medial prefrontal cortex which is important for facilitating flexibility when learning rules change. LC noradrenergic cells participate in both of these functions, but it is not clear how this small population of neurons modulates these partially distinct processes. Here we review anatomical, behavioral, and electrophysiological studies to assess how LC noradrenergic neurons regulate these different aspects of learning and memory. Previous work has demonstrated that subpopulations of LC noradrenergic cells innervate specific brain regions suggesting heterogeneity of function in LC neurons. Furthermore, noradrenaline in mPFC and amygdala has distinct effects on emotional learning and cognitive flexibility. Finally, neural recording data show that LC neurons respond during associative learning and when previously learned task contingencies change. Together, these studies suggest a working model in which distinct and potentially opposing subsets of LC neurons modulate particular learning functions through restricted efferent connectivity with amygdala or mPFC. This type of model may provide a general framework for understanding other neuromodulatory systems, which also exhibit cell type heterogeneity and projection specificity. PMID:26330494

Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or Medulloblastoma

ClinicalTrials.gov

2018-06-28

Constitutional Mismatch Repair Deficiency Syndrome; Lynch Syndrome; Malignant Glioma; Progressive Ependymoma; Progressive Medulloblastoma; Recurrent Brain Neoplasm; Recurrent Childhood Ependymoma; Recurrent Diffuse Intrinsic Pontine Glioma; Recurrent Medulloblastoma; Refractory Brain Neoplasm; Refractory Diffuse Intrinsic Pontine Glioma; Refractory Ependymoma; Refractory Medulloblastoma

Opinion: uracil DNA glycosylase (UNG) plays distinct and non-canonical roles in somatic hypermutation and class switch recombination.

PubMed

Yousif, Ashraf S; Stanlie, Andre; Begum, Nasim A; Honjo, Tasuku

2014-10-01

Activation-induced cytidine deaminase (AID) is essential to class switch recombination (CSR) and somatic hypermutation (SHM). Uracil DNA glycosylase (UNG), a member of the base excision repair complex, is required for CSR. The role of UNG in CSR and SHM is extremely controversial. AID deficiency in mice abolishes both CSR and SHM, while UNG-deficient mice have drastically reduced CSR but augmented SHM raising a possibility of differential functions of UNG in CSR and SHM. Interestingly, UNG has been associated with a CSR-specific repair adapter protein Brd4, which interacts with acetyl histone 4, γH2AX and 53BP1 to promote non-homologous end joining during CSR. A non-canonical scaffold function of UNG, but not the catalytic activity, can be attributed to the recruitment of essential repair proteins associated with the error-free repair during SHM, and the end joining during CSR. © The Japanese Society for Immunology. 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Integrity of immunoglobulin variable regions is supported by GANP during AID-induced somatic hypermutation in germinal center B cells

PubMed Central

Eid, Mohammed Mansour Abbas; Shimoda, Mayuko; Singh, Shailendra Kumar; Almofty, Sarah Ameen; Pham, Phuong; Goodman, Myron F.; Maeda, Kazuhiko; Sakaguchi, Nobuo

2017-01-01

Abstract Immunoglobulin affinity maturation depends on somatic hypermutation (SHM) in immunoglobulin variable (IgV) regions initiated by activation-induced cytidine deaminase (AID). AID induces transition mutations by C→U deamination on both strands, causing C:G→T:A. Error-prone repairs of U by base excision and mismatch repairs (MMRs) create transversion mutations at C/G and mutations at A/T sites. In Neuberger’s model, it remained to be clarified how transition/transversion repair is regulated. We investigate the role of AID-interacting GANP (germinal center-associated nuclear protein) in the IgV SHM profile. GANP enhances transition mutation of the non-transcribed strand G and reduces mutation at A, restricted to GYW of the AID hotspot motif. It reduces DNA polymerase η hotspot mutations associated with MMRs followed by uracil-DNA glycosylase. Mutation comparison between IgV complementary and framework regions (FWRs) by Bayesian statistical estimation demonstrates that GANP supports the preservation of IgV FWR genomic sequences. GANP works to maintain antibody structure by reducing drastic changes in the IgV FWR in affinity maturation. PMID:28541550

APOBEC3A associates with human papillomavirus genome integration in oropharyngeal cancers.

PubMed

Kondo, S; Wakae, K; Wakisaka, N; Nakanishi, Y; Ishikawa, K; Komori, T; Moriyama-Kita, M; Endo, K; Murono, S; Wang, Z; Kitamura, K; Nishiyama, T; Yamaguchi, K; Shigenobu, S; Muramatsu, M; Yoshizaki, T

2017-03-23

The prevalence of human papillomavirus (HPV)-related oropharyngeal cancers has been increasing in developed countries. We recently demonstrated that members of the apolipoprotein B mRNA-editing catalytic polypeptide 3 (APOBEC3, A3) family, which are antiviral factors, can induce hypermutation of HPV DNA in vitro. In the present study, we found numerous C-to-T and G-to-A hypermutations in the HPV16 genome in oropharyngeal cancer (OPC) biopsy samples using differential DNA denaturation PCR and next-generation sequencing. A3s were more abundantly expressed in HPV16-positive OPCs than in HPV-negative, as assessed using immunohistochemistry and reverse transcription quantitative PCR. In addition, interferons upregulated A3s in an HPV16-positive OPC cell line. Furthermore, quantitative PCR analysis of HPV DNA suggests that APOBEC3A (A3A) expression is strongly correlated with the integration of HPV DNA. These results suggest that HPV16 infection may upregulate A3A expression, thereby increasing the chance of viral DNA integration. The role of A3A in HPV-induced carcinogenesis is discussed.

Somatic Hypermutation-Induced Changes in the Structure and Dynamics of HIV-1 Broadly Neutralizing Antibodies.

PubMed

Davenport, Thaddeus M; Gorman, Jason; Joyce, M Gordon; Zhou, Tongqing; Soto, Cinque; Guttman, Miklos; Moquin, Stephanie; Yang, Yongping; Zhang, Baoshan; Doria-Rose, Nicole A; Hu, Shiu-Lok; Mascola, John R; Kwong, Peter D; Lee, Kelly K

2016-08-02

Antibody somatic hypermutation (SHM) and affinity maturation enhance antigen recognition by modifying antibody paratope structure to improve its complementarity with the target epitope. SHM-induced changes in paratope dynamics may also contribute to antibody maturation, but direct evidence of this is limited. Here, we examine two classes of HIV-1 broadly neutralizing antibodies (bNAbs) for SHM-induced changes in structure and dynamics, and delineate the effects of these changes on interactions with the HIV-1 envelope glycoprotein (Env). In combination with new and existing structures of unmutated and affinity matured antibody Fab fragments, we used hydrogen/deuterium exchange with mass spectrometry to directly measure Fab structural dynamics. Changes in antibody structure and dynamics were positioned to improve complementarity with Env, with changes in dynamics primarily observed at the paratope peripheries. We conclude that SHM optimizes paratope complementarity to conserved HIV-1 epitopes and restricts the mobility of paratope-peripheral residues to minimize clashes with variable features on HIV-1 Env. Copyright © 2016 Elsevier Ltd. All rights reserved.

Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers.

PubMed

Shlien, Adam; Campbell, Brittany B; de Borja, Richard; Alexandrov, Ludmil B; Merico, Daniele; Wedge, David; Van Loo, Peter; Tarpey, Patrick S; Coupland, Paul; Behjati, Sam; Pollett, Aaron; Lipman, Tatiana; Heidari, Abolfazl; Deshmukh, Shriya; Avitzur, Na'ama; Meier, Bettina; Gerstung, Moritz; Hong, Ye; Merino, Diana M; Ramakrishna, Manasa; Remke, Marc; Arnold, Roland; Panigrahi, Gagan B; Thakkar, Neha P; Hodel, Karl P; Henninger, Erin E; Göksenin, A Yasemin; Bakry, Doua; Charames, George S; Druker, Harriet; Lerner-Ellis, Jordan; Mistry, Matthew; Dvir, Rina; Grant, Ronald; Elhasid, Ronit; Farah, Roula; Taylor, Glenn P; Nathan, Paul C; Alexander, Sarah; Ben-Shachar, Shay; Ling, Simon C; Gallinger, Steven; Constantini, Shlomi; Dirks, Peter; Huang, Annie; Scherer, Stephen W; Grundy, Richard G; Durno, Carol; Aronson, Melyssa; Gartner, Anton; Meyn, M Stephen; Taylor, Michael D; Pursell, Zachary F; Pearson, Christopher E; Malkin, David; Futreal, P Andrew; Stratton, Michael R; Bouffet, Eric; Hawkins, Cynthia; Campbell, Peter J; Tabori, Uri

2015-03-01

DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10(-13)). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.

Preliminary validation of the Perceived Locus of Causality scale for academic motivation in the context of university studies (PLOC-U).

PubMed

Sánchez de Miguel, Manuel; Lizaso, Izarne; Hermosilla, Daniel; Alcover, Carlos-Maria; Goudas, Marios; Arranz-Freijó, Enrique

2017-12-01

Research has shown that self-determination theory can be useful in the study of motivation in sport and other forms of physical activity. The Perceived Locus of Causality (PLOC) scale was originally designed to study both. The current research presents and validates the new PLOC-U scale to measure academic motivation in the university context. We tested levels of self-determination before and after academic examinations. Also, we analysed degree of internalization of extrinsic motivation in students' practical activities. Two hundred and eighty-seven Spanish university students participated in the study. Data were collected at two time points to check the reliability and stability of PLOC-U by a test-retest procedure. Confirmatory factor analysis was performed on the PLOC-U. Also convergent validity was tested against the Academic Motivation Scale (EME-E). Confirmatory factor analysis showed optimum fit and good reliability of PLOC-U. It also presented excellent convergent validity with the EME-E and good stability over time. Our findings did not show any significant correlation between self-determination and expected results before academic examinations, but it did so afterwards, revealing greater regulation by and integration of extrinsic motivation. The high score obtained for extrinsic motivation points to a greater regulation associated with an external contingency (rewards in the practical coursework). PLOC-U is a good instrument for the measurement of academic motivation and provides a new tool to analyse self-determination among university students. © 2017 The British Psychological Society.

Red-shifted fluorescent proteins mPlum and mRaspberry and polynucleotides encoding the same

DOEpatents

Tsien, Roger Y [La Jolla, CA; Wang, Lei [San Diego, CA

2008-07-01

Methods using somatic hypermutation (SHM) for producing polypeptide and nucleic acid variants, and nucleic acids encoding such polypeptide variants are disclosed. Such variants may have desired properties. Also disclosed are novel polypeptides, such as improved fluorescent proteins, produced by the novel methods, and nucleic acids, vectors, and host cells comprising such vectors.

Does evaluative learning rely on the perception of contingency?: manipulating contingency and US density during evaluative conditioning.

PubMed

Kattner, Florian; Ellermeier, Wolfgang

2011-01-01

An experiment is reported studying the impact of objective contingency and contingency judgments on cross-modal evaluative conditioning (EC). Both contingency judgments and evaluative responses were measured after a contingency learning task in which previously neutral sounds served as either weak or strong predictors of affective pictures. Experimental manipulations of contingency and US density were shown to affect contingency judgments. Stronger contingencies were perceived with high contingency and with low US density. The contingency learning task also produced a reliable EC effect. The magnitude of this effect was influenced by an interaction of statistical contingency and US density. Furthermore, the magnitude of EC was correlated with the subjective contingency judgments. Taken together, the results imply that propositional knowledge about the CS-US relationship, as reflected in contingency judgments, moderates evaluative learning. The data are discussed with respect to different accounts of EC.

Contingency proportion systematically influences contingency learning.

PubMed

Forrin, Noah D; MacLeod, Colin M

2018-01-01

In the color-word contingency learning paradigm, each word appears more often in one color (high contingency) than in the other colors (low contingency). Shortly after beginning the task, color identification responses become faster on the high-contingency trials than on the low-contingency trials-the contingency learning effect. Across five groups, we varied the high-contingency proportion in 10% steps, from 80% to 40%. The size of the contingency learning effect was positively related to high-contingency proportion, with the effect disappearing when high contingency was reduced to 40%. At the two highest contingency proportions, the magnitude of the effect increased over trials, the pattern suggesting that there was an increasing cost for the low-contingency trials rather than an increasing benefit for the high-contingency trials. Overall, the results fit a modified version of Schmidt's (2013, Acta Psychologica, 142, 119-126) parallel episodic processing account in which prior trial instances are routinely retrieved from memory and influence current trial performance.

Stereotyped topography of different elevated contingent negative variation components in children with migraine without aura points towards a subcortical dysfunction.

PubMed

Bender, Stephan; Weisbrod, Matthias; Resch, Franz; Oelkers-Ax, Rieke

2007-02-01

Increased negativity during contingent negative variation (CNV) is thought to reflect abnormal neural activation in adult migraineurs' attention related processing. Findings in childhood and adolescence have yielded less clear results. This study characterizes the age-dependent development of CNV topography in migraine during childhood in order to elucidate the origin and cerebral generators of described CNV elevations. A large sample of children with primary headache (migraine with/without aura, tension type headache) and healthy controls aged 6-18 years was examined in a CNV paradigm using 64-channel high resolution DC-EEG. Patients were tested for diagnose-related topographic group differences of initial CNV (iCNV), late CNV (lCNV) and postimperative negative variation (PINV). All three CNV components of 6-11-year-old migraineurs without aura showed elevated negativity over the supplementary motor area (SMA) and around the vertex. Migraine children lacked age-dependent development of late CNV around Cz as previously reported. However, they showed a normal development of late CNV over pre-/primary motor cortex (MI). There was no marked elevation of iCNV amplitude over frontal areas (orienting reaction) nor specific amplitude elevations over "motor" or "sensory" areas during sustained attention (late CNV). Additional "pre-mature" activation e.g., in the locus coeruleus (leading to diffuse cortical activation summing up to a maximum over the vertex) or the basal ganglia (interacting with SMA) explained the rather stereotyped CNV elevation around the vertex better than a specific implication of the cortical systems responsible for orienting, motor preparation or sensory attention.

Rgs13 constrains early B cell responses and limits germinal center sizes.

PubMed

Hwang, Il-Young; Hwang, Kyung-Sun; Park, Chung; Harrison, Kathleen A; Kehrl, John H

2013-01-01

Germinal centers (GCs) are microanatomic structures that develop in secondary lymphoid organs in response to antigenic stimulation. Within GCs B cells clonally expand and their immunoglobulin genes undergo class switch recombination and somatic hypermutation. Transcriptional profiling has identified a number of genes that are prominently expressed in GC B cells. Among them is Rgs13, which encodes an RGS protein with a dual function. Its canonical function is to accelerate the intrinsic GTPase activity of heterotrimeric G-protein α subunits at the plasma membrane, thereby limiting heterotrimeric G-protein signaling. A unique, non-canonical function of RGS13 occurs following translocation to the nucleus, where it represses CREB transcriptional activity. The functional role of RGS13 in GC B cells is unknown. To create a surrogate marker for Rgs13 expression and a loss of function mutation, we inserted a GFP coding region into the Rgs13 genomic locus. Following immunization GFP expression rapidly increased in activated B cells, persisted in GC B cells, but declined in newly generated memory B and plasma cells. Intravital microscopy of the inguinal lymph node (LN) of immunized mice revealed the rapid appearance of GFP(+) cells at LN interfollicular regions and along the T/B cell borders, and eventually within GCs. Analysis of WT, knock-in, and mixed chimeric mice indicated that RGS13 constrains extra-follicular plasma cell generation, GC size, and GC B cell numbers. Analysis of select cell cycle and GC specific genes disclosed an aberrant gene expression profile in the Rgs13 deficient GC B cells. These results indicate that RGS13, likely acting at cell membranes and in nuclei, helps coordinate key decision points during the expansion and differentiation of naive B cells.

Understanding the Pathogenicity of Burkholderia contaminans, an Emerging Pathogen in Cystic Fibrosis.

PubMed

Nunvar, Jaroslav; Kalferstova, Lucie; Bloodworth, Ruhi A M; Kolar, Michal; Degrossi, Jose; Lubovich, Silvina; Cardona, Silvia T; Drevinek, Pavel

2016-01-01

Several bacterial species from the Burkholderia cepacia complex (Bcc) are feared opportunistic pathogens that lead to debilitating lung infections with a high risk of developing fatal septicemia in cystic fibrosis (CF) patients. However, the pathogenic potential of other Bcc species is yet unknown. To elucidate clinical relevance of Burkholderia contaminans, a species frequently isolated from CF respiratory samples in Ibero-American countries, we aimed to identify its key virulence factors possibly linked with an unfavorable clinical outcome. We performed a genome-wide comparative analysis of two isolates of B. contaminans ST872 from sputum and blood culture of a female CF patient in Argentina. RNA-seq data showed significant changes in expression for quorum sensing-regulated virulence factors and motility and chemotaxis. Furthermore, we detected expression changes in a recently described low-oxygen-activated (lxa) locus which encodes stress-related proteins, and for two clusters responsible for the biosynthesis of antifungal and hemolytic compounds pyrrolnitrin and occidiofungin. Based on phenotypic assays that confirmed changes in motility and in proteolytic, hemolytic and antifungal activities, we were able to distinguish two phenotypes of B. contaminans that coexisted in the host and entered her bloodstream. Whole genome sequencing revealed that the sputum and bloodstream isolates (each representing a distinct phenotype) differed by over 1,400 mutations as a result of a mismatch repair-deficient hypermutable state of the sputum isolate. The inferred lack of purifying selection against nonsynonymous mutations and the high rate of pseudogenization in the derived isolate indicated limited evolutionary pressure during evolution in the nutrient-rich, stable CF sputum environment. The present study is the first to examine the genomic and transcriptomic differences between longitudinal isolates of B. contaminans. Detected activity of a number of putative virulence factors implies a genuine pathogenic nature of this novel Bcc species.

Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies.

PubMed

Durandy, Anne; Taubenheim, Nadine; Peron, Sophie; Fischer, Alain

2007-01-01

B-cell intrinsic immunoglobulin class switch recombination (Ig-CSR) deficiencies, previously termed hyper-IgM syndromes, are genetically determined conditions characterized by normal or elevated serum IgM levels and an absence or very low levels of IgG, IgA, and IgE. As a function of the molecular mechanism, the defective CSR is variably associated to a defect in the generation of somatic hypermutations (SHMs) in the Ig variable region. The study of Ig-CSR deficiencies contributed to a better delineation of the mechanisms underlying CSR and SHM, the major events of antigen-triggered antibody maturation. Four Ig-CSR deficiency phenotypes have been so far reported: the description of the activation-induced cytidine deaminase (AID) deficiency (Ig-CSR deficiency 1), caused by recessive mutations of AICDA gene, characterized by a defect in CSR and SHM, clearly established the role of AID in the induction of the Ig gene rearrangements underlying CSR and SHM. A CSR-specific function of AID has, however, been detected by the observation of a selective CSR defect caused by mutations affecting the C-terminus of AID. Ig-CSR deficiency 2 is the consequence of uracil-N-glycosylase (UNG) deficiency. Because UNG, a molecule of the base excision repair machinery, removes uracils from DNA and AID deaminates cytosines into uracils, that observation indicates that the AID-UNG pathway directly targets DNA of switch regions from the Ig heavy-chain locus to induce the CSR process. Ig-CSR deficiencies 3 and 4 are characterized by a selective CSR defect resulting from blocks at distinct steps of CSR. A further understanding of the CSR machinery is expected from their molecular definition.

XRCC1 suppresses somatic hypermutation and promotes alternative nonhomologous end joining in Igh genes.

PubMed

Saribasak, Huseyin; Maul, Robert W; Cao, Zheng; McClure, Rhonda L; Yang, William; McNeill, Daniel R; Wilson, David M; Gearhart, Patricia J

2011-10-24

Activation-induced deaminase (AID) deaminates cytosine to uracil in immunoglobulin genes. Uracils in DNA can be recognized by uracil DNA glycosylase and abasic endonuclease to produce single-strand breaks. The breaks are repaired either faithfully by DNA base excision repair (BER) or mutagenically to produce somatic hypermutation (SHM) and class switch recombination (CSR). To unravel the interplay between repair and mutagenesis, we decreased the level of x-ray cross-complementing 1 (XRCC1), a scaffold protein involved in BER. Mice heterozygous for XRCC1 showed a significant increase in the frequencies of SHM in Igh variable regions in Peyer's patch cells, and of double-strand breaks in the switch regions during CSR. Although the frequency of CSR was normal in Xrcc1(+/-) splenic B cells, the length of microhomology at the switch junctions decreased, suggesting that XRCC1 also participates in alternative nonhomologous end joining. Furthermore, Xrcc1(+/-) B cells had reduced Igh/c-myc translocations during CSR, supporting a role for XRCC1 in microhomology-mediated joining. Our results imply that AID-induced single-strand breaks in Igh variable and switch regions become substrates simultaneously for BER and mutagenesis pathways.

Integrity of immunoglobulin variable regions is supported by GANP during AID-induced somatic hypermutation in germinal center B cells.

PubMed

Eid, Mohammed Mansour Abbas; Shimoda, Mayuko; Singh, Shailendra Kumar; Almofty, Sarah Ameen; Pham, Phuong; Goodman, Myron F; Maeda, Kazuhiko; Sakaguchi, Nobuo

2017-05-01

Immunoglobulin affinity maturation depends on somatic hypermutation (SHM) in immunoglobulin variable (IgV) regions initiated by activation-induced cytidine deaminase (AID). AID induces transition mutations by C→U deamination on both strands, causing C:G→T:A. Error-prone repairs of U by base excision and mismatch repairs (MMRs) create transversion mutations at C/G and mutations at A/T sites. In Neuberger's model, it remained to be clarified how transition/transversion repair is regulated. We investigate the role of AID-interacting GANP (germinal center-associated nuclear protein) in the IgV SHM profile. GANP enhances transition mutation of the non-transcribed strand G and reduces mutation at A, restricted to GYW of the AID hotspot motif. It reduces DNA polymerase η hotspot mutations associated with MMRs followed by uracil-DNA glycosylase. Mutation comparison between IgV complementary and framework regions (FWRs) by Bayesian statistical estimation demonstrates that GANP supports the preservation of IgV FWR genomic sequences. GANP works to maintain antibody structure by reducing drastic changes in the IgV FWR in affinity maturation. © The Author 2017. Published by Oxford University Press on behalf of The Japanese Society for Immunology.

DNA polymerase ι functions in the generation of tandem mutations during somatic hypermutation of antibody genes.

PubMed

Maul, Robert W; MacCarthy, Thomas; Frank, Ekaterina G; Donigan, Katherine A; McLenigan, Mary P; Yang, William; Saribasak, Huseyin; Huston, Donald E; Lange, Sabine S; Woodgate, Roger; Gearhart, Patricia J

2016-08-22

DNA polymerase ι (Pol ι) is an attractive candidate for somatic hypermutation in antibody genes because of its low fidelity. To identify a role for Pol ι, we analyzed mutations in two strains of mice with deficiencies in the enzyme: 129 mice with negligible expression of truncated Pol ι, and knock-in mice that express full-length Pol ι that is catalytically inactive. Both strains had normal frequencies and spectra of mutations in the variable region, indicating that loss of Pol ι did not change overall mutagenesis. We next examined if Pol ι affected tandem mutations generated by another error-prone polymerase, Pol ζ. The frequency of contiguous mutations was analyzed using a novel computational model to determine if they occur during a single DNA transaction or during two independent events. Analyses of 2,000 mutations from both strains indicated that Pol ι-compromised mice lost the tandem signature, whereas C57BL/6 mice accumulated significant amounts of double mutations. The results support a model where Pol ι occasionally accesses the replication fork to generate a first mutation, and Pol ζ extends the mismatch with a second mutation. @2016.

DNA polymerase ι functions in the generation of tandem mutations during somatic hypermutation of antibody genes

PubMed Central

Donigan, Katherine A.; Huston, Donald E.; Lange, Sabine S.

2016-01-01

DNA polymerase ι (Pol ι) is an attractive candidate for somatic hypermutation in antibody genes because of its low fidelity. To identify a role for Pol ι, we analyzed mutations in two strains of mice with deficiencies in the enzyme: 129 mice with negligible expression of truncated Pol ι, and knock-in mice that express full-length Pol ι that is catalytically inactive. Both strains had normal frequencies and spectra of mutations in the variable region, indicating that loss of Pol ι did not change overall mutagenesis. We next examined if Pol ι affected tandem mutations generated by another error-prone polymerase, Pol ζ. The frequency of contiguous mutations was analyzed using a novel computational model to determine if they occur during a single DNA transaction or during two independent events. Analyses of 2,000 mutations from both strains indicated that Pol ι–compromised mice lost the tandem signature, whereas C57BL/6 mice accumulated significant amounts of double mutations. The results support a model where Pol ι occasionally accesses the replication fork to generate a first mutation, and Pol ζ extends the mismatch with a second mutation. PMID:27455952

Comprehensive molecular characterization of human colon and rectal cancer.

PubMed

2012-07-18

To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.

40 CFR 264.53 - Copies of contingency plan.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 25 2010-07-01 2010-07-01 false Copies of contingency plan. 264.53... Contingency Plan and Emergency Procedures § 264.53 Copies of contingency plan. A copy of the contingency plan... called upon to provide emergency services. [Comment: The contingency plan must be submitted to the...

Learning, awareness, and instruction: subjective contingency awareness does matter in the colour-word contingency learning paradigm.

PubMed

Schmidt, James R; De Houwer, Jan

2012-12-01

In three experiments, each of a set colour-unrelated distracting words was presented most often in a particular target print colour (e.g., "month" most often in red). In Experiment 1, half of the participants were told the word-colour contingencies in advance (instructed) and half were not (control). The instructed group showed a larger learning effect. This instruction effect was fully explained by increases in subjective awareness with instruction. In Experiment 2, contingency instructions were again given, but no contingencies were actually present. Although many participants claimed to be aware of these (non-existent) contingencies, they did not produce an instructed contingency effect. In Experiment 3, half of the participants were given contingency instructions that did not correspond to the correct contingencies. Participants with these false instructions learned the actual contingencies worse than controls. Collectively, our results suggest that conscious contingency knowledge might play a moderating role in the strength of implicit learning. Copyright © 2012 Elsevier Inc. All rights reserved.

The acquisition of simple associations as observed in color-word contingency learning.

PubMed

Lin, Olivia Y-H; MacLeod, Colin M

2018-01-01

Three experiments investigated the learning of simple associations in a color-word contingency task. Participants responded manually to the print colors of 3 words, with each word associated strongly to 1 of the 3 colors and weakly to the other 2 colors. Despite the words being irrelevant, response times to high-contingency stimuli and to low-contingency stimuli quickly diverged. This high-low difference remained quite constant over successive blocks of trials, evidence of stable contingency learning. Inclusion of a baseline condition-an item having no color-word contingency-permitted separation of the contingency learning effect into 2 components: a cost due to low contingency and a benefit due to high contingency. Both cost and benefit were quick to acquire, quick to extinguish, and quick to reacquire. The color-word contingency task provides a simple way to directly study the learning of associations. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Step 1: Human System Integration (HSI) FY05 Pilot-Technology Interface Requirements for Contingency Management

NASA Technical Reports Server (NTRS)

2005-01-01

This document involves definition of technology interface requirements for Contingency Management. This was performed through a review of Contingency Management-related, HSI requirements documents, standards, and recommended practices. Technology concepts in use by the Contingency Management Work Package were considered. Beginning with HSI high-level functional requirements for Contingency Management, and Contingency Management technology elements, HSI requirements for the interface to the pilot were identified. Results of the analysis describe (1) the information required by the pilot to have knowledge of system failures and associated contingency procedures, and (2) the control capability needed by the pilot to obtain system status and procedure information. Fundamentally, these requirements provide the candidate Contingency Management technology concepts with the necessary human-related elements to make them compatible with human capabilities and limitations. The results of the analysis describe how Contingency Management operations and functions should interface with the pilot to provide the necessary Contingency Management functionality to the UA-pilot system. Requirements and guidelines for Contingency Management are partitioned into four categories: (1) Health and Status and (2) Contingency Management. Each requirement is stated and is supported with a rationale and associated reference(s).

Contingency learning in human fear conditioning involves the ventral striatum.

PubMed

Klucken, Tim; Tabbert, Katharina; Schweckendiek, Jan; Merz, Christian Josef; Kagerer, Sabine; Vaitl, Dieter; Stark, Rudolf

2009-11-01

The ability to detect and learn contingencies between fearful stimuli and their predictive cues is an important capacity to cope with the environment. Contingency awareness refers to the ability to verbalize the relationships between conditioned and unconditioned stimuli. Although there is a heated debate about the influence of contingency awareness on conditioned fear responses, neural correlates behind the formation process of contingency awareness have gained only little attention in human fear conditioning. Recent animal studies indicate that the ventral striatum (VS) could be involved in this process, but in human studies the VS is mostly associated with positive emotions. To examine this question, we reanalyzed four recently published classical fear conditioning studies (n = 117) with respect to the VS at three distinct levels of contingency awareness: subjects, who did not learn the contingencies (unaware), subjects, who learned the contingencies during the experiment (learned aware) and subjects, who were informed about the contingencies in advance (instructed aware). The results showed significantly increased activations in the left and right VS in learned aware compared to unaware subjects. Interestingly, this activation pattern was only found in learned but not in instructed aware subjects. We assume that the VS is not involved when contingency awareness does not develop during conditioning or when contingency awareness is unambiguously induced already prior to conditioning. VS involvement seems to be important for the transition from a contingency unaware to a contingency aware state. Implications for fear conditioning models as well as for the contingency awareness debate are discussed.

The expanding polymerase universe.

PubMed

Goodman, M F; Tippin, B

2000-11-01

Over the past year, the number of known prokaryotic and eukaryotic DNA polymerases has exploded. Many of these newly discovered enzymes copy aberrant bases in the DNA template over which 'respectable' polymerases fear to tread. The next step is to unravel their functions, which are thought to range from error-prone copying of DNA lesions, somatic hypermutation and avoidance of skin cancer, to restarting stalled replication forks and repairing double-stranded DNA breaks.

Directed evolution of an angiopoietin-2 ligand trap by somatic hypermutation and cell surface display.

PubMed

Brindle, Nicholas P J; Sale, Julian E; Arakawa, Hiroshi; Buerstedde, Jean-Marie; Nuamchit, Teonchit; Sharma, Shikha; Steele, Kathryn H

2013-11-15

Tie2 is a receptor tyrosine kinase that is essential for the development and maintenance of blood vessels through binding the soluble ligands angiopoietin 1 (Ang1) and 2 (Ang2). Ang1 is constitutively produced by perivascular cells and is protective of the adult vasculature. Ang2 plays an important role in blood vessel formation and is normally expressed during development. However, its re-expression in disease states, including cancer and sepsis, results in destabilization of blood vessels contributing to the pathology of these conditions. Ang2 is thus an attractive therapeutic target. Here we report the directed evolution of a ligand trap for Ang2 by harnessing the B cell somatic hypermutation machinery and coupling this to selectable cell surface display of a Tie2 ectodomain. Directed evolution produced an unexpected combination of mutations resulting in loss of Ang1 binding but maintenance of Ang2 binding. A soluble form of the evolved ectodomain binds Ang2 but not Ang1. Furthermore, the soluble evolved ectodomain blocks Ang2 effects on endothelial cells without interfering with Ang1 activity. Our study has created a novel Ang2 ligand trap and provided proof of concept for combining surface display and exogenous gene diversification in B cells for evolution of a non-immunoglobulin target.

Changes in RNA polymerase II progression influence somatic hypermutation of Ig-related genes by AID

PubMed Central

Kodgire, Prashant; Mukkawar, Priyanka; Ratnam, Sarayu; Martin, Terence E.

2013-01-01

Somatic hypermutation (SHM) of Ig genes is initiated by the activation-induced cytidine deaminase (AID), and requires target gene transcription. We previously proposed that AID may associate with the RNA polymerase II (Pol). Here, to determine aspects of the transcription process required for SHM, we knocked-in a transcription terminator into an Ig gene variable region in DT40 chicken B cell line. We found that the human β-globin terminator was an efficient inhibitor of downstream transcription in these cells. The terminator reduced mutations downstream of the poly(A) signal, suggesting that the process of transcription is essential for efficient SHM and that AID has better access to its target when Pol is in the elongating rather than terminating mode. Mutations upstream of the poly(A) site were almost doubled in the active terminator clones compared with an inactivated terminator, and this region showed more single-stranded DNA, indicating that Pol pausing assists SHM. Moreover, the nontranscribed DNA strand was the preferred SHM target upstream of the active terminator. Pol pausing during poly(A) site recognition may facilitate persistence of negative supercoils, exposing the coding single strand and possibly allowing the nascent RNA intermittent reannealing with the template strand, for prolonged access of AID. PMID:23752228

Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination

PubMed Central

HWANG, JOYCE K.; ALT, FREDERICK W.; YEAP, LENG-SIEW

2015-01-01

The primary antibody repertoire is generated by mechanisms involving the assembly of the exons that encode the antigen-binding variable regions of immunoglobulin heavy (IgH) and light (IgL) chains during the early development of B lymphocytes. After antigen-dependent activation, mature B lymphocytes can further alter their IgH and IgL variable region exons by the process of somatic hypermutation (SHM), which allows the selection of B cells in which SHMs resulted in the production of antibodies with increased antigen affinity. In addition, during antigen-dependent activation, B cells can also change the constant region of their IgH chain through a DNA double-strand-break (DSB) dependent process referred to as IgH class switch recombination (CSR), which generates B cell progeny that produce antibodies with different IgH constant region effector functions that are best suited for a elimination of a particular pathogen or in a particular setting. Both the mutations that underlie SHM and the DSBs that underlie CSR are initiated in target genes by activation-induced cytidine deaminase (AID). This review describes in depth the processes of SHM and CSR with a focus on mechanisms that direct AID cytidine deamination in activated B cells and mechanisms that promote the differential outcomes of such cytidine deamination. PMID:26104555

Hypermutable DNA chronicles the evolution of human colon cancer

PubMed Central

Naxerova, Kamila; Brachtel, Elena; Salk, Jesse J.; Seese, Aaron M.; Power, Karen; Abbasi, Bardia; Snuderl, Matija; Chiang, Sarah; Kasif, Simon; Jain, Rakesh K.

2014-01-01

Intratumor genetic heterogeneity reflects the evolutionary history of a cancer and is thought to influence treatment outcomes. Here we report that a simple PCR-based assay interrogating somatic variation in hypermutable polyguanine (poly-G) repeats can provide a rapid and reliable assessment of mitotic history and clonal architecture in human cancer. We use poly-G repeat genotyping to study the evolution of colon carcinoma. In a cohort of 22 patients, we detect poly-G variants in 91% of tumors. Patient age is positively correlated with somatic mutation frequency, suggesting that some poly-G variants accumulate before the onset of carcinogenesis during normal division in colonic stem cells. Poorly differentiated tumors have fewer mutations than well-differentiated tumors, possibly indicating a shorter mitotic history of the founder cell in these cancers. We generate poly-G mutation profiles of spatially separated samples from primary carcinomas and matched metastases to build well-supported phylogenetic trees that illuminate individual patients’ path of metastatic progression. Our results show varying degrees of intratumor heterogeneity among patients. Finally, we show that poly-G mutations can be found in other cancers than colon carcinoma. Our approach can generate reliable maps of intratumor heterogeneity in large numbers of patients with minimal time and cost expenditure. PMID:24753616

Altering the spectrum of immunoglobulin V gene somatic hypermutation by modifying the active site of AID.

PubMed

Wang, Meng; Rada, Cristina; Neuberger, Michael S

2010-01-18

High-affinity antibodies are generated by somatic hypermutation with nucleotide substitutions introduced into the IgV in a semirandom fashion, but with intrinsic mutational hotspots strategically located to optimize antibody affinity maturation. The process is dependent on activation-induced deaminase (AID), an enzyme that can deaminate deoxycytidine in DNA in vitro, where its activity is sensitive to the identity of the 5'-flanking nucleotide. As a critical test of whether such DNA deamination activity underpins antibody diversification and to gain insight into the extent to which the antibody mutation spectrum is dependent on the intrinsic substrate specificity of AID, we investigated whether it is possible to change the IgV mutation spectrum by altering AID's active site such that it prefers a pyrimidine (rather than a purine) flanking the targeted deoxycytidine. Consistent with the DNA deamination mechanism, B cells expressing the modified AID proteins yield altered IgV mutation spectra (exhibiting a purine-->pyrimidine shift in flanking nucleotide preference) and altered hotspots. However, AID-catalyzed deamination of IgV targets in vitro does not yield the same degree of hotspot dominance to that observed in vivo, indicating the importance of features beyond AID's active site and DNA local sequence environment in determining in vivo hotspot dominance.

Intraspecific and heteroplasmic variations, gene losses and inversions in the chloroplast genome of Astragalus membranaceus.

PubMed

Lei, Wanjun; Ni, Dapeng; Wang, Yujun; Shao, Junjie; Wang, Xincun; Yang, Dan; Wang, Jinsheng; Chen, Haimei; Liu, Chang

2016-02-22

Astragalus membranaceus is an important medicinal plant in Asia. Several of its varieties have been used interchangeably as raw materials for commercial production. High resolution genetic markers are in urgent need to distinguish these varieties. Here, we sequenced and analyzed the chloroplast genome of A. membranaceus (Fisch.) Bunge var. mongholicus (Bunge) P.K. Hsiao using the next generation DNA sequencing technology. The genome was assembled using Abyss and then subjected to gene prediction using CPGAVAS and repeat analysis using MISA, Tandem Repeats Finder, and REPuter. Finally, the genome was subjected phylogenetic and comparative genomic analyses. The complete genome is 123,582 bp long, containing only one copy of the inverted repeat. Gene prediction revealed 110 genes encoding 76 proteins, 30 tRNAs, and four rRNAs. Five intra-specific hypermutation loci were identified, three of which are heteroplasmic. Furthermore, three gene losses and two large inversions were identified. Comparative genomic analyses demonstrated the dynamic nature of the Papilionoideae chloroplast genomes, which showed occurrence of numerous hypermutation loci, frequent gene losses, and fragment inversions. Results obtained herein elucidate the complex evolutionary history of chloroplast genomes and have laid the foundation for the identification of genetic markers to distinguish A. membranaceus varieties.

HIV-1 adaptation studies reveal a novel Env-mediated homeostasis mechanism for evading lethal hypermutation by APOBEC3G

PubMed Central

Ikeda, Terumasa; Albin, John S.; Li, Ming; Thali, Markus

2018-01-01

HIV-1 replication normally requires Vif-mediated neutralization of APOBEC3 antiviral enzymes. Viruses lacking Vif succumb to deamination-dependent and -independent restriction processes. Here, HIV-1 adaptation studies were leveraged to ask whether viruses with an irreparable vif deletion could develop resistance to restrictive levels of APOBEC3G. Several resistant viruses were recovered with multiple amino acid substitutions in Env, and these changes alone are sufficient to protect Vif-null viruses from APOBEC3G-dependent restriction in T cell lines. Env adaptations cause decreased fusogenicity, which results in higher levels of Gag-Pol packaging. Increased concentrations of packaged Pol in turn enable faster virus DNA replication and protection from APOBEC3G-mediated hypermutation of viral replication intermediates. Taken together, these studies reveal that a moderate decrease in one essential viral activity, namely Env-mediated fusogenicity, enables the virus to change other activities, here, Gag-Pol packaging during particle production, and thereby escape restriction by the antiviral factor APOBEC3G. We propose a new paradigm in which alterations in viral homeostasis, through compensatory small changes, constitute a general mechanism used by HIV-1 and other viral pathogens to escape innate antiviral responses and other inhibitions including antiviral drugs. PMID:29677220

Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bonsignori, Mattia; Zhou, Tongqing; Sheng, Zizhang

Here, we report that antibodies with ontogenies from V H1-2 or V H1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. We define with longitudinal sampling from time-of-infection the development of a V H1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%), and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, andmore » extraordinary level of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled V H1-2. Lastly, we integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.« less

Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody

DOE PAGES

Bonsignori, Mattia; Zhou, Tongqing; Sheng, Zizhang; ...

2016-04-01

Here, we report that antibodies with ontogenies from V H1-2 or V H1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. We define with longitudinal sampling from time-of-infection the development of a V H1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%), and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, andmore » extraordinary level of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled V H1-2. Lastly, we integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.« less

Cell Cycle Regulates Nuclear Stability of AID and Determines the Cellular Response to AID

PubMed Central

Le, Quy; Maizels, Nancy

2015-01-01

AID (Activation Induced Deaminase) deaminates cytosines in DNA to initiate immunoglobulin gene diversification and to reprogram CpG methylation in early development. AID is potentially highly mutagenic, and it causes genomic instability evident as translocations in B cell malignancies. Here we show that AID is cell cycle regulated. By high content screening microscopy, we demonstrate that AID undergoes nuclear degradation more slowly in G1 phase than in S or G2-M phase, and that mutations that affect regulatory phosphorylation or catalytic activity can alter AID stability and abundance. We directly test the role of cell cycle regulation by fusing AID to tags that destabilize nuclear protein outside of G1 or S-G2/M phases. We show that enforced nuclear localization of AID in G1 phase accelerates somatic hypermutation and class switch recombination, and is well-tolerated; while nuclear AID compromises viability in S-G2/M phase cells. We identify AID derivatives that accelerate somatic hypermutation with minimal impact on viability, which will be useful tools for engineering genes and proteins by iterative mutagenesis and selection. Our results further suggest that use of cell cycle tags to regulate nuclear stability may be generally applicable to studying DNA repair and to engineering the genome. PMID:26355458

Striatal dopamine depletion in rats produces variable effects on contingency detection: task-related influences.

PubMed

Braun, Stephanie; Hauber, Wolfgang

2012-02-01

Dopamine (DA) depletion of the posterior dorsomedial striatum (pDMS) can impair the capability of rats to detect changes in the causal efficacy of actions. Here we sought to characterize in more detail the effects of pDMS DA depletions on contingency detection as a function of different contingency degradation training protocols. In experiment 1, sham controls and rats with pDMS DA depletions received limited contingency degradation training (4 days) that involved an invariable and high degree of degradation to one of two contingencies controlling instrumental choice behaviour. The results demonstrated that lesioned rats were insensitive to contingency manipulations both during contingency degradation training and in the subsequent extinction test. Experiment 2 further indicated that rats with pDMS DA depletion subjected to extended contingency degradation training (12 days) became sensitive to contingency manipulations during the training phase but not in the subsequent extinction test. In experiment 3, an extended but more complex contingency degradation training protocol (12 days) was used that involved a gradual shift from a low to an intermediate and a high degree of contingency degradation rather than a high and invariable degree of contingency degradation as in experiments 1 and 2. Notably, lesioned rats were sensitive to contingency manipulations both during the contingency degradation training phase and in the subsequent extinction test. Thus, pDMS DA depletions can impair the capability to detect changes in the causal efficacy of actions; however, the occurrence and pattern of impairments depend on the contingency degradation training protocol being used. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

40 CFR 265.54 - Amendment of contingency plan.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 27 2012-07-01 2012-07-01 false Amendment of contingency plan. 265.54... DISPOSAL FACILITIES Contingency Plan and Emergency Procedures § 265.54 Amendment of contingency plan. The contingency plan must be reviewed, and immediately amended, if necessary, whenever: (a) Applicable regulations...

40 CFR 265.54 - Amendment of contingency plan.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 26 2014-07-01 2014-07-01 false Amendment of contingency plan. 265.54... DISPOSAL FACILITIES Contingency Plan and Emergency Procedures § 265.54 Amendment of contingency plan. The contingency plan must be reviewed, and immediately amended, if necessary, whenever: (a) Applicable regulations...

48 CFR 31.205-7 - Contingencies.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Contingencies. 31.205-7... Contingencies. (a) Contingency, as used in this subpart, means a possible future event or condition arising from... contingencies are generally unallowable for historical costing purposes because such costing deals with costs...

40 CFR 264.54 - Amendment of contingency plan.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 25 2010-07-01 2010-07-01 false Amendment of contingency plan. 264.54 Section 264.54 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES... Contingency Plan and Emergency Procedures § 264.54 Amendment of contingency plan. The contingency plan must be...

40 CFR 265.54 - Amendment of contingency plan.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 25 2010-07-01 2010-07-01 false Amendment of contingency plan. 265.54... DISPOSAL FACILITIES Contingency Plan and Emergency Procedures § 265.54 Amendment of contingency plan. The contingency plan must be reviewed, and immediately amended, if necessary, whenever: (a) Applicable regulations...

40 CFR 264.54 - Amendment of contingency plan.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 26 2014-07-01 2014-07-01 false Amendment of contingency plan. 264.54... Contingency Plan and Emergency Procedures § 264.54 Amendment of contingency plan. The contingency plan must be reviewed, and immediately amended, if necessary, whenever: (a) The facility permit is revised; (b) The plan...

40 CFR 264.54 - Amendment of contingency plan.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 27 2012-07-01 2012-07-01 false Amendment of contingency plan. 264.54... Contingency Plan and Emergency Procedures § 264.54 Amendment of contingency plan. The contingency plan must be reviewed, and immediately amended, if necessary, whenever: (a) The facility permit is revised; (b) The plan...

48 CFR 403.405 - Misrepresentations or violations of the Covenant Against Contingent Fees.

Code of Federal Regulations, 2010 CFR

2010-10-01

... violations of the Covenant Against Contingent Fees. 403.405 Section 403.405 Federal Acquisition Regulations... Contingent Fees 403.405 Misrepresentations or violations of the Covenant Against Contingent Fees. (a) A suspected misrepresentation or violation of the Covenant Against Contingent Fees shall be documented in...

Psychophysics of associative learning: Quantitative properties of subjective contingency.

PubMed

Maia, Susana; Lefèvre, Françoise; Jozefowiez, Jérémie

2018-01-01

Allan and collaborators (Allan, Hannah, Crump, & Siegel, 2008; Allan, Siegel, & Tangen, 2005; Siegel, Allan, Hannah, & Crump, 2009) recently proposed to apply signal detection theory to the analysis of contingency judgment tasks. When exposed to a flow of stimuli, participants are asked to judge whether there is a contingent relation between a cue and an outcome, that is, whether the subjective cue-outcome contingency exceeds a decision threshold. In this context, we tested the following hypotheses regarding the relation between objective and subjective cue-outcome contingency: (a) The underlying distributions of subjective cue-outcome contingency are Gaussian; (b) The mean distribution of subjective contingency is a linear function of objective cue-outcome contingency; and (c) The variance in the distribution of subjective contingency is constant. The hypotheses were tested by combining a streamed-trial contingency assessment task with a confidence rating procedure. Participants were exposed to rapid flows of stimuli at the end of which they had to judge whether an outcome was more (Experiment 1) or less (Experiment 2) likely to appear following a cue and how sure they were of their judgment. We found that although Hypothesis A seems reasonable, Hypotheses B and C were not. Regarding Hypothesis B, participants were more sensitive to positive than to negative contingencies. Regarding Hypothesis C, the perceived cue-outcome contingency became more variable when the contingency became more positive or negative, but only to a slight extent. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Use of continuous transdermal alcohol monitoring during a contingency management procedure to reduce excessive alcohol use.

PubMed

Dougherty, Donald M; Hill-Kapturczak, Nathalie; Liang, Yuanyuan; Karns, Tara E; Cates, Sharon E; Lake, Sarah L; Mullen, Jillian; Roache, John D

2014-09-01

Research on contingency management to treat excessive alcohol use is limited due to feasibility issues with monitoring adherence. This study examined the effectiveness of using transdermal alcohol monitoring as a continuous measure of alcohol use to implement financial contingencies to reduce heavy drinking. Twenty-six male and female drinkers (from 21 to 39 years old) were recruited from the community. Participants were randomly assigned to one of the two treatment sequences. Sequence 1 received 4 weeks of no financial contingency (i.e., $0) drinking followed by 4 weeks each of $25 and then $50 contingency management; Sequence 2 received 4 weeks of $25 contingency management followed by 4 weeks each of no contingency (i.e., $0) and then $50 contingency management. During the $25 and $50 contingency management conditions, participants were paid each week when the Secure Continuous Remote Alcohol Monitor (SCRAM-II™) identified no heavy drinking days. Participants in both contingency management conditions had fewer drinking episodes and reduced frequencies of heavy drinking compared to the $0 condition. Participants randomized to Sequence 2 (receiving $25 contingency before the $0 condition) exhibited less frequent drinking and less heavy drinking in the $0 condition compared to participants from Sequence 1. Transdermal alcohol monitoring can be used to implement contingency management programs to reduce excessive alcohol consumption. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Use of Continuous Transdermal Alcohol Monitoring during a Contingency Management Procedure to Reduce Excessive Alcohol Use

PubMed Central

Dougherty, Donald M.; Hill-Kapturczak, Nathalie; Liang, Yuanyuan; Karns, Tara E.; Cates, Sharon E.; Lake, Sarah L.; Mullen, Jillian; Roache, John D.

2014-01-01

Background Research on contingency management to treat excessive alcohol use is limited due to feasibility issues with monitoring adherence. This study examined the effectiveness of using transdermal alcohol monitoring as a continuous measure of alcohol use to implement financial contingencies to reduce heavy drinking. Methods Twenty-six male and female drinkers (from 21–39 years old) were recruited from the community. Participants were randomly assigned to one of two treatment sequences. Sequence 1 received 4 weeks of no financial contingency (i.e., $0) drinking followed by 4 weeks each of $25 and then $50 contingency management; Sequence 2 received 4 weeks of $25 contingency management followed by 4 weeks each of no contingency (i.e., $0) and then $50 contingency management. During the $25 and $50 contingency management conditions, participants were paid each week when the Secure Continuous Remote Alcohol Monitor (SCRAM-II™) identified no heavy drinking days. Results Participants in both contingency management conditions had fewer drinking episodes and reduced frequencies of heavy drinking compared to the $0 condition. Participants randomized to Sequence 2 (receiving $25 contingency before the $0 condition) exhibited less frequent drinking and less heavy drinking in the $0 condition compared to participants from Sequence 1. Conclusions Transdermal alcohol monitoring can be used to implement contingency management programs to reduce excessive alcohol consumption. PMID:25064019

30 CFR 282.26 - Contingency Plan.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 2 2010-07-01 2010-07-01 false Contingency Plan. 282.26 Section 282.26 Mineral... § 282.26 Contingency Plan. (a) When required by the Director, a lessee shall include a Contingency Plan as part of its request for approval of a Delineation, Testing, or Mining Plan. The Contingency Plan...

40 CFR 264.53 - Copies of contingency plan.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 26 2014-07-01 2014-07-01 false Copies of contingency plan. 264.53... Contingency Plan and Emergency Procedures § 264.53 Copies of contingency plan. A copy of the contingency plan and all revisions to the plan must be: (a) Maintained at the facility; and (b) Submitted to all local...

40 CFR 265.52 - Content of contingency plan.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 26 2011-07-01 2011-07-01 false Content of contingency plan. 265.52... DISPOSAL FACILITIES Contingency Plan and Emergency Procedures § 265.52 Content of contingency plan. (a) The contingency plan must describe the actions facility personnel must take to comply with §§ 265.51 and 265.56 in...

40 CFR 265.52 - Content of contingency plan.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 27 2012-07-01 2012-07-01 false Content of contingency plan. 265.52... DISPOSAL FACILITIES Contingency Plan and Emergency Procedures § 265.52 Content of contingency plan. (a) The contingency plan must describe the actions facility personnel must take to comply with §§ 265.51 and 265.56 in...

40 CFR 267.54 - When must I amend the contingency plan?

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 28 2013-07-01 2013-07-01 false When must I amend the contingency plan... STANDARDIZED PERMIT Contingency Plan and Emergency Procedures § 267.54 When must I amend the contingency plan? You must review, and immediately amend the contingency plan, if necessary, whenever: (a) The facility...

40 CFR 265.53 - Copies of contingency plan.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 26 2011-07-01 2011-07-01 false Copies of contingency plan. 265.53... DISPOSAL FACILITIES Contingency Plan and Emergency Procedures § 265.53 Copies of contingency plan. A copy of the contingency plan and all revisions to the plan must be: (a) Maintained at the facility; and (b...

40 CFR 264.53 - Copies of contingency plan.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 27 2013-07-01 2013-07-01 false Copies of contingency plan. 264.53... Contingency Plan and Emergency Procedures § 264.53 Copies of contingency plan. A copy of the contingency plan and all revisions to the plan must be: (a) Maintained at the facility; and (b) Submitted to all local...

40 CFR 265.52 - Content of contingency plan.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 26 2014-07-01 2014-07-01 false Content of contingency plan. 265.52... DISPOSAL FACILITIES Contingency Plan and Emergency Procedures § 265.52 Content of contingency plan. (a) The contingency plan must describe the actions facility personnel must take to comply with §§ 265.51 and 265.56 in...

40 CFR 267.54 - When must I amend the contingency plan?

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 28 2012-07-01 2012-07-01 false When must I amend the contingency plan... STANDARDIZED PERMIT Contingency Plan and Emergency Procedures § 267.54 When must I amend the contingency plan? You must review, and immediately amend the contingency plan, if necessary, whenever: (a) The facility...

40 CFR 267.54 - When must I amend the contingency plan?

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 27 2014-07-01 2014-07-01 false When must I amend the contingency plan... STANDARDIZED PERMIT Contingency Plan and Emergency Procedures § 267.54 When must I amend the contingency plan? You must review, and immediately amend the contingency plan, if necessary, whenever: (a) The facility...

40 CFR 264.53 - Copies of contingency plan.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 27 2012-07-01 2012-07-01 false Copies of contingency plan. 264.53... Contingency Plan and Emergency Procedures § 264.53 Copies of contingency plan. A copy of the contingency plan and all revisions to the plan must be: (a) Maintained at the facility; and (b) Submitted to all local...

40 CFR 264.53 - Copies of contingency plan.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 26 2011-07-01 2011-07-01 false Copies of contingency plan. 264.53... Contingency Plan and Emergency Procedures § 264.53 Copies of contingency plan. A copy of the contingency plan and all revisions to the plan must be: (a) Maintained at the facility; and (b) Submitted to all local...

40 CFR 265.52 - Content of contingency plan.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 27 2013-07-01 2013-07-01 false Content of contingency plan. 265.52... DISPOSAL FACILITIES Contingency Plan and Emergency Procedures § 265.52 Content of contingency plan. (a) The contingency plan must describe the actions facility personnel must take to comply with §§ 265.51 and 265.56 in...

40 CFR 265.53 - Copies of contingency plan.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 27 2012-07-01 2012-07-01 false Copies of contingency plan. 265.53... DISPOSAL FACILITIES Contingency Plan and Emergency Procedures § 265.53 Copies of contingency plan. A copy of the contingency plan and all revisions to the plan must be: (a) Maintained at the facility; and (b...

40 CFR 265.53 - Copies of contingency plan.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 26 2014-07-01 2014-07-01 false Copies of contingency plan. 265.53... DISPOSAL FACILITIES Contingency Plan and Emergency Procedures § 265.53 Copies of contingency plan. A copy of the contingency plan and all revisions to the plan must be: (a) Maintained at the facility; and (b...

40 CFR 265.53 - Copies of contingency plan.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 27 2013-07-01 2013-07-01 false Copies of contingency plan. 265.53... DISPOSAL FACILITIES Contingency Plan and Emergency Procedures § 265.53 Copies of contingency plan. A copy of the contingency plan and all revisions to the plan must be: (a) Maintained at the facility; and (b...

48 CFR 303.405 - Misrepresentations or violations of the Covenant Against Contingent Fees clause.

Code of Federal Regulations, 2010 CFR

2010-10-01

... violations of the Covenant Against Contingent Fees clause. 303.405 Section 303.405 Federal Acquisition... INTEREST Contingent Fees 303.405 Misrepresentations or violations of the Covenant Against Contingent Fees... Covenant Against Contingent Fees clause to the Contracting Officer. (b)(4) The HCA shall provide a copy of...

40 CFR 265.53 - Copies of contingency plan.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 25 2010-07-01 2010-07-01 false Copies of contingency plan. 265.53... DISPOSAL FACILITIES Contingency Plan and Emergency Procedures § 265.53 Copies of contingency plan. A copy of the contingency plan and all revisions to the plan must be: (a) Maintained at the facility; and (b...

25 CFR 39.500 - What emergency and contingency funds are available?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false What emergency and contingency funds are available? 39... SCHOOL EQUALIZATION PROGRAM Contingency Fund § 39.500 What emergency and contingency funds are available... unforeseen contingencies affecting educational programs; (b) Can carry over to the next fiscal year a maximum...

40 CFR 264.52 - Content of contingency plan.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 26 2014-07-01 2014-07-01 false Content of contingency plan. 264.52... Contingency Plan and Emergency Procedures § 264.52 Content of contingency plan. (a) The contingency plan must describe the actions facility personnel must take to comply with §§ 264.51 and 264.56 in response to fires...

40 CFR 267.52 - What must be in the contingency plan?

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 27 2011-07-01 2011-07-01 false What must be in the contingency plan... STANDARDIZED PERMIT Contingency Plan and Emergency Procedures § 267.52 What must be in the contingency plan? (a) Your contingency plan must: (1) Describe the actions facility personnel will take to comply with §§ 267...

40 CFR 267.52 - What must be in the contingency plan?

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 27 2014-07-01 2014-07-01 false What must be in the contingency plan... STANDARDIZED PERMIT Contingency Plan and Emergency Procedures § 267.52 What must be in the contingency plan? (a) Your contingency plan must: (1) Describe the actions facility personnel will take to comply with §§ 267...

40 CFR 264.52 - Content of contingency plan.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 27 2013-07-01 2013-07-01 false Content of contingency plan. 264.52... Contingency Plan and Emergency Procedures § 264.52 Content of contingency plan. (a) The contingency plan must describe the actions facility personnel must take to comply with §§ 264.51 and 264.56 in response to fires...

40 CFR 264.52 - Content of contingency plan.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 26 2011-07-01 2011-07-01 false Content of contingency plan. 264.52... Contingency Plan and Emergency Procedures § 264.52 Content of contingency plan. (a) The contingency plan must describe the actions facility personnel must take to comply with §§ 264.51 and 264.56 in response to fires...

40 CFR 267.52 - What must be in the contingency plan?

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 28 2013-07-01 2013-07-01 false What must be in the contingency plan... STANDARDIZED PERMIT Contingency Plan and Emergency Procedures § 267.52 What must be in the contingency plan? (a) Your contingency plan must: (1) Describe the actions facility personnel will take to comply with §§ 267...

40 CFR 267.52 - What must be in the contingency plan?

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 28 2012-07-01 2012-07-01 false What must be in the contingency plan... STANDARDIZED PERMIT Contingency Plan and Emergency Procedures § 267.52 What must be in the contingency plan? (a) Your contingency plan must: (1) Describe the actions facility personnel will take to comply with §§ 267...

25 CFR 39.503 - How can a school use contingency funds?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false How can a school use contingency funds? 39.503 Section 39.503 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION THE INDIAN SCHOOL EQUALIZATION PROGRAM Contingency Fund § 39.503 How can a school use contingency funds? Contingency funds can be...

45 CFR 264.77 - How will we determine if a State met its Contingency Fund expenditure requirements?

Code of Federal Regulations, 2010 CFR

2010-10-01

... Contingency Fund expenditure requirements? 264.77 Section 264.77 Public Welfare Regulations Relating to Public... Contingency Fund? § 264.77 How will we determine if a State met its Contingency Fund expenditure requirements? (a) States receiving contingency funds for a fiscal year must complete the quarterly TANF Financial...

25 CFR 39.501 - What is an emergency or unforeseen contingency?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false What is an emergency or unforeseen contingency? 39.501... EQUALIZATION PROGRAM Contingency Fund § 39.501 What is an emergency or unforeseen contingency? An emergency or unforeseen contingency is an event that meets all of the following criteria: (a) It could not be planned for...

Singularity-free interpretation of the thermodynamics of supercooled water

NASA Astrophysics Data System (ADS)

Sastry, Srikanth; Debenedetti, Pablo G.; Sciortino, Francesco; Stanley, H. E.

1996-06-01

The pronounced increases in isothermal compressibility, isobaric heat capacity, and in the magnitude of the thermal expansion coefficient of liquid water upon supercooling have been interpreted either in terms of a continuous, retracing spinodal curve bounding the superheated, stretched, and supercooled states of liquid water, or in terms of a metastable, low-temperature critical point. Common to these two scenarios is the existence of singularities associated with diverging density fluctuations at low temperature. We show that the increase in compressibility upon lowering the temperature of a liquid that expands on cooling, like water, is not contingent on any singular behavior, but rather is a thermodynamic necessity. We perform a thermodynamic analysis for an anomalous liquid (i.e., one that expands when cooled) in the absence of a retracing spinodal and show that one may in general expect a locus of compressibility extrema in the anomalous regime. Our analysis suggests that the simplest interpretation of the behavior of supercooled water consistent with experimental observations is free of singularities. We then develop a waterlike lattice model that exhibits no singular behavior, while capturing qualitative aspects of the thermodynamics of water.

Fitness landscape transformation through a single amino acid change in the rho terminator.

PubMed

Freddolino, Peter L; Goodarzi, Hani; Tavazoie, Saeed

2012-05-01

Regulatory networks allow organisms to match adaptive behavior to the complex and dynamic contingencies of their native habitats. Upon a sudden transition to a novel environment, the mismatch between the native behavior and the new niche provides selective pressure for adaptive evolution through mutations in elements that control gene expression. In the case of core components of cellular regulation and metabolism, with broad control over diverse biological processes, such mutations may have substantial pleiotropic consequences. Through extensive phenotypic analyses, we have characterized the systems-level consequences of one such mutation (rho*) in the global transcriptional terminator Rho of Escherichia coli. We find that a single amino acid change in Rho results in a massive change in the fitness landscape of the cell, with widely discrepant fitness consequences of identical single locus perturbations in rho* versus rho(WT) backgrounds. Our observations reveal the extent to which a single regulatory mutation can transform the entire fitness landscape of the cell, causing a massive change in the interpretation of individual mutations and altering the evolutionary trajectories which may be accessible to a bacterial population.

No evidence for the effect of MHC on male mating success in the brown bear.

PubMed

Kuduk, Katarzyna; Babik, Wieslaw; Bellemain, Eva; Valentini, Alice; Zedrosser, Andreas; Taberlet, Pierre; Kindberg, Jonas; Swenson, Jon E; Radwan, Jacek

2014-01-01

Mate choice is thought to contribute to the maintenance of the spectacularly high polymorphism of the Major Histocompatibility Complex (MHC) genes, along with balancing selection from parasites, but the relative contribution of the former mechanism is debated. Here, we investigated the association between male MHC genotype and mating success in the brown bear. We analysed fragments of sequences coding for the peptide-binding region of the highly polymorphic MHC class I and class II DRB genes, while controlling for genome-wide effects using a panel of 18 microsatellite markers. Male mating success did not depend on the number of alleles shared with the female or amino-acid distance between potential mates at either locus. Furthermore, we found no indication of female mating preferences for MHC similarity being contingent on the number of alleles the females carried. Finally, we found no significant association between the number of MHC alleles a male carried and his mating success. Thus, our results provided no support for the role of mate choice in shaping MHC polymorphism in the brown bear.

Investigating Group Contingencies to Promote Brief Abstinence from Cigarette Smoking

PubMed Central

Meredith, Steven E.; Dallery, Jesse

2013-01-01

In contingency management (CM), monetary incentives are contingent on evidence of drug abstinence. Typically, incentives (e.g., “vouchers” exchangeable for goods or services) are contingent on individual performance. We programmed vouchers contingent on group performance to investigate whether these contingencies would promote brief abstinence from cigarette smoking. Thirty-two participants were divided into small teams (n = 3 per team). During three 5-day within-subject experimental conditions, participants submitted video recordings of breath carbon monoxide (CO) measures twice daily via Mōtiv8 Systems™, an Internet-based remote monitoring application. During the interdependent contingency condition, participants earned vouchers each time they and their teammates submitted breath CO samples indicative of abstinence (i.e., negative samples). During the independent contingency condition, participants earned vouchers each time they submitted negative samples, regardless of their teammates' performance. During the no vouchers condition, no monetary incentives were contingent on abstinence. In addition, half of the participants (n = 16) could communicate with their teammates through an online peer support forum. Although forum access did not appear to promote smoking abstinence, monetary incentives did promote brief abstinence. Significantly more negative samples were submitted when vouchers were contingent on individual performance (56%) or team performance (53%) relative to when no vouchers were available (35%; F = 6.9, p = 0.002). The results show that interdependent contingencies can promote brief abstinence from cigarette smoking. Moreover, the results suggest that these contingencies may help lower treatment costs and promote social support. PMID:23421358

25 CFR 39.502 - How does a school apply for contingency funds?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false How does a school apply for contingency funds? 39.502... EQUALIZATION PROGRAM Contingency Fund § 39.502 How does a school apply for contingency funds? To apply for contingency funds, a school must send a request to the ELO. The ELO must send the request to the Director for...

45 CFR 264.72 - What requirements are imposed on a State if it receives contingency funds?

Code of Federal Regulations, 2010 CFR

2010-10-01

... receives contingency funds? 264.72 Section 264.72 Public Welfare Regulations Relating to Public Welfare... Contingency Fund? § 264.72 What requirements are imposed on a State if it receives contingency funds? (a)(1) A State must meet a Contingency Fund MOE level of 100 percent of historic State expenditures for FY 1994...

45 CFR 264.70 - What makes a State eligible to receive a provisional payment of contingency funds?

Code of Federal Regulations, 2010 CFR

2010-10-01

... provisional payment of contingency funds? 264.70 Section 264.70 Public Welfare Regulations Relating to Public... Contingency Fund? § 264.70 What makes a State eligible to receive a provisional payment of contingency funds? (a) In order to receive a provisional payment of contingency funds, a State must: (1) Be a needy...

Motor contingency learning and infants with Spina Bifida.

PubMed

Taylor, Heather B; Barnes, Marcia A; Landry, Susan H; Swank, Paul; Fletcher, Jack M; Huang, Furong

2013-02-01

Infants with Spina Bifida (SB) were compared to typically developing infants (TD) using a conjugate reinforcement paradigm at 6 months-of-age (n = 98) to evaluate learning, and retention of a sensory-motor contingency. Analyses evaluated infant arm-waving rates at baseline (wrist not tethered to mobile), during acquisition of the sensory-motor contingency (wrist tethered), and immediately after the acquisition phase and then after a delay (wrist not tethered), controlling for arm reaching ability, gestational age, and socioeconomic status. Although both groups responded to the contingency with increased arm-waving from baseline to acquisition, 15% to 29% fewer infants with SB than TD were found to learn the contingency depending on the criterion used to determine contingency learning. In addition, infants with SB who had learned the contingency had more difficulty retaining the contingency over time when sensory feedback was absent. The findings suggest that infants with SB do not learn motor contingencies as easily or at the same rate as TD infants, and are more likely to decrease motor responses when sensory feedback is absent. Results are discussed with reference to research on contingency learning in infants with and without neurodevelopmental disorders, and with reference to motor learning in school-age children with SB.

Does contingency in adults' responding influence 12-month-old infants' social referencing?

PubMed

Stenberg, Gunilla

2017-11-01

In two experiments we examined the influence of contingent versus non-contingent responding on infant social referencing behavior. EXPERIMENT 1: Forty 12-month-old infants were exposed to an ambiguous toy in a social referencing situation. In one condition an unfamiliar adult who in a previous play situation had responded contingently to the infant's looks gave the infant positive information about the toy. In the other condition an unfamiliar adult who previously had not responded contingently delivered the positive information. EXPERIMENT 2: Forty-eight 12-month-old infants participated in Experiment 2. In this experiment it was examined whether the familiarity of the adult influences infants' reactions to contingency in responding. In one condition a parent who previously had responded contingently to the infant's looks provided positive information about the ambiguous toy, and in the other condition a parent who previously had not responded contingently provided the positive information. The infants looked more at the contingent experimenter in Experimenter 1, and also played more with the toy after receiving positive information from the contingent experimenter. No differences in looking at the parent and in playing with the toy were found in Experiment 2. The results indicate that contingency in responding, as well as the familiarity of the adult, influence infants' social referencing behavior. Copyright © 2017 Elsevier Inc. All rights reserved.

Does contingency in adults' responding influence 12-month-old infants' social referencing?

PubMed

Stenberg, Gunilla

2017-02-01

In two experiments we examined the influence of contingent versus non-contingent responding on infant social referencing behavior. EXPERIMENT 1: Forty 12-month-old infants were exposed to an ambiguous toy in a social referencing situation. In one condition an unfamiliar adult who in a previous play situation had responded contingently to the infant's looks gave the infant positive information about the toy. In the other condition an unfamiliar adult who previously had not responded contingently delivered the positive information. EXPERIMENT 2: Forty-eight 12-month-old infants participated in Experiment 2. In this experiment it was examined whether the familiarity of the adult influences infants' reactions to contingency in responding. In one condition a parent who previously had responded contingently to the infant's looks provided positive information about the ambiguous toy, and in the other condition a parent who previously had not responded contingently provided the positive information. The infants looked more at the contingent experimenter in Experimenter 1, and also played more with the toy after receiving positive information from the contingent experimenter. No differences in looking at the parent and in playing with the toy were found in Experiment 2. The results indicate that contingency in responding, as well as the familiarity of the adult, influence infants' social referencing behavior. Copyright © 2016 Elsevier Inc. All rights reserved.

Better Off Jobless? Scarring Effects of Contingent Employment in Japan

PubMed Central

Yu, Wei-hsin

2011-01-01

Previous research fails to address whether contingent employment benefits individuals’ careers more than the alternative they often face: being without a job. Using work history data from Japan, this study shows that accepting a contingent job delays individuals’ transition to standard employment more than remaining jobless. Moreover, having a contingent job, rather than having no job, leads Japanese men to have lower occupational status after they transition back to standard employment. I argue that in a highly segmented labor market like Japan’s, the strict separation of labor pools for standard and contingent jobs makes being labeled as a contingent worker particularly detrimental. Meanwhile, the legacy of Japan’s welfare corporatism alleviates the stigma of unemployment, making individuals better off jobless than having a contingent job. This research thus demonstrates the importance of labor-market contexts in shaping the scarring effects of contingent work arrangements. PMID:22859864

Heart Rate Reactivity during Contingency Learning in 5- to 10-Month-Old at-Risk and Non-Risk Babies

ERIC Educational Resources Information Center

Millar, W. S.; Weir, C. G.

2007-01-01

The study investigated the dynamic relation between contingency learning and heart rate with risk and non-risk babies 5- to 10-months-old. Four groups were compared in a two contingency treatments (contingent, yoked) x two risk status design. Concurrent heart rate was monitored during three phases of a contingency learning task (baseline,…

HIV evolution in early infection: selection pressures, patterns of insertion and deletion, and the impact of APOBEC.

PubMed

Wood, Natasha; Bhattacharya, Tanmoy; Keele, Brandon F; Giorgi, Elena; Liu, Michael; Gaschen, Brian; Daniels, Marcus; Ferrari, Guido; Haynes, Barton F; McMichael, Andrew; Shaw, George M; Hahn, Beatrice H; Korber, Bette; Seoighe, Cathal

2009-05-01

The pattern of viral diversification in newly infected individuals provides information about the host environment and immune responses typically experienced by the newly transmitted virus. For example, sites that tend to evolve rapidly across multiple early-infection patients could be involved in enabling escape from common early immune responses, could represent adaptation for rapid growth in a newly infected host, or could represent reversion from less fit forms of the virus that were selected for immune escape in previous hosts. Here we investigated the diversification of HIV-1 env coding sequences in 81 very early B subtype infections previously shown to have resulted from transmission or expansion of single viruses (n = 78) or two closely related viruses (n = 3). In these cases, the sequence of the infecting virus can be estimated accurately, enabling inference of both the direction of substitutions as well as distinction between insertion and deletion events. By integrating information across multiple acutely infected hosts, we find evidence of adaptive evolution of HIV-1 env and identify a subset of codon sites that diversified more rapidly than can be explained by a model of neutral evolution. Of 24 such rapidly diversifying sites, 14 were either i) clustered and embedded in CTL epitopes that were verified experimentally or predicted based on the individual's HLA or ii) in a nucleotide context indicative of APOBEC-mediated G-to-A substitutions, despite having excluded heavily hypermutated sequences prior to the analysis. In several cases, a rapidly evolving site was embedded both in an APOBEC motif and in a CTL epitope, suggesting that APOBEC may facilitate early immune escape. Ten rapidly diversifying sites could not be explained by CTL escape or APOBEC hypermutation, including the most frequently mutated site, in the fusion peptide of gp41. We also examined the distribution, extent, and sequence context of insertions and deletions, and we provide evidence that the length variation seen in hypervariable loop regions of the envelope glycoprotein is a consequence of selection and not of mutational hotspots. Our results provide a detailed view of the process of diversification of HIV-1 following transmission, highlighting the role of CTL escape and hypermutation in shaping viral evolution during the establishment of new infections.

HIV Evolution in Early Infection: Selection Pressures, Patterns of Insertion and Deletion, and the Impact of APOBEC

PubMed Central

Wood, Natasha; Bhattacharya, Tanmoy; Keele, Brandon F.; Giorgi, Elena; Liu, Michael; Gaschen, Brian; Daniels, Marcus; Ferrari, Guido; Haynes, Barton F.; McMichael, Andrew; Shaw, George M.; Hahn, Beatrice H.; Korber, Bette; Seoighe, Cathal

2009-01-01

The pattern of viral diversification in newly infected individuals provides information about the host environment and immune responses typically experienced by the newly transmitted virus. For example, sites that tend to evolve rapidly across multiple early-infection patients could be involved in enabling escape from common early immune responses, could represent adaptation for rapid growth in a newly infected host, or could represent reversion from less fit forms of the virus that were selected for immune escape in previous hosts. Here we investigated the diversification of HIV-1 env coding sequences in 81 very early B subtype infections previously shown to have resulted from transmission or expansion of single viruses (n = 78) or two closely related viruses (n = 3). In these cases, the sequence of the infecting virus can be estimated accurately, enabling inference of both the direction of substitutions as well as distinction between insertion and deletion events. By integrating information across multiple acutely infected hosts, we find evidence of adaptive evolution of HIV-1 env and identify a subset of codon sites that diversified more rapidly than can be explained by a model of neutral evolution. Of 24 such rapidly diversifying sites, 14 were either i) clustered and embedded in CTL epitopes that were verified experimentally or predicted based on the individual's HLA or ii) in a nucleotide context indicative of APOBEC-mediated G-to-A substitutions, despite having excluded heavily hypermutated sequences prior to the analysis. In several cases, a rapidly evolving site was embedded both in an APOBEC motif and in a CTL epitope, suggesting that APOBEC may facilitate early immune escape. Ten rapidly diversifying sites could not be explained by CTL escape or APOBEC hypermutation, including the most frequently mutated site, in the fusion peptide of gp41. We also examined the distribution, extent, and sequence context of insertions and deletions, and we provide evidence that the length variation seen in hypervariable loop regions of the envelope glycoprotein is a consequence of selection and not of mutational hotspots. Our results provide a detailed view of the process of diversification of HIV-1 following transmission, highlighting the role of CTL escape and hypermutation in shaping viral evolution during the establishment of new infections. PMID:19424423

Revisiting the relation between contingency awareness and attention: evaluative conditioning relies on a contingency focus.

PubMed

Kattner, Florian

2012-01-01

Although evaluative conditioning has occasionally been demonstrated in the absence of contingency awareness, many recent studies imply that its acquisition depends on the availability of attentional resources during conditioning. In previous experiments attention has typically been manipulated in a general way rather than looking at the particular focus of attention. The present study investigated the role of a focus on the CS-US contingency. Two separate distraction tasks were designed that either diverted attention from the stimuli or directed it to the stimuli while drawing attention away from the contingency between the stimuli. Both types of distraction were shown to eliminate evaluative conditioning. Significant evaluative conditioning was observed in a third group of participants who were required to attend the contingencies. A mediation analysis showed that the observed discrepancy in evaluative conditioning effects between groups was mediated by contingency awareness. The results imply that attention in terms of a stimulus focus is not sufficient for evaluative conditioning to occur. Rather, attention to the contingencies between stimuli appears to be crucial in evaluative conditioning, because it is supposed to foster the acquisition of contingency awareness.

Relative speed of processing determines color-word contingency learning.

PubMed

Forrin, Noah D; MacLeod, Colin M

2017-10-01

In three experiments, we tested a relative-speed-of-processing account of color-word contingency learning, a phenomenon in which color identification responses to high-contingency stimuli (words that appear most often in particular colors) are faster than those to low-contingency stimuli. Experiment 1 showed equally large contingency-learning effects whether responding was to the colors or to the words, likely due to slow responding to both dimensions because of the unfamiliar mapping required by the key press responses. For Experiment 2, participants switched to vocal responding, in which reading words is considerably faster than naming colors, and we obtained a contingency-learning effect only for color naming, the slower dimension. In Experiment 3, previewing the color information resulted in a reduced contingency-learning effect for color naming, but it enhanced the contingency-learning effect for word reading. These results are all consistent with contingency learning influencing performance only when the nominally irrelevant feature is faster to process than the relevant feature, and therefore are entirely in accord with a relative-speed-of-processing explanation.

Dogs Identify Agents in Third-Party Interactions on the Basis of the Observed Degree of Contingency.

PubMed

Tauzin, Tibor; Kovács, Krisztina; Topál, József

2016-08-01

To investigate whether dogs could recognize contingent reactivity as a marker of agents' interaction, we performed an experiment in which dogs were presented with third-party contingent events. In the perfect-contingency condition, dogs were shown an unfamiliar self-propelled agent (SPA) that performed actions corresponding to audio clips of verbal commands played by a computer. In the high-but-imperfect-contingency condition, the SPA responded to the verbal commands on only two thirds of the trials; in the low-contingency condition, the SPA responded to the commands on only one third of the trials. In the test phase, the SPA approached one of two tennis balls, and then the dog was allowed to choose one of the balls. The proportion of trials on which a dog chose the object indicated by the SPA increased with the degree of contingency: Dogs chose the target object significantly above chance level only in the perfect-contingency condition. This finding suggests that dogs may use the degree of temporal contingency observed in third-party interactions as a cue to identify agents. © The Author(s) 2016.

Electrophysiological brain indices of risk behavior modification induced by contingent feedback.

PubMed

Megías, Alberto; Torres, Miguel Angel; Catena, Andrés; Cándido, Antonio; Maldonado, Antonio

2018-02-01

The main aim of this research was to study the effects of response feedback on risk behavior and the neural and cognitive mechanisms involved, as a function of the feedback contingency. Sixty drivers were randomly assigned to one of three feedback groups: contingent, non-contingent and no feedback. The participants' task consisted of braking or not when confronted with a set of risky driving situations, while their electroencephalographic activity was continuously recorded. We observed that contingent feedback, as opposed to non-contingent feedback, promoted changes in the response bias towards safer decisions. This behavioral modification implied a higher demand on cognitive control, reflected in a larger amplitude of the N400 component. Moreover, the contingent feedback, being predictable and entailing more informative value, gave rise to smaller SPN and larger FRN scores when compared with non-contingent feedback. Taken together, these findings provide a new and complex insight into the neurophysiological basis of the influence of feedback contingency on the processing of decision-making under risk. We suggest that response feedback, when contingent upon the risky behavior, appears to improve the functionality of the brain mechanisms involved in decision-making and can be a powerful tool for reducing the tendency to choose risky options in risk-prone individuals. Copyright © 2018 Elsevier B.V. All rights reserved.

Motor Contingency Learning and Infants with Spina Bifida

PubMed Central

Taylor, Heather B.; Barnes, Marcia A.; Landry, Susan H.; Swank, Paul; Fletcher, Jack M.; Huang, Furong

2014-01-01

Infants with Spina Bifida (SB) were compared to typically developing infants (TD) using a conjugate reinforcement paradigm at 6 months-of-age (n = 98) to evaluate learning, and retention of a sensory-motor contingency. Analyses evaluated infant arm-waving rates at baseline (wrist not tethered to mobile), during acquisition of the sensory-motor contingency (wrist tethered), and immediately after the acquisition phase and then after a delay (wrist not tethered), controlling for arm reaching ability, gestational age, and socioeconomic status. Although both groups responded to the contingency with increased arm-waving from baseline to acquisition, 15% to 29% fewer infants with SB than TD were found to learn the contingency depending on the criterion used to determine contingency learning. In addition, infants with SB who had learned the contingency had more difficulty retaining the contingency over time when sensory feedback was absent. The findings suggest that infants with SB do not learn motor contingencies as easily or at the same rate as TD infants, and are more likely to decrease motor responses when sensory feedback is absent. Results are discussed with reference to research on contingency learning in infants with and without neurodevelopmental disorders, and with reference to motor learning in school-age children with SB. PMID:23298791

I spy with my little eye - the detection of intentional contingency in early psychosis.

PubMed

Fett, Anne-Kathrin J; González Berdugo, Clara Isabel; Hanssen, Esther; Lemmers-Jansen, Imke; Shergill, Sukhi S; Krabbendam, Lydia

2015-01-01

Paranoid delusions have been associated with a tendency to over-attribute intentionality and contingency to others' actions and incidental events in individuals with chronic psychosis. However, this hyper-associative perception bias has not been investigated in the early illness stages of psychosis, during which it may play a particularly crucial role in the formation of symptoms. We used an experimental paradigm with 20 short film clips of simple animate and inanimate shapes that either moved in a contingent or non-contingent manner to investigate the perception of contingency in 38 adolescents with early psychosis and 93 healthy control adolescents. Participants rated the contingency between the shapes' movements on a scale from 0 to 10. The data were analysed with multilevel regression analyses to account for repeated measures within subjects. There were no significant differences between patients and controls; both perceived the contingency of the shapes' movements similarly across all conditions and patients' contingency perception was unrelated to their levels of paranoid delusions. Contingency perception was unimpaired in patients with early psychosis, suggesting that it might still be intact in the early illness stages. Future studies should set out to determine whether the early illness stages could offer a window for interventions that counteract the development of hyper-associative perceptions of contingency.

Fanca deficiency reduces A/T transitions in somatic hypermutation and alters class switch recombination junctions in mouse B cells

PubMed Central

Nguyen, Thuy Vy; Riou, Lydia

2014-01-01

Fanconi anemia is a rare genetic disorder that can lead to bone marrow failure, congenital abnormalities, and increased risk for leukemia and cancer. Cells with loss-of-function mutations in the FANC pathway are characterized by chromosome fragility, altered mutability, and abnormal regulation of the nonhomologous end-joining (NHEJ) pathway. Somatic hypermutation (SHM) and immunoglobulin (Ig) class switch recombination (CSR) enable B cells to produce high-affinity antibodies of various isotypes. Both processes are initiated after the generation of dG:dU mismatches by activation-induced cytidine deaminase. Whereas SHM involves an error-prone repair process that introduces novel point mutations into the Ig gene, the mismatches generated during CSR are processed to create double-stranded breaks (DSBs) in DNA, which are then repaired by the NHEJ pathway. As several lines of evidence suggest a possible role for the FANC pathway in SHM and CSR, we analyzed both processes in B cells derived from Fanca−/− mice. Here we show that Fanca is required for the induction of transition mutations at A/T residues during SHM and that despite globally normal CSR function in splenic B cells, Fanca is required during CSR to stabilize duplexes between pairs of short microhomology regions, thereby impeding short-range recombination downstream of DSB formation. PMID:24799500

Fanca deficiency reduces A/T transitions in somatic hypermutation and alters class switch recombination junctions in mouse B cells.

PubMed

Nguyen, Thuy Vy; Riou, Lydia; Aoufouchi, Saïd; Rosselli, Filippo

2014-06-02

Fanconi anemia is a rare genetic disorder that can lead to bone marrow failure, congenital abnormalities, and increased risk for leukemia and cancer. Cells with loss-of-function mutations in the FANC pathway are characterized by chromosome fragility, altered mutability, and abnormal regulation of the nonhomologous end-joining (NHEJ) pathway. Somatic hypermutation (SHM) and immunoglobulin (Ig) class switch recombination (CSR) enable B cells to produce high-affinity antibodies of various isotypes. Both processes are initiated after the generation of dG:dU mismatches by activation-induced cytidine deaminase. Whereas SHM involves an error-prone repair process that introduces novel point mutations into the Ig gene, the mismatches generated during CSR are processed to create double-stranded breaks (DSBs) in DNA, which are then repaired by the NHEJ pathway. As several lines of evidence suggest a possible role for the FANC pathway in SHM and CSR, we analyzed both processes in B cells derived from Fanca(-/-) mice. Here we show that Fanca is required for the induction of transition mutations at A/T residues during SHM and that despite globally normal CSR function in splenic B cells, Fanca is required during CSR to stabilize duplexes between pairs of short microhomology regions, thereby impeding short-range recombination downstream of DSB formation. © 2014 Nguyen et al.

Target sequence accessibility limits activation-induced cytidine deaminase activity in primary mediastinal B-cell lymphoma.

PubMed

Popov, Sergey W; Moldenhauer, Gerhard; Wotschke, Beate; Brüderlein, Silke; Barth, Thomas F; Dorsch, Karola; Ritz, Olga; Möller, Peter; Leithäuser, Frank

2007-07-15

Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) in activated B lymphocytes and is potentially implicated in genomic instability of B-cell malignancies. For unknown reasons, B-cell neoplasms often lack SHM and CSR in spite of high AID expression. Here, we show that primary mediastinal B-cell lymphoma (PMBL), an immunoglobulin (Ig)-negative lymphoma that possesses hypermutated, class-switched Ig genes, expresses high levels of AID with an intact primary structure but does not do CSR in 14 of 16 cases analyzed. Absence of CSR coincided with low Ig germ-line transcription, whereas high level germ-line transcription was observed only in those two cases with active CSR. Interleukin-4/CD40L costimulation induced CSR and a marked up-regulation of germ-line transcription in the PMBL-derived cell line MedB-1. In the PMBL cell line Karpas 1106P, CSR was not inducible and germ-line transcription remained low on stimulation. However, Karpas 1106P, but not MedB-1, had ongoing SHM of the Ig gene and BCL6. These genes were transcribed in Karpas 1106P, whereas transcription was undetectable or low in MedB-1 cells. Thus, accessibility of the target sequences seems to be a major limiting factor for AID-dependent somatic gene diversification in PMBL.

Characterization of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in Shanghai, China: molecular and cytogenetic characteristics, IgV gene restriction and hypermutation patterns.

PubMed

Irons, Richard D; Le, Anh; Bao, Liming; Zhu, Xiongzeng; Ryder, John; Wang, Xiao Qin; Ji, Meirong; Chen, Yan; Wu, Xichun; Lin, Guowei

2009-12-01

The clinical, cytogenetic and molecular features of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), a disease previously considered to be rare in Asia, were examined in consecutive series of 70 cases diagnosed by our laboratory over a 30-month period. Clonal abnormalities were observed in 80% of CLL/SLL cases using a combination of conventional cytogenetic and fluorescence in situ hybridization (FISH) analysis. Those involving 14q32/IGH were the most frequent (24 cases), followed by trisomy 12 and 11q abnormalities. IgV(H) gene usage was non-random with over-representation of V(H)4-34, V(H)3-23 and a previously unreported increase in V(H)3-48 gene use. Somatic hypermutation (SHM) of IgV(H) germline sequences was observed in 56.5% of cases with stereotyped patterns of SHM observed in V(H)4-34 heavy chain complimentary-determining (HCDR1) and framework region CFR2 sequences. These findings in a Chinese population suggest subtle geographical differences in IgV(H) gene usage while the remarkably specific pattern of SHM suggest that a relatively limited set of antigens may be involved in the development of this disease worldwide. IgV(H) gene mutation status was a significant predictor of initial survival in CLL/SLL. However, an influence of karyotype on prognosis was not observed.

Usefulness of a Darwinian System in a Biotechnological Application: Evolution of Optical Window Fluorescent Protein Variants under Selective Pressure

PubMed Central

Ng, David; Pauli, Jutta; Resch-Genger, Ute; Kühn, Enrico; Heuer, Steffen; Beisker, Wolfgang; Köster, Reinhard W.; Zitzelsberger, Horst; Caldwell, Randolph B

2014-01-01

With rare exceptions, natural evolution is an extremely slow process. One particularly striking exception in the case of protein evolution is in the natural production of antibodies. Developing B cells activate and diversify their immunoglobulin (Ig) genes by recombination, gene conversion (GC) and somatic hypermutation (SHM). Iterative cycles of hypermutation and selection continue until antibodies of high antigen binding specificity emerge (affinity maturation). The avian B cell line DT40, a cell line which is highly amenable to genetic manipulation and exhibits a high rate of targeted integration, utilizes both GC and SHM. Targeting the DT40's diversification machinery onto transgenes of interest inserted into the Ig loci and coupling selective pressure based on the desired outcome mimics evolution. Here we further demonstrate the usefulness of this platform technology by selectively pressuring a large shift in the spectral properties of the fluorescent protein eqFP615 into the highly stable and advanced optical imaging expediting fluorescent protein Amrose. The method is advantageous as it is time and cost effective and no prior knowledge of the outcome protein's structure is necessary. Amrose was evolved to have high excitation at 633 nm and excitation/emission into the far-red, which is optimal for whole-body and deep tissue imaging as we demonstrate in the zebrafish and mouse model. PMID:25192257

Subclones in B-lymphoma cell lines: isogenic models for the study of gene regulation

PubMed Central

Quentmeier, Hilmar; Pommerenke, Claudia; Ammerpohl, Ole; Geffers, Robert; Hauer, Vivien; MacLeod, Roderick AF; Nagel, Stefan; Romani, Julia; Rosati, Emanuela; Rosén, Anders; Uphoff, Cord C; Zaborski, Margarete; Drexler, Hans G

2016-01-01

Genetic heterogeneity though common in tumors has been rarely documented in cell lines. To examine how often B-lymphoma cell lines are comprised of subclones, we performed immunoglobulin (IG) heavy chain hypermutation analysis. Revealing that subclones are not rare in B-cell lymphoma cell lines, 6/49 IG hypermutated cell lines (12%) consisted of subclones with individual IG mutations. Subclones were also identified in 2/284 leukemia/lymphoma cell lines exhibiting bimodal CD marker expression. We successfully isolated 10 subclones from four cell lines (HG3, SU-DHL-5, TMD-8, U-2932). Whole exome sequencing was performed to molecularly characterize these subclones. We describe in detail the clonal structure of cell line HG3, derived from chronic lymphocytic leukemia. HG3 consists of three subclones each bearing clone-specific aberrations, gene expression and DNA methylation patterns. While donor patient leukemic cells were CD5+, two of three HG3 subclones had independently lost this marker. CD5 on HG3 cells was regulated by epigenetic/transcriptional mechanisms rather than by alternative splicing as reported hitherto. In conclusion, we show that the presence of subclones in cell lines carrying individual mutations and characterized by sets of differentially expressed genes is not uncommon. We show also that these subclones can be useful isogenic models for regulatory and functional studies. PMID:27566572

Usefulness of a Darwinian system in a biotechnological application: evolution of optical window fluorescent protein variants under selective pressure.

PubMed

Schoetz, Ulrike; Deliolanis, Nikolaos C; Ng, David; Pauli, Jutta; Resch-Genger, Ute; Kühn, Enrico; Heuer, Steffen; Beisker, Wolfgang; Köster, Reinhard W; Zitzelsberger, Horst; Caldwell, Randolph B

2014-01-01

With rare exceptions, natural evolution is an extremely slow process. One particularly striking exception in the case of protein evolution is in the natural production of antibodies. Developing B cells activate and diversify their immunoglobulin (Ig) genes by recombination, gene conversion (GC) and somatic hypermutation (SHM). Iterative cycles of hypermutation and selection continue until antibodies of high antigen binding specificity emerge (affinity maturation). The avian B cell line DT40, a cell line which is highly amenable to genetic manipulation and exhibits a high rate of targeted integration, utilizes both GC and SHM. Targeting the DT40's diversification machinery onto transgenes of interest inserted into the Ig loci and coupling selective pressure based on the desired outcome mimics evolution. Here we further demonstrate the usefulness of this platform technology by selectively pressuring a large shift in the spectral properties of the fluorescent protein eqFP615 into the highly stable and advanced optical imaging expediting fluorescent protein Amrose. The method is advantageous as it is time and cost effective and no prior knowledge of the outcome protein's structure is necessary. Amrose was evolved to have high excitation at 633 nm and excitation/emission into the far-red, which is optimal for whole-body and deep tissue imaging as we demonstrate in the zebrafish and mouse model.

Rapid extraction of auditory feature contingencies.

PubMed

Bendixen, Alexandra; Prinz, Wolfgang; Horváth, János; Trujillo-Barreto, Nelson J; Schröger, Erich

2008-07-01

Contingent relations between sensory events render the environment predictable and thus facilitate adaptive behavior. The human capacity to detect such relations has been comprehensively demonstrated in paradigms in which contingency rules were task-relevant or in which they applied to motor behavior. The extent to which contingencies can also be extracted from events that are unrelated to the current goals of the organism has remained largely unclear. The present study addressed the emergence of contingency-related effects for behaviorally irrelevant auditory stimuli and the cortical areas involved in the processing of such contingency rules. Contingent relations between different features of temporally separate events were embedded in a new dynamic protocol. Participants were presented with the auditory stimulus sequences while their attention was captured by a video. The mismatch negativity (MMN) component of the event-related brain potential (ERP) was employed as an electrophysiological correlate of contingency detection. MMN generators were localized by means of scalp current density (SCD) and primary current density (PCD) analyses with variable resolution electromagnetic tomography (VARETA). Results show that task-irrelevant contingencies can be extracted from about fifteen to twenty successive events conforming to the contingent relation. Topographic and tomographic analyses reveal the involvement of the auditory cortex in the processing of contingency violations. The present data provide evidence for the rapid encoding of complex extrapolative relations in sensory areas. This capacity is of fundamental importance for the organism in its attempt to model the sensory environment outside the focus of attention.

48 CFR 18.201 - Contingency operation.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Contingency operation. 18.201 Section 18.201 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION CONTRACTING METHODS AND CONTRACT TYPES EMERGENCY ACQUISITIONS Emergency Acquisition Flexibilities 18.201 Contingency operation. (a) Contingency operation is...

Supervisory Styles: A Contingency Framework

ERIC Educational Resources Information Center

Boehe, Dirk Michael

2016-01-01

While the contingent nature of doctoral supervision has been acknowledged, the literature on supervisory styles has yet to deliver a theory-based contingency framework. A contingency framework can assist supervisors and research students in identifying appropriate supervisory styles under varying circumstances. The conceptual study reported here…

The Earth Science Afternoon Constellation Contingency Procedures

NASA Technical Reports Server (NTRS)

Case, Warren F.; Richon, Karen

2005-01-01

The Earth Science Afternoon Constellation comprises NASA missions Aqua, Aura, CloudSat and the Orbiting Carbon Observatory (OCO), the joint NASA/CNES mission CALIPSO and the CNES mission PARASOL. Both NASA and CNES offices are responsible for ensuring that contingency plans or other arrangements exist to cope with contingencies within their respective jurisdictions until the conclusion of all Afternoon Constellation operations. The Mission Operations Working Group, comprised of members from each of the missions, has developed the high-level procedures for maintaining the safety of this constellation. Each contingency situation requires detailed analyses before any decisions are made. This paper describes these procedures, and includes defining what constitutes a contingency situation, the pertinent parameters involved in the contingency analysis and guidelines for the actions required, based on the results of the contingency analyses.

47 CFR 73.3517 - Contingent applications.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 4 2010-10-01 2010-10-01 false Contingent applications. 73.3517 Section 73... BROADCAST SERVICES Rules Applicable to All Broadcast Stations § 73.3517 Contingent applications. Contingent applications for new stations and for changes in facilities of existing stations are not acceptable for filing...

78 FR 44909 - Regional Reliability Standard BAL-002-WECC-2-Contingency Reserve

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-25

...] Regional Reliability Standard BAL-002-WECC-2--Contingency Reserve AGENCY: Federal Energy Regulatory...-002-WECC-2 (Contingency Reserve). The North American Electric Reliability Corporation (NERC) and... contingency reserve required to ensure reliability under normal and abnormal conditions. The Commission also...

50 CFR 296.3 - Fishermen's contingency fund.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 50 Wildlife and Fisheries 9 2011-10-01 2011-10-01 false Fishermen's contingency fund. 296.3... ADMINISTRATION, DEPARTMENT OF COMMERCE CONTINENTAL SHELF FISHERMEN'S CONTINGENCY FUND § 296.3 Fishermen's contingency fund. (a) General. There is established in the Treasury of the United States the Fishermen's...

50 CFR 296.3 - Fishermen's contingency fund.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 50 Wildlife and Fisheries 7 2010-10-01 2010-10-01 false Fishermen's contingency fund. 296.3... ADMINISTRATION, DEPARTMENT OF COMMERCE CONTINENTAL SHELF FISHERMEN'S CONTINGENCY FUND § 296.3 Fishermen's contingency fund. (a) General. There is established in the Treasury of the United States the Fishermen's...

30 CFR 218.152 - Fishermen's Contingency Fund.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 2 2010-07-01 2010-07-01 false Fishermen's Contingency Fund. 218.152 Section 218.152 Mineral Resources MINERALS MANAGEMENT SERVICE, DEPARTMENT OF THE INTERIOR MINERALS REVENUE..., Offshore § 218.152 Fishermen's Contingency Fund. Upon the establishment of the Fishermen's Contingency Fund...

Dissociating contingency awareness and conditioned attitudes: evidence of contingency-unaware evaluative conditioning.

PubMed

Hütter, Mandy; Sweldens, Steven; Stahl, Christoph; Unkelbach, Christian; Klauer, Karl Christoph

2012-08-01

Whether human evaluative conditioning can occur without contingency awareness has been the subject of an intense and ongoing debate for decades, troubled by a wide array of methodological difficulties. Following recent methodological innovations, the available evidence currently points to the conclusion that evaluative conditioning effects do not occur without contingency awareness. In a simulation, we demonstrate, however, that these innovations are strongly biased toward the conclusion that evaluative conditioning requires contingency awareness, confounding the measurement of contingency memory with conditioned attitudes. We adopt a process-dissociation procedure to separate the memory and attitude components. In 4 studies, the attitude parameter is validated using existing attitudes and applied to probe for contingency-unaware evaluative conditioning. A fifth experiment incorporates a time-delay manipulation confirming the dissociability of the attitude and memory components. The results indicate that evaluative conditioning can produce attitudes without conscious awareness of the contingencies. Implications for theories of evaluative conditioning and associative learning are discussed. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

Contingent imitation increases verbal interaction in children with autism spectrum disorders.

PubMed

Ishizuka, Yuka; Yamamoto, Jun-Ichi

2016-11-01

Several studies have suggested that contingent adult imitation increase nonverbal communication, such as attention and proximity to adults, in children with autism spectrum disorders. However, few studies have shown the effect of contingent imitation on verbal communication. This study examined whether children with autism were able to promote verbal interaction such as vocal imitation, vocalization, and vocal turn-taking via contingent imitation. We used an alternating treatment design composed of the conditions of contingent imitation and control for six children with autism (aged 33-63 months). For contingent imitation condition, adults imitated children's vocalization immediately. For control condition, adults did not imitate but gave a vocal response immediately. Results showed that in contingent imitation condition, all children increased the number of vocal imitations and vocal turn-takings compared with control condition. The number of vocalizations increased in both condition for all children. Overall, it is suggested that all children promote verbal interaction via contingent imitation. © The Author(s) 2016.

Contingency management: perspectives of Australian service providers.

PubMed

Cameron, Jacqui; Ritter, Alison

2007-03-01

Given the very positive and extensive research evidence demonstrating efficacy and effectiveness of contingency management, it is important that Australia explore whether contingency management has a role to play in our own treatment context. Qualitative interviews were conducted with 30 experienced alcohol and drug practitioners, service managers and policy-makers in Victoria. Interviewees were selected to represent the range of drug treatment services types and included rural representation. A semi-structured interview schedule, covering their perceptions and practices of contingency management was used. All interviews were transcribed verbatim and analysed using N2 qualitative data analysis program. The majority of key informants were positively inclined toward contingency management, notwithstanding some concerns about the philosophical underpinnings. Concerns were raised in relation to the use of monetary rewards. Examples of the use of contingency management provided by key informants demonstrated an over-inclusive definition: all the examples did not adhere to the key principles of contingency management. This may create problems if a structured contingency management were to be introduced in Australia. Contingency management is an important adjunctive treatment intervention and its use in Australia has the potential to enhance treatment outcomes. No unmanageable barriers were identified in this study.

The role of feedback contingency in perceptual category learning.

PubMed

Ashby, F Gregory; Vucovich, Lauren E

2016-11-01

Feedback is highly contingent on behavior if it eventually becomes easy to predict, and weakly contingent on behavior if it remains difficult or impossible to predict even after learning is complete. Many studies have demonstrated that humans and nonhuman animals are highly sensitive to feedback contingency, but no known studies have examined how feedback contingency affects category learning, and current theories assign little or no importance to this variable. Two experiments examined the effects of contingency degradation on rule-based and information-integration category learning. In rule-based tasks, optimal accuracy is possible with a simple explicit rule, whereas optimal accuracy in information-integration tasks requires integrating information from 2 or more incommensurable perceptual dimensions. In both experiments, participants each learned rule-based or information-integration categories under either high or low levels of feedback contingency. The exact same stimuli were used in all 4 conditions, and optimal accuracy was identical in every condition. Learning was good in both high-contingency conditions, but most participants showed little or no evidence of learning in either low-contingency condition. Possible causes of these effects, as well as their theoretical implications, are discussed. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

The Role of Feedback Contingency in Perceptual Category Learning

PubMed Central

Ashby, F. Gregory; Vucovich, Lauren E.

2016-01-01

Feedback is highly contingent on behavior if it eventually becomes easy to predict, and weakly contingent on behavior if it remains difficult or impossible to predict even after learning is complete. Many studies have demonstrated that humans and nonhuman animals are highly sensitive to feedback contingency, but no known studies have examined how feedback contingency affects category learning, and current theories assign little or no importance to this variable. Two experiments examined the effects of contingency degradation on rule-based and information-integration category learning. In rule-based tasks, optimal accuracy is possible with a simple explicit rule, whereas optimal accuracy in information-integration tasks requires integrating information from two or more incommensurable perceptual dimensions. In both experiments, participants each learned rule-based or information-integration categories under either high or low levels of feedback contingency. The exact same stimuli were used in all four conditions and optimal accuracy was identical in every condition. Learning was good in both high-contingency conditions, but most participants showed little or no evidence of learning in either low-contingency condition. Possible causes of these effects are discussed, as well as their theoretical implications. PMID:27149393

77 FR 76815 - Handling of Animals; Contingency Plans

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-31

... contingency plan system be implemented to accommodate small businesses. As a practical matter, one would... No. APHIS-2006-0159] RIN 0579-AC69 Handling of Animals; Contingency Plans AGENCY: Animal and Plant... regulations to add requirements for contingency planning and training of personnel by research facilities and...

The UNG2 Arg88Cys variant abrogates RPA-mediated recruitment of UNG2 to single-stranded DNA.

PubMed

Torseth, Kathrin; Doseth, Berit; Hagen, Lars; Olaisen, Camilla; Liabakk, Nina-Beate; Græsmann, Heidi; Durandy, Anne; Otterlei, Marit; Krokan, Hans E; Kavli, Bodil; Slupphaug, Geir

2012-06-01

In human cell nuclei, UNG2 is the major uracil-DNA glycosylase initiating DNA base excision repair of uracil. In activated B cells it has an additional role in facilitating mutagenic processing of AID-induced uracil at Ig loci and UNG-deficient patients develop hyper-IgM syndrome characterized by impaired class-switch recombination and disturbed somatic hypermutation. How UNG2 is recruited to either error-free or mutagenic uracil processing remains obscure, but likely involves regulated interactions with other proteins. The UNG2 N-terminal domain contains binding motifs for both proliferating cell nuclear antigen (PCNA) and replication protein A (RPA), but the relative contribution of these interactions to genomic uracil processing is not understood. Interestingly, a heterozygous germline single-nucleotide variant leading to Arg88Cys (R88C) substitution in the RPA-interaction motif of UNG2 has been observed in humans, but with unknown functional relevance. Here we demonstrate that UNG2-R88C protein is expressed from the variant allele in a lymphoblastoid cell line derived from a heterozygous germ line carrier. Enzyme activity as well as localization in replication foci of UNG2-R88C was similar to that of WT. However, binding to RPA was essentially abolished by the R88C substitution, whereas binding to PCNA was unaffected. Moreover, we show that disruption of the PCNA-binding motif impaired recruitment of UNG2 to S-phase replication foci, demonstrating that PCNA is a major factor for recruitment of UNG2 to unperturbed replication forks. Conversely, in cells treated with hydroxyurea, RPA mediated recruitment of UNG2 to stalled replication forks independently of functional PCNA binding. Modulation of PCNA- versus RPA-binding may thus constitute a functional switch for UNG2 in cells subsequent to genotoxic stress and potentially also during the processing of uracil at the immunoglobulin locus in antigen-stimulated B cells. Copyright © 2012 Elsevier B.V. All rights reserved.

Contingency contracting with school problems

PubMed Central

Cantrell, Robert P.; Cantrell, Mary Lynn; Huddleston, Clifton M.; Wooldridge, Ralph L.

1969-01-01

Contingency contracting procedures used in managing problems with school-age children involved analyzing teacher and/or parental reports of behavior problem situations, isolating the most probable contingencies then in effect, the range of reinforcers presently available, and the ways in which they were obtained. The authors prepared written contracts delineating remediative changes in reinforcement contingencies. These contracts specified ways in which the child could obtain existing individualized reinforcers contingent upon approximations to desired appropriate behaviors chosen as incompatible with the referral problem behaviors. Contract procedures were administered by the natural contingency managers, parents and/or teachers, who kept daily records of contracted behaviors and reinforcers. These records were sent to the authors and provided feedback on the progress of the case. Initial results of this procedure have been sufficiently encouraging to warrant recommending an experimental analysis of contingency contracting as a clinical method. PMID:16795222

Contingency learning is reduced for high conflict stimuli.

PubMed

Whitehead, Peter S; Brewer, Gene A; Patwary, Nowed; Blais, Chris

2016-09-16

Recent theories have proposed that contingency learning occurs independent of control processes. These parallel processing accounts propose that behavioral effects originally thought to be products of control processes are in fact products solely of contingency learning. This view runs contrary to conflict-mediated Hebbian-learning models that posit control and contingency learning are parts of an interactive system. In this study we replicate the contingency learning effect and modify it to further test the veracity of the parallel processing accounts in comparison to conflict-mediated Hebbian-learning models. This is accomplished by manipulating conflict to test for an interaction, or lack thereof, between conflict and contingency learning. The results are consistent with conflict-mediated Hebbian-learning in that the addition of conflict reduces the magnitude of the contingency learning effect. Copyright © 2016 Elsevier B.V. All rights reserved.

The Effects of Non-Contingent Reinforcement on Children.

ERIC Educational Resources Information Center

Tramill, James L.; Kleinhammer, P. Jeannie

Typical learned helplessness research has involved the presentation of non-contingent, aversive events followed by measures of performance on subsequent tasks; recent investigations have focused on the effect of non-contingent rewards. To examine the effects of non-contingent rewards on children, two studies were conducted, in which children were…

A Review of the Use of Group Contingencies in Preschool Settings

ERIC Educational Resources Information Center

Pokorski, Elizabeth A.; Barton, Erin E.; Ledford, Jennifer R.

2017-01-01

Individual contingency management systems have been used successfully to improve behaviors in school settings--including preschools--but often come with associated challenges in time and personnel management. Group contingencies, in the form of independent, interdependent, and dependent contingencies, have been used in preschools to address these…

Treating aerophagia with contingent physical guidance.

PubMed

Garcia, D; Starin, S; Churchill, R M

2001-01-01

Contingent physical guidance was used to treat chronic aerophagia. This consisted of guiding the participant's hand over her mouth following each attempt to engage in aerophagia. A wristwatch was then correlated with the contingent physical guidance procedure. Responding remained low in the presence of the wristwatch, even after contingent physical guidance was withdrawn.

76 FR 73719 - Order Contingently Delegating Authority to the Chairman, the General Counsel, and the Chief...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-29

... NATIONAL LABOR RELATIONS BOARD Order Contingently Delegating Authority to the Chairman, the...: Notice of Order Contingently Delegating Authority to the Chairman, the General Counsel, and the Chief Administrative Law Judge. SUMMARY: The National Labor Relations Board has issued an Order contingently delegating...

Contingency diagrams as teaching tools.

PubMed

Mattaini, M A

1995-01-01

Contingency diagrams are particularly effective teaching tools, because they provide a means for students to view the complexities of contingency networks present in natural and laboratory settings while displaying the elementary processes that constitute those networks. This paper sketches recent developments in this visualization technology and illustrates approaches for using contingency diagrams in teaching.

77 FR 66783 - National Oil and Hazardous Substances Pollution Contingency Plan; Revision To Increase Public...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-07

...-AG73] National Oil and Hazardous Substances Pollution Contingency Plan; Revision To Increase Public... Contingency Plan, to acknowledge advancements in technologies used to manage and convey information to the... Substances Pollution Contingency Plan (NCP), to acknowledge advancements in technologies used to manage and...

Effects of Individual and Group Contingency Interventions on Attendance in Adolescent Part-Time Employees

ERIC Educational Resources Information Center

Berkovits, Shira Melody; Sturmey, Peter; Alvero, Alicia M.

2012-01-01

This study examined the effects of individual and group monetary contingencies on the attendance of adolescent part-time employees. Attendance increased in both individual and group contingency phases; however staff questionnaire responses indicated a preference for the individual contingencies. Future research should consider staff acceptability…

48 CFR 252.232-7011 - Payments in Support of Emergencies and Contingency Operations.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Emergencies and Contingency Operations. 252.232-7011 Section 252.232-7011 Federal Acquisition Regulations... Emergencies and Contingency Operations. As prescribed in section 232.908, use the following clause: PAYMENTS IN SUPPORT OF EMERGENCIES AND CONTINGENCY OPERATIONS (JUL 2010) (a) Definitions of pertinent terms...

40 CFR 51.1012 - Requirement for contingency measures.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 2 2010-07-01 2010-07-01 false Requirement for contingency measures... Implementation of PM2.5 National Ambient Air Quality Standards § 51.1012 Requirement for contingency measures... contingency measures to be undertaken if the area fails to make reasonable further progress, or fails to...

49 CFR 1542.301 - Contingency plan.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 9 2010-10-01 2010-10-01 false Contingency plan. 1542.301 Section 1542.301..., DEPARTMENT OF HOMELAND SECURITY CIVIL AVIATION SECURITY AIRPORT SECURITY Contingency Measures § 1542.301 Contingency plan. (a) Each airport operator required to have a security program under § 1542.103(a) and (b...

40 CFR 264.227 - Emergency repairs; contingency plans.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 25 2010-07-01 2010-07-01 false Emergency repairs; contingency plans... FACILITIES Surface Impoundments § 264.227 Emergency repairs; contingency plans. (a) A surface impoundment... days after detecting the problem. (c) As part of the contingency plan required in subpart D of this...

Contingency Software in Autonomous Systems

NASA Technical Reports Server (NTRS)

Lutz, Robyn; Patterson-Hine, Ann

2006-01-01

This viewgraph presentation reviews the development of contingency software for autonomous systems. Autonomous vehicles currently have a limited capacity to diagnose and mitigate failures. There is a need to be able to handle a broader range of contingencies. The goals of the project are: 1. Speed up diagnosis and mitigation of anomalous situations.2.Automatically handle contingencies, not just failures.3.Enable projects to select a degree of autonomy consistent with their needs and to incrementally introduce more autonomy.4.Augment on-board fault protection with verified contingency scripts

Counterfactual reasoning for regretted situations involving controllable versus uncontrollable events: the modulating role of contingent self-esteem.

PubMed

Wilkinson, Meredith R; Ball, Linden J; Alford, David

2015-01-01

We report a study that examined the modulating impact of contingent self-esteem on regret intensity for regretted outcomes associated with controllable versus uncontrollable events. The Contingent Self-Esteem Scale (e.g., Kernis & Goldman, 2006) was used to assess the extent to which a person's sense of self-worth is based on self and others' expectations. We found that there was an influence of self-esteem contingency for controllable but not for uncontrollable regret types. For controllable regret types individuals with a high contingent (i.e., unstable) self-esteem reported greater regret intensity than those with a low contingent (i.e., stable) self-esteem. We interpret this finding as reflecting a functional and adaptive role of high contingent self-esteem in terms of mobilizing the application of counterfactual reasoning and planning mechanisms that can enable personal expectations to be achieved in the future.

Counterfactual Reasoning for Regretted Situations Involving Controllable Versus Uncontrollable Events: The Modulating Role of Contingent Self-Esteem

PubMed Central

Wilkinson, Meredith R.; Ball, Linden J.; Alford, David

2015-01-01

We report a study that examined the modulating impact of contingent self-esteem on regret intensity for regretted outcomes associated with controllable versus uncontrollable events. The Contingent Self-Esteem Scale (e.g., Kernis & Goldman, 2006) was used to assess the extent to which a person’s sense of self-worth is based on self and others’ expectations. We found that there was an influence of self-esteem contingency for controllable but not for uncontrollable regret types. For controllable regret types individuals with a high contingent (i.e., unstable) self-esteem reported greater regret intensity than those with a low contingent (i.e., stable) self-esteem. We interpret this finding as reflecting a functional and adaptive role of high contingent self-esteem in terms of mobilizing the application of counterfactual reasoning and planning mechanisms that can enable personal expectations to be achieved in the future. PMID:25883697

Contingent workers: Workers' compensation data analysis strategies and limitations.

PubMed

Foley, Michael; Ruser, John; Shor, Glenn; Shuford, Harry; Sygnatur, Eric

2014-07-01

The growth of the contingent workforce presents many challenges in the occupational safety and health arena. State and federal laws impose obligations and rights on employees and employers, but contingent work raises issues regarding responsibilities to maintain a safe workplace and difficulties in collecting and reporting data on injuries and illnesses. Contingent work may involve uncertainty about the length of employment, control over the labor process, degree of regulatory, or statutory protections, and access to benefits under workers' compensation. The paper highlights differences in regulatory protections and benefits among various types of contingent workers and how these different arrangements affect safety incentives. It discusses challenges caused by contingent work for accurate data reporting in existing injury and illness surveillance and benefit programs, differences between categories of contingent work in their coverage in various data sources, and opportunities for overcoming obstacles to effectively using workers' compensation data. © 2014 Wiley Periodicals, Inc.

Development of Medical Technology for Contingency Response to Marrow Toxic Agents

DTIC Science & Technology

1. Contingency Preparedness: Collect information from transplant centers, build awareness of the Transplant Center Contingency Planning Committee and...Matched Donors: Increase operational efficiencies that accelerate the search process and increase patient access are key to preparedness in a contingency ...Transplantation: Create a platform that facilitates multicenter collaboration and data management.

The Role of Feedback Contingency in Perceptual Category Learning

ERIC Educational Resources Information Center

Ashby, F. Gregory; Vucovich, Lauren E.

2016-01-01

Feedback is highly contingent on behavior if it eventually becomes easy to predict, and weakly contingent on behavior if it remains difficult or impossible to predict even after learning is complete. Many studies have demonstrated that humans and nonhuman animals are highly sensitive to feedback contingency, but no known studies have examined how…

Treating aerophagia with contingent physical guidance.

PubMed Central

Garcia, D; Starin, S; Churchill, R M

2001-01-01

Contingent physical guidance was used to treat chronic aerophagia. This consisted of guiding the participant's hand over her mouth following each attempt to engage in aerophagia. A wristwatch was then correlated with the contingent physical guidance procedure. Responding remained low in the presence of the wristwatch, even after contingent physical guidance was withdrawn. PMID:11317995

40 CFR 267.53 - Who must have copies of the contingency plan?

Code of Federal Regulations, 2014 CFR

2014-07-01

... contingency plan? 267.53 Section 267.53 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... UNDER A STANDARDIZED PERMIT Contingency Plan and Emergency Procedures § 267.53 Who must have copies of the contingency plan? (a) You must maintain a copy of the plan with all revisions at the facility; and...

40 CFR 267.53 - Who must have copies of the contingency plan?

Code of Federal Regulations, 2012 CFR

2012-07-01

... contingency plan? 267.53 Section 267.53 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... UNDER A STANDARDIZED PERMIT Contingency Plan and Emergency Procedures § 267.53 Who must have copies of the contingency plan? (a) You must maintain a copy of the plan with all revisions at the facility; and...

40 CFR 267.53 - Who must have copies of the contingency plan?

Code of Federal Regulations, 2011 CFR

2011-07-01

... contingency plan? 267.53 Section 267.53 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... UNDER A STANDARDIZED PERMIT Contingency Plan and Emergency Procedures § 267.53 Who must have copies of the contingency plan? (a) You must maintain a copy of the plan with all revisions at the facility; and...

40 CFR 267.53 - Who must have copies of the contingency plan?

Code of Federal Regulations, 2013 CFR

2013-07-01

... contingency plan? 267.53 Section 267.53 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... UNDER A STANDARDIZED PERMIT Contingency Plan and Emergency Procedures § 267.53 Who must have copies of the contingency plan? (a) You must maintain a copy of the plan with all revisions at the facility; and...

40 CFR 109.5 - Development and implementation criteria for State, local and regional oil removal contingency plans.

Code of Federal Regulations, 2013 CFR

2013-07-01

... assistance from Federal authorities operating under existing national and regional contingency plans. (3) A... criteria for State, local and regional oil removal contingency plans. 109.5 Section 109.5 Protection of... OIL REMOVAL CONTINGENCY PLANS § 109.5 Development and implementation criteria for State, local and...

40 CFR 109.5 - Development and implementation criteria for State, local and regional oil removal contingency plans.

Code of Federal Regulations, 2014 CFR

2014-07-01

... assistance from Federal authorities operating under existing national and regional contingency plans. (3) A... for State, local and regional oil removal contingency plans. 109.5 Section 109.5 Protection of... OIL REMOVAL CONTINGENCY PLANS § 109.5 Development and implementation criteria for State, local and...

48 CFR 225.7303-4 - Contingent fees.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Contingent fees. 225.7303....7303-4 Contingent fees. (a) Except as provided in paragraph (b) of this subsection, contingent fees are generally allowable under DoD contracts, provided— (1) The fees are paid to a bona fide employee or a bona...

78 FR 64402 - Approval and Promulgation of Implementation Plans; California; South Coast; Contingency Measures...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-29

...] Approval and Promulgation of Implementation Plans; California; South Coast; Contingency Measures for 1997...) contingency measure requirements for the 1997 annual and 24-hour national ambient air quality standard (NAAQS... Contingency Measures for the 2007 PM 2.5 SIP'' (dated October 2011), which the California Air Resources Board...

The Graduate School and Its Organizational Structure: A Contingency Theory Approach.

ERIC Educational Resources Information Center

Sanford, Judith Babcock

Contingency theory, the formal structure of graduate schools, and the applicability of contingency variables to graduate schools as organizations are examined. Contingency theory is based on an open systems concept that views an organization as composed of many interdependent parts that are interacting with one another. It also holds that under…

78 FR 34303 - Approval and Promulgation of Implementation Plans; North Carolina; Removal of Stage II Gasoline...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-07

... associated maintenance plans, North Carolina provided contingency measures that included regulation 15A North... contingency measures that were also included in the 1- hour ozone maintenance plans. These contingency... the contingency measures in its SIP for the Charlotte-Gastonia, Greensboro-Winston-Salem-High Point...

29 CFR 4022.27 - Phase-in of guarantee of unpredictable contingent event benefits.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 29 Labor 9 2014-07-01 2014-07-01 false Phase-in of guarantee of unpredictable contingent event... Guaranteed Benefits § 4022.27 Phase-in of guarantee of unpredictable contingent event benefits. (a) Scope... event benefit (UCEB) and that is payable with respect to an unpredictable contingent event (UCE) that...

An Analysis of Group-Oriented Contingencies and Associated Side Effects in Preschool Children

ERIC Educational Resources Information Center

Payne, Steven W.; Dozier, Claudia L.; Briggs, Adam M.; Newquist, Matthew H.

2017-01-01

Group-oriented contingencies are arranged to target the behavior of a group of people simultaneously. Overall, group-oriented contingencies have been shown to be effective in both decreasing problem behavior and increasing appropriate behavior. However, results are mixed regarding which type(s) of group-oriented contingency is most effective for…

Early Child Contingency Learning and Detection: Research Evidence and Implications for Practice

ERIC Educational Resources Information Center

Dunst, Carl J.; Trivette, Carol M.; Raab, Melinda; Masiello, Tracy L.

2008-01-01

The types of contingency experiences infants and young children are typically exposed to are examined with a focus on the implications for early childhood intervention with young children who have developmental disabilities and delays. Studies of response-contingent child learning, the manner in which contingencies are not under direct child…

40 CFR 267.53 - Who must have copies of the contingency plan?

Code of Federal Regulations, 2010 CFR

2010-07-01

... contingency plan? 267.53 Section 267.53 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... UNDER A STANDARDIZED PERMIT Contingency Plan and Emergency Procedures § 267.53 Who must have copies of the contingency plan? (a) You must maintain a copy of the plan with all revisions at the facility; and...

Contingent self-worth moderates the relationship between school stressors and psychological stress responses.

PubMed

Ishizu, Kenichiro

2017-04-01

This study examined the moderating role of contingent self-worth on the relationships between school stressors and psychological stress responses among Japanese adolescents. A total of 371 Japanese junior high school students (184 boys and 187 girls, M age  = 12.79 years, SD = 0.71) completed the Japanese version of the Self-Worth Contingency Questionnaire and a mental health checklist at two points separated by a two-month interval. Hierarchical multiple regression analyses were then used to determine whether contingent self-worth moderated the relationship between school stressors and psychological stress responses. The results indicated that, when psychological stress responses were controlled for at Time 1, contingent self-worth did not predict the psychological stress responses at Time 2. However, a two-way interaction between contingent self-worth and stressors was found to significantly influence psychological stress responses, thus indicating that stressors had a stronger impact on psychological stress responses among those with high contingent self-worth compared to those with low contingent self-worth. Copyright © 2017 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

Contingency Management of Health Care Organizations: It Depends.

PubMed

Olden, Peter C

Managers in health care organizations (HCOs) must perform many processes and activities, such as planning goals, designing organization structure, leading people, motivating employees, making decisions, and resolving conflict. How they do all this strongly affects the performance and outcomes of their organizations and themselves. Some managers develop a usual way of performing their jobs and achieve some success with a preferred method of leading or a favorite approach to motivating. However, their success will be limited if they always rely on a standard "1-size-fits-all" approach. This is because contingency factors influence the effectiveness of a given approach to managing. The "best" approach depends on contingency factors, including the situation and the people involved. Managers should choose an approach to fit with the changing contingency factors. This article explains why and how managers should develop a contingency approach to managing HCOs. The development of contingency theory is briefly described. Practical application of contingency management is explained for leading, motivating, decision making, and resolving conflict. By using a contingency approach, managers can be more effective when managing their HCOs.

Equilibria of perceptrons for simple contingency problems.

PubMed

Dawson, Michael R W; Dupuis, Brian

2012-08-01

The contingency between cues and outcomes is fundamentally important to theories of causal reasoning and to theories of associative learning. Researchers have computed the equilibria of Rescorla-Wagner models for a variety of contingency problems, and have used these equilibria to identify situations in which the Rescorla-Wagner model is consistent, or inconsistent, with normative models of contingency. Mathematical analyses that directly compare artificial neural networks to contingency theory have not been performed, because of the assumed equivalence between the Rescorla-Wagner learning rule and the delta rule training of artificial neural networks. However, recent results indicate that this equivalence is not as straightforward as typically assumed, suggesting a strong need for mathematical accounts of how networks deal with contingency problems. One such analysis is presented here, where it is proven that the structure of the equilibrium for a simple network trained on a basic contingency problem is quite different from the structure of the equilibrium for a Rescorla-Wagner model faced with the same problem. However, these structural differences lead to functionally equivalent behavior. The implications of this result for the relationships between associative learning, contingency theory, and connectionism are discussed.

Contingency learning is not affected by conflict experience: Evidence from a task conflict-free, item-specific Stroop paradigm.

PubMed

Levin, Yulia; Tzelgov, Joseph

2016-02-01

A contingency learning account of the item-specific proportion congruent effect has been described as an associative stimulus-response learning process that has nothing to do with controlling the Stroop conflict. As supportive evidence, contingency learning has been demonstrated with response conflict-free stimuli, such as neutral words. However, what gives rise to response conflict and to Stroop interference in general is task conflict. The present study investigated whether task conflict can constitute a trigger or, alternatively, a booster to the contingency learning process. This was done by employing a "task conflict-free" condition (i.e., geometric shapes) and comparing it with a "task conflict" condition (i.e., neutral words). The results showed a significant contingency learning effect in both conditions, refuting the possibility that contingency learning is triggered by the presence of a task conflict. Contingency learning was also not enhanced by the task conflict experience, indicating its complete insensitivity to Stroop conflict(s). Thus, the results showed no evidence that performance optimization as a result of contingency learning is greater under conflict, implying that contingency learning is not recruited to assist the control system to overcome conflict. Copyright © 2015 Elsevier B.V. All rights reserved.

Influence of contingency awareness on neural, electrodermal and evaluative responses during fear conditioning

PubMed Central

Merz, Christian J.; Klucken, Tim; Schweckendiek, Jan; Vaitl, Dieter; Wolf, Oliver T.; Stark, Rudolf

2011-01-01

In an fMRI study, effects of contingency awareness on conditioned responses were assessed in three groups comprising 118 subjects. A differential fear-conditioning paradigm with visual conditioned stimuli, an electrical unconditioned stimulus and two distractors was applied. The instructed aware group was informed about the contingencies, whereas the distractors prevented contingency detection in the unaware group. The third group (learned aware) was not informed about the contingencies, but learned them despite the distractors. Main effects of contingency awareness on conditioned responses emerged in several brain structures. Post hoc tests revealed differential dorsal anterior cingulate, insula and ventral striatum responses in aware conditioning only, whereas the amygdala was activated independent of contingency awareness. Differential responses of the hippocampus were specifically observed in learned aware subjects, indicating a role in the development of contingency awareness. The orbitofrontal cortex showed varying response patterns: lateral structures showed higher responses in instructed aware than unaware subjects, the opposite was true for medial parts. Conditioned subjective and electrodermal responses emerged only in the two aware groups. These results confirm the independence of conditioned amygdala responses from contingency awareness and indicate specific neural circuits for different aspects of fear acquisition in unaware, learned aware and instructed aware subjects. PMID:20693389

Does temporal contiguity moderate contingency learning in a speeded performance task?

PubMed

Schmidt, James R; De Houwer, Jan

2012-01-01

In four experiments, we varied the time between the onset of distracting nonwords and target colour words in a word-word version of the colour-word contingency learning paradigm. Contingencies were created by pairing a distractor nonword more often with one target colour word than with other colour words. A contingency effect corresponds to faster responses to the target colour word on high-contingency trials (i.e., distractor nonword followed by the target colour word with which it appears most often) than on low-contingency trials (i.e., distractor nonword followed by a target colour word with which it appears only occasionally). Roughly equivalent-sized contingency effects were found at stimulus-onset asynchronies (SOAs) of 50, 250, and 450 ms in Experiment 1, and 50, 500, and 1,000 ms in Experiment 2. In Experiment 3, a contingency effect was observed at SOAs of -50, -200, and -350 ms. In Experiment 4, interstimulus interval (ISI) was varied along with SOA, and learning was equivalent for 200-, 700-, and 1,200-ms SOAs. Together, these experiments suggest that the distracting stimulus does not need to be presented in close temporal contiguity with the response to induce learning. Relations to past research on causal judgement and implications for further contingency learning research are discussed.

Internet-based group contingency management to promote abstinence from cigarette smoking: A feasibility study

PubMed Central

Meredith, Steven E.; Grabinski, Michael J.; Dallery, Jesse

2011-01-01

Background In contingency management (CM) interventions, monetary consequences are contingent on evidence of drug abstinence. Typically, these consequences are contingent on individual performance. Consequences contingent on group performance may promote social support (e.g., praise). Methods Thus, to combine social support with the monetary incentives of CM, we integrated independent and interdependent group contingencies of reinforcement into an Internet-based intervention to promote smoking abstinence. Breath carbon monoxide (CO) measures were compared between treatment conditions and a baseline control condition. Thirteen participants were divided into 5 groups or “teams” (n = 2–3 per team). Each participant submitted video recordings of CO measurement twice daily via the Internet. Teammates could monitor each other’s progress and communicate with one another through an online peer support forum. During a 4-day tapering condition, vouchers exchangeable for goods were contingent on gradual reductions in breath CO. During a 10-day abstinence induction condition, vouchers were contingent on abstinence (CO ≤4 ppm). In both treatment conditions, concurrent independent and interdependent group contingencies were arranged (i.e., a mixed contingency arrangement). Results Less than 1% of CO samples submitted during baseline were ≤4 ppm, compared to 57% submitted during abstinence induction. Sixty-five percent of participants’ comments on the online peer support forum were rated as positive by independent observers. Participants rated the intervention favorably on a treatment acceptability questionnaire. Conclusion The results suggest that the intervention is feasible and acceptable for promoting abstinence from cigarette smoking. PMID:21414733

Impaired awareness of action-outcome contingency and causality during healthy ageing and following ventromedial prefrontal cortex lesions.

PubMed

O'Callaghan, Claire; Vaghi, Matilde M; Brummerloh, Berit; Cardinal, Rudolf N; Robbins, Trevor W

2018-02-02

Detecting causal relationships between actions and their outcomes is fundamental to guiding goal-directed behaviour. The ventromedial prefrontal cortex (vmPFC) has been extensively implicated in computing these environmental contingencies, via animal lesion models and human neuroimaging. However, whether the vmPFC is critical for contingency learning, and whether it can occur without subjective awareness of those contingencies, has not been established. To address this, we measured response adaption to contingency and subjective awareness of action-outcome relationships in individuals with vmPFC lesions and healthy elderly subjects. We showed that in both vmPFC damage and ageing, successful behavioural adaptation to variations in action-outcome contingencies was maintained, but subjective awareness of these contingencies was reduced. These results highlight two contexts where performance and awareness have been dissociated, and show that learning response-outcome contingencies to guide behaviour can occur without subjective awareness. Preserved responding in the vmPFC group suggests that this region is not critical for computing action-outcome contingencies to guide behaviour. In contrast, our findings highlight a critical role for the vmPFC in supporting awareness, or metacognitive ability, during learning. We further advance the hypothesis that responding to changing environmental contingencies, whilst simultaneously maintaining conscious awareness of those statistical regularities, is a form of dual-tasking that is impaired in ageing due to reduced prefrontal function. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Mobile Wastewater Treatment Technology for Contingency Bases

DTIC Science & Technology

2012-05-24

Def nse Cent rgy and Environment Contingency Base Wastewater Treatment Options Option Advantages Disadvantages Tanking and Trucking Offsite Low...National Defense Center for Energy and Environment Mobile Wastewater Treatment f or Contingency Bases, May 2012 1 National Def nse Cent rgy and...Environment DoD Executive Agent Mobile Wastewater Treatment Technology for Contingency Bases Shan Abeywickrama, NDCEE/CTC Elizabeth Keysar

48 CFR 50.205-3 - Authorization of offers contingent upon SAFETY Act designation or certification before contract...

Code of Federal Regulations, 2011 CFR

2011-10-01

...— (i) For offers contingent upon SAFETY Act designation, a pre-qualification designation notice or a block designation; or (ii) For offers contingent upon SAFETY Act certification, a block certification... contingent upon SAFETY Act designation or certification before contract award. 50.205-3 Section 50.205-3...

25 CFR 39.504 - May schools carry over contingency funds to a subsequent fiscal year?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false May schools carry over contingency funds to a subsequent fiscal year? 39.504 Section 39.504 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION THE INDIAN SCHOOL EQUALIZATION PROGRAM Contingency Fund § 39.504 May schools carry over contingency...

Temporal contingency

PubMed Central

Gallistel, C.R.; Craig, Andrew R.; Shahan, Timothy A.

2015-01-01

Contingency, and more particularly temporal contingency, has often figured in thinking about the nature of learning. However, it has never been formally defined in such a way as to make it a measure that can be applied to most animal learning protocols. We use elementary information theory to define contingency in such a way as to make it a measurable property of almost any conditioning protocol. We discuss how making it a measurable construct enables the exploration of the role of different contingencies in the acquisition and performance of classically and operantly conditioned behavior. PMID:23994260

When does self-esteem relate to deviant behavior? The role of contingencies of self-worth.

PubMed

Ferris, D Lance; Brown, Douglas J; Lian, Huiwen; Keeping, Lisa M

2009-09-01

Researchers have assumed that low self-esteem predicts deviance, but empirical results have been mixed. This article draws upon recent theoretical developments regarding contingencies of self-worth to clarify the self-esteem/deviance relation. It was predicted that self-esteem level would relate to deviance only when self-esteem was not contingent on workplace performance. In this manner, contingent self-esteem is a boundary condition for self-consistency/behavioral plasticity theory predictions. Using multisource data collected from 123 employees over 6 months, the authors examined the interaction between level (high/low) and type (contingent/noncontingent) of self-esteem in predicting workplace deviance. Results support the hypothesized moderating effects of contingent self-esteem; implications for self-esteem theories are discussed.

Skype me! Socially Contingent Interactions Help Toddlers Learn Language

PubMed Central

Roseberry, Sarah; Hirsh-Pasek, Kathy; Golinkoff, Roberta Michnick

2013-01-01

Language learning takes place in the context of social interactions, yet the mechanisms that render social interactions useful for learning language remain unclear. This paper focuses on whether social contingency might support word learning. Toddlers aged 24- to 30-months (N=36) were exposed to novel verbs in one of three conditions: live interaction training, socially contingent video training over video chat, and non-contingent video training (yoked video). Results suggest that children only learned novel verbs in socially contingent interactions (live interactions and video chat). The current study highlights the importance of social contingency in interactions for language learning and informs the literature on learning through screen media as the first study to examine word learning through video chat technology. PMID:24112079

Effects of Behavioral Contingencies on Adolescent Active Videogame Play and Overall Activity: A Randomized Trial.

PubMed

Norman, Gregory J; Adams, Marc A; Ramirez, Ernesto R; Carlson, Jordan A; Kerr, Jacqueline; Godbole, Suneeta; Dillon, Lindsay; Marshall, Simon J

2013-06-01

This study evaluated the effect of four active videogames (AVGs) varying in behavioral contingencies (behavior-consequence relations) on adolescent AVG play and overall activity levels over 4 weeks. Each AVG, manufactured by SSD/Xavix(®) (Shiseido Co. of Japan, Tokyo, Japan), was coded and scored for the number of positive and aversive behavioral contingencies within the games. "Bowling" and "Tennis" were classified as having "higher contingency scores," and "Boxing" and aerobic fitness training were classified as having "lower contingency scores." Adolescents (n=63; 11-15 years old; 62% male; 38% Hispanic; 44% overweight or obese) were randomized to play one of the four AVGs at home and recorded game play sessions in a paper log. Baseline and week 4 assessments were completed at home; week 1, 2, and 3 assessments were completed by telephone. Accelerometers were worn during baseline and weeks 1 and 4. Accelerometer-measured sedentary and light activity hours/day were stable over time, whereas moderate-vigorous physical activity minutes/day increased in the higher contingency group and decreased in the lower contingency group (interaction effect, 6.43, P=0.024). Reported game play minutes decreased in both groups from week 1 to week 4 (-29.42 minutes, P=0.001). There was some support for the hypothesis that AVGs with more behavioral contingencies, compared with AVGs with fewer behavioral contingencies, result in more physical activity. However, overall AVG play decreased substantially after the first week. Further study is needed to better understand how behavioral contingencies can be used in AVGs to enhance their potential to provide health benefits to game players.

Cyber Contingency Analysis version 1.x

DOE Office of Scientific and Technical Information (OSTI.GOV)

Contingency analysis based approach for quantifying and examining the resiliency of a cyber system in respect to confidentiality, integrity and availability. A graph representing an organization's cyber system and related resources is used for the availability contingency analysis. The mission critical paths associated with an organization are used to determine the consequences of a potential contingency. A node (or combination of nodes) are removed from the graph to analyze a particular contingency. The value of all mission critical paths that are disrupted by that contingency are used to quantify its severity. A total severity score can be calculated based onmore » the complete list of all these contingencies. A simple n1 analysis can be done in which only one node is removed at a time for the analysis. We can also compute nk analysis, where k is the number of nodes to simultaneously remove for analysis. A contingency risk score can also be computed, which takes the probability of the contingencies into account. In addition to availability, we can also quantify confidentiality and integrity scores for the system. These treat user accounts as potential contingencies. The amount (and type) of files that an account can read to is used to compute the confidentiality score. The amount (and type) of files that an account can write to is used to compute the integrity score. As with availability analysis, we can use this information to compute total severity scores in regards to confidentiality and integrity. We can also take probability into account to compute associated risk scores.« less

Evaluation of Counter-Based Dynamic Load Balancing Schemes for Massive Contingency Analysis on Over 10,000 Cores

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Yousu; Huang, Zhenyu; Rice, Mark J.

Contingency analysis studies are necessary to assess the impact of possible power system component failures. The results of the contingency analysis are used to ensure the grid reliability, and in power market operation for the feasibility test of market solutions. Currently, these studies are performed in real time based on the current operating conditions of the grid with a set of pre-selected contingency list, which might result in overlooking some critical contingencies caused by variable system status. To have a complete picture of a power grid, more contingencies need to be studied to improve grid reliability. High-performance computing techniques holdmore » the promise of being able to perform the analysis for more contingency cases within a much shorter time frame. This paper evaluates the performance of counter-based dynamic load balancing schemes for a massive contingency analysis program on 10,000+ cores. One million N-2 contingency analysis cases with a Western Electricity Coordinating Council power grid model have been used to demonstrate the performance. The speedup of 3964 with 4096 cores and 7877 with 10240 cores are obtained. This paper reports the performance of the load balancing scheme with a single counter and two counters, describes disk I/O issues, and discusses other potential techniques for further improving the performance.« less

MATERNAL ANXIETY SYMPTOMS AND MOTHER–INFANT SELF- AND INTERACTIVE CONTINGENCY

PubMed Central

Beebe, Beatrice; Steele, Miriam; Jaffe, Joseph; Buck, Karen A.; Chen, Henian; Cohen, Patricia; Kaitz, Marsha; Markese, Sara; Andrews, Howard; Margolis, Amy; Feldstein, Stanley

2014-01-01

Associations of maternal self-report anxiety-related symptoms with mother–infant 4-month face-to-face play were investigated in 119 pairs. Attention, affect, spatial orientation, and touch were coded from split-screen videotape on a 1-s time base. Self- and interactive contingency were assessed by time-series methods. Because anxiety symptoms signal emotional dysregulation, we expected to find atypical patterns of mother–infant interactive contingencies, and of degree of stability/lability within an individual’s own rhythms of behavior (self-contingencies). Consistent with our optimum midrange model, maternal anxiety-related symptoms biased the interaction toward interactive contingencies that were both heightened (vigilant) in some modalities and lowered (withdrawn) in others; both may be efforts to adapt to stress. Infant self-contingency was lowered (“destabilized”) with maternal anxiety symptoms; however, maternal self-contingency was both lowered in some modalities and heightened (overly stable) in others. Interactive contingency patterns were characterized by intermodal discrepancies, confusing forms of communication. For example, mothers vigilantly monitored infants visually, but withdrew from contingently coordinating with infants emotionally, as if mothers were “looking through” them. This picture fits descriptions of mothers with anxiety symptoms as overaroused/fearful, leading to vigilance, but dealing with their fear through emotional distancing. Infants heightened facial affect coordination (vigilance), but dampened vocal affect coordination (withdrawal), with mother’s face—a pattern of conflict. The maternal and infant patterns together generated a mutual ambivalence. PMID:25983359

Breaking the Myth of Flexible Work: Contingent Work in Toronto. A Study Conducted by the Contingent Workers Project.

ERIC Educational Resources Information Center

de Wolff, Alice

A survey of 205 people, 4 group interviews with approximately 30 people, and 6 design and analysis meetings involving approximately 40 people were conducted in a 1999 participatory study of contingent workers in Toronto. (Contingent work was defined to be lower-waged forms of non-permanent work arrangements that include contracting, employment…

Effects of leader contingent and noncontingent reward and punishment behaviors on subordinate performance and satisfaction.

PubMed

Podsakoff, P M; Todor, W D; Skov, R

1982-12-01

This study investigated the nature of the relationships between leader reward and punishment behaviors and subordinate performance and satisfaction. Only performance-contingent reward behavior was found to affect subordinate performance significantly. Positive relationships were found between leader contingent reward behavior and employee satisfaction. Contingent punishment had no effects on subordinate performance or satisfaction.

Contingency diagrams as teaching tools

PubMed Central

Mattaini, Mark A.

1995-01-01

Contingency diagrams are particularly effective teaching tools, because they provide a means for students to view the complexities of contingency networks present in natural and laboratory settings while displaying the elementary processes that constitute those networks. This paper sketches recent developments in this visualization technology and illustrates approaches for using contingency diagrams in teaching. ImagesFigure 2Figure 3Figure 4 PMID:22478208

76 FR 80442 - Self-Regulatory Organizations; NASDAQ OMX PHLX LLC; Notice of Filing and Immediate Effectiveness...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-23

... 1014(b)(i) and (ii). \\7\\ A contingency order is a limit or market order to buy or sell that is contingent upon a condition being satisfied while the order is at the post. For certain options contingency orders, the contingency involves buying or selling the underlying security (generally called ``stock'' in...

25 CFR 39.505 - What are the reporting requirements for the use of the contingency fund?

Code of Federal Regulations, 2010 CFR

2010-04-01

... contingency fund? 39.505 Section 39.505 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION THE INDIAN SCHOOL EQUALIZATION PROGRAM Contingency Fund § 39.505 What are the reporting requirements for the use of the contingency fund? (a) At the end of each fiscal year, Bureau/OIEP shall send an...

Can contingency learning alone account for item-specific control? Evidence from within- and between-language ISPC effects.

PubMed

Atalay, Nart Bedin; Misirlisoy, Mine

2012-11-01

The item-specific proportion congruence (ISPC) manipulation (Jacoby, Lindsay, & Hessels, 2003) produces larger Stroop interference for mostly congruent items than mostly incongruent items. This effect has been attributed to dynamic control over word-reading processes. However, proportion congruence of an item in the ISPC manipulation is completely confounded with response contingency, suggesting the alternative hypothesis, that the ISPC effect is a result of learning response contingencies (Schmidt & Besner, 2008). The current study asks whether the ISPC effect can be explained by a pure stimulus-response contingency-learning account, or whether other control processes play a role as well, by comparing within- and between-language conditions in a bilingual task. Experiment 1 showed that contingency learning for noncolor words was larger for the within-language than the between-language condition. Experiment 2 revealed significant ISPC effects for both within- and between-language conditions; importantly, the effect was larger in the former. The results of the contingency analyses for Experiment 2 were parallel to that of Experiment 1 and did not show an interaction between contingency and congruency. Put together, these sets of results support the view that contingency-learning processes dominate color-word ISPC effects.

Attenuation of the contingency detection effect in the extrastriate body area in autism spectrum disorder.

PubMed

Okamoto, Yuko; Kitada, Ryo; Tanabe, Hiroki C; Hayashi, Masamichi J; Kochiyama, Takanori; Munesue, Toshio; Ishitobi, Makoto; Saito, Daisuke N; Yanaka, Hisakazu T; Omori, Masao; Wada, Yuji; Okazawa, Hidehiko; Sasaki, Akihiro T; Morita, Tomoyo; Itakura, Shoji; Kosaka, Hirotaka; Sadato, Norihiro

2014-10-01

Detection of the contingency between one's own behavior and consequent social events is important for normal social development, and impaired contingency detection may be a cause of autism spectrum disorder (ASD). To depict the neural underpinnings of this contingency effect, 19 adults with ASD and 22 control participants underwent functional MRI while imitating another's actions and their actions being imitated by the other. As the extrastriate body area (EBA) receives efference copies of one's own movements, we predicted that the EBA would show an atypical response during contingency detection in ASD. We manipulated two factors: the congruency of the executed and observed actions, and the order of action execution and observation. Both groups showed the congruency effect in the bilateral EBA during imitation. When action preceded observation, the left EBA of the control group showed the congruency effect, representing the response to being imitated, indicating contingency detection. The ASD group showed a reduced contingency effect in the left EBA. These results indicate that the function of the EBA in the contingency detection is altered in ASD. Copyright © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Contingency bias in probability judgement may arise from ambiguity regarding additional causes.

PubMed

Mitchell, Chris J; Griffiths, Oren; More, Pranjal; Lovibond, Peter F

2013-09-01

In laboratory contingency learning tasks, people usually give accurate estimates of the degree of contingency between a cue and an outcome. However, if they are asked to estimate the probability of the outcome in the presence of the cue, they tend to be biased by the probability of the outcome in the absence of the cue. This bias is often attributed to an automatic contingency detection mechanism, which is said to act via an excitatory associative link to activate the outcome representation at the time of testing. We conducted 3 experiments to test alternative accounts of contingency bias. Participants were exposed to the same outcome probability in the presence of the cue, but different outcome probabilities in the absence of the cue. Phrasing the test question in terms of frequency rather than probability and clarifying the test instructions reduced but did not eliminate contingency bias. However, removal of ambiguity regarding the presence of additional causes during the test phase did eliminate contingency bias. We conclude that contingency bias may be due to ambiguity in the test question, and therefore it does not require postulation of a separate associative link-based mechanism.

Performance Evaluation of Counter-Based Dynamic Load Balancing Schemes for Massive Contingency Analysis with Different Computing Environments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Yousu; Huang, Zhenyu; Chavarría-Miranda, Daniel

Contingency analysis is a key function in the Energy Management System (EMS) to assess the impact of various combinations of power system component failures based on state estimation. Contingency analysis is also extensively used in power market operation for feasibility test of market solutions. High performance computing holds the promise of faster analysis of more contingency cases for the purpose of safe and reliable operation of today’s power grids with less operating margin and more intermittent renewable energy sources. This paper evaluates the performance of counter-based dynamic load balancing schemes for massive contingency analysis under different computing environments. Insights frommore » the performance evaluation can be used as guidance for users to select suitable schemes in the application of massive contingency analysis. Case studies, as well as MATLAB simulations, of massive contingency cases using the Western Electricity Coordinating Council power grid model are presented to illustrate the application of high performance computing with counter-based dynamic load balancing schemes.« less

Contingency Contractor Optimization Phase 3 Sustainment Software Design Document - Contingency Contractor Optimization Tool - Prototype

DOE Office of Scientific and Technical Information (OSTI.GOV)

Durfee, Justin David; Frazier, Christopher Rawls; Bandlow, Alisa

This document describes the final software design of the Contingency Contractor Optimization Tool - Prototype. Its purpose is to provide the overall architecture of the software and the logic behind this architecture. Documentation for the individual classes is provided in the application Javadoc. The Contingency Contractor Optimization project is intended to address Department of Defense mandates by delivering a centralized strategic planning tool that allows senior decision makers to quickly and accurately assess the impacts, risks, and mitigation strategies associated with utilizing contract support. The Contingency Contractor Optimization Tool - Prototype was developed in Phase 3 of the OSD ATLmore » Contingency Contractor Optimization project to support strategic planning for contingency contractors. The planning tool uses a model to optimize the Total Force mix by minimizing the combined total costs for selected mission scenarios. The model optimizes the match of personnel types (military, DoD civilian, and contractors) and capabilities to meet mission requirements as effectively as possible, based on risk, cost, and other requirements.« less

On statistical independence of a contingency matrix

NASA Astrophysics Data System (ADS)

Tsumoto, Shusaku; Hirano, Shoji

2005-03-01

A contingency table summarizes the conditional frequencies of two attributes and shows how these two attributes are dependent on each other with the information on a partition of universe generated by these attributes. Thus, this table can be viewed as a relation between two attributes with respect to information granularity. This paper focuses on several characteristics of linear and statistical independence in a contingency table from the viewpoint of granular computing, which shows that statistical independence in a contingency table is a special form of linear dependence. The discussions also show that when a contingency table is viewed as a matrix, called a contingency matrix, its rank is equal to 1.0. Thus, the degree of independence, rank plays a very important role in extracting a probabilistic model from a given contingency table. Furthermore, it is found that in some cases, partial rows or columns will satisfy the condition of statistical independence, which can be viewed as a solving process of Diophatine equations.

On the role of attention in generating explicit awareness of contingent relations: evidence from spatial priming.

PubMed

Fiacconi, Chris M; Milliken, Bruce

2011-12-01

In a series of four experiments, we examine the hypothesis that selective attention is crucial for the generation of conscious knowledge of contingency information. We investigated this question using a spatial priming task in which participants were required to localize a target letter in a probe display. In Experiment 1, participants kept track of the frequency with which the predictive letter in the prime appeared in various locations. This manipulation had a negligible impact on contingency awareness. Subsequent experiments requiring participants to attend to features (color, location) of the predictive letter increased contingency awareness somewhat, but there remained a large proportion of individuals who remained unaware of the strong contingency. Together the results of our experiments suggest that the construct of attention does not fully capture the processes that lead to contingency awareness, and suggest a critical role for bottom-up feature integration in explicit contingency learning. Copyright © 2011 Elsevier Inc. All rights reserved.

The Parallel Episodic Processing (PEP) model: dissociating contingency and conflict adaptation in the item-specific proportion congruent paradigm.

PubMed

Schmidt, James R

2013-01-01

The present work introduces a computational model, the Parallel Episodic Processing (PEP) model, which demonstrates that contingency learning achieved via simple storage and retrieval of episodic memories can explain the item-specific proportion congruency effect in the colour-word Stroop paradigm. The current work also presents a new experimental procedure to more directly dissociate contingency biases from conflict adaptation (i.e., proportion congruency). This was done with three different types of incongruent words that allow a comparison of: (a) high versus low contingency while keeping proportion congruency constant, and (b) high versus low proportion congruency while keeping contingency constant. Results demonstrated a significant contingency effect, but no effect of proportion congruence. It was further shown that the proportion congruency associated with the colour does not matter, either. Thus, the results quite directly demonstrate that ISPC effects are not due to conflict adaptation, but instead to contingency learning biases. Copyright © 2012 Elsevier B.V. All rights reserved.

Temporal dynamics of contingency extraction from tonal and verbal auditory sequences.

PubMed

Bendixen, Alexandra; Schwartze, Michael; Kotz, Sonja A

2015-09-01

Consecutive sound events are often to some degree predictive of each other. Here we investigated the brain's capacity to detect contingencies between consecutive sounds by means of electroencephalography (EEG) during passive listening. Contingencies were embedded either within tonal or verbal stimuli. Contingency extraction was measured indirectly via the elicitation of the mismatch negativity (MMN) component of the event-related potential (ERP) by contingency violations. MMN results indicate that structurally identical forms of predictability can be extracted from both tonal and verbal stimuli. We also found similar generators to underlie the processing of contingency violations across stimulus types, as well as similar performance in an active-listening follow-up test. However, the process of passive contingency extraction was considerably slower (twice as many rule exemplars were needed) for verbal than for tonal stimuli These results suggest caution in transferring findings on complex predictive regularity processing obtained with tonal stimuli directly to the speech domain. Copyright © 2014 Elsevier Inc. All rights reserved.

48 CFR 1632.770 - Contingency reserve payments.

Code of Federal Regulations, 2010 CFR

2010-10-01

... FINANCING Contract Funding 1632.770 Contingency reserve payments. (a) Payments from the contingency reserve... advise the carrier of its decision. However, OPM shall not unreasonably withhold approval for amounts...

Causal judgment from contingency information: relation between subjective reports and individual tendencies in judgment.

PubMed

White, P A

2000-04-01

In two experiments, participants made causal judgments from contingency information for problems with different objective contingencies. After the judgment task, the participants reported how their judgments had changed following each type of contingency information. Some reported idiosyncratic tendencies--in other words, tendencies contrary to those expected under associative-learning and normative rule induction models of contingency judgment. These idiosyncratic reports tended to be better predictors of the judgments of those who made them than did the models. The results are consistent with the view that causal judgment from contingency information is made, at least in part, by deliberative use of acquired and sometimes idiosyncratic notions of evidential value, the outcomes of which tend, in aggregate, to be highly correlated with the outcomes of normative procedures.

APOBEC3A Expression in Penile Squamous Cell Carcinoma.

PubMed

Heller, Martina; Prigge, Elena-Sophie; Kaczorowski, Adam; von Knebel Doeberitz, Magnus; Hohenfellner, Markus; Duensing, Stefan

2017-11-23

APOBECs (apolipoprotein B mRNA-editing catalytic polypeptides) are cytidine deaminases that have been implicated in the host defense against viruses by blocking viral replication. They have also been shown to play a role in genome hypermutation in several human cancers. An APOBEC3 hypermutation signature has been discovered in cervical cancer, which is intimately associated with infection by high-risk human papillomaviruses (HPVs). At the same time, HPV genomes themselves are subject to DNA editing by APOBECs. Similar to cervical cancer, a proportion of penile squamous cell carcinomas (SCCs) is etiologically driven by high-risk HPVs, but very little is known about the role of APOBECs in penile SCC development and progression. A series of 34 penile SCCs was analyzed for the expression of APOBEC3A protein by immunohistochemistry. HPV genotyping was carried out using a bead-based multiplex hybridization assay preceded by BSGP5+6+ primer-based amplification. We found a frequent reduction of APOBEC3A protein expression in the invasive parts of the majority of HPV-negative penile SCCs. In contrast, the majority of HPV-positive penile SCCs retained APOBEC3A expression during malignant progression. Our results suggest that APOBEC3A expression is downregulated during progression towards invasiveness in HPV-negative penile SCC, but maintained in HPV-positive penile SCC. How high-risk HPV-infected tumor cells tolerate high APOBEC3A, which appears to exert tumor suppressive functions in HPV-negative penile SCCs, remains to be elucidated. © 2017 S. Karger AG, Basel.

Examination of Msh6- and Msh3-deficient mice in class switching reveals overlapping and distinct roles of MutS homologues in antibody diversification.

PubMed

Li, Ziqiang; Scherer, Stefan J; Ronai, Diana; Iglesias-Ussel, Maria D; Peled, Jonathan U; Bardwell, Philip D; Zhuang, Min; Lee, KyeRyoung; Martin, Alberto; Edelmann, Winfried; Scharff, Matthew D

2004-07-05

Somatic hypermutation and class switch recombination (CSR) contribute to the somatic diversification of antibodies. It has been shown that MutS homologue (Msh)6 (in conjunction with Msh2) but not Msh3 is involved in generating A/T base substitutions in somatic hypermutation. However, their roles in CSR have not yet been reported. Here we show that Msh6(-)(/)(-) mice have a decrease in CSR, whereas Msh3(-)(/)(-) mice do not. When switch regions were analyzed for mutations, deficiency in Msh6 was associated with an increase in transition mutations at G/C basepairs, mutations at RGYW/WRCY hotspots, and a small increase in the targeting of G/C bases. In addition, Msh6(-)(/)(-) mice exhibited an increase in the targeting of recombination sites to GAGCT/GGGGT consensus repeats and hotspots in Sgamma3 but not in Smicro. In contrast to Msh2(-)(/)(-) mice, deficiency in Msh6 surprisingly did not change the characteristics of Smicro-Sgamma3 switch junctions. However, Msh6(-)(/)(-) mice exhibited a change in the positioning of Smicro and Sgamma3 junctions. Although none of these changes were seen in Msh3(-)(/)(-) mice, they had a higher percentage of large inserts in their switch junctions. Together, our data suggest that MutS homologues Msh2, Msh3, and Msh6 play overlapping and distinct roles during antibody diversification processes.

[B lymphocyte clonal evolution of human reactive lymph nodes revealed by lineage tree analysis].

PubMed

Tabibian-Keissar, Hilla; Schiby, Ginette; Azogui-Rosenthal, Noemie; Hazanov, Helena; Rakovsky, Aviya Shapira; Michaeli, Miri; Rosenblatt, Kinneret; Mehr, Ramit; Barshack, Iris

2013-06-01

Hypermutation and selection processes, characterizing T-dependent B cell responses taking place in germinal centers of lymph nodes, lead to B cell receptor affinity maturation. Those immune responses lead to the development of memory B cells and plasma cells that secrete high amounts of antibody molecules. The dynamics of B cell clonal evolution during affinity maturation has significant importance in infectious and autoimmune diseases, malignancies and aging. Immunoglobulin (Ig) gene mutational Lineage tree construction by comparing variable regions of Ig-gene sequences to the Ig germline gene is an interesting approach for studying B cell cLonal evolution. Lineage tree shapes and Ig gene mutations can be evaluated not only qualitatively and intuitively, but also quantitatively, and thus reveal important information related to hypermutation and selection. In this paper we describe the experimental protocols that we used for PCR amplification of Igvariable region genes from human formalin fixed paraffin embedded reactive lymph node tissues and the subsequent bioinformatical analyses of sequencing data using Ig mutational lineage trees. B cell populations of three out of four reactive Lymph node tissues were composed of several clones. Most of the Ig gene mutational lineage trees were small and narrow. Significant differences were not detected by quantification of Lineage trees. B lymphocyte clones that were detected in human reactive lymph node tissues represent major responding clones in normal polyclonal immune response. This result is in line with the polyclonal profile of B Lymphocyte populations that reside in reactive lymph node tissues.

Evidence that selected amplification of a bacterial lac frameshift allele stimulates Lac(+) reversion (adaptive mutation) with or without general hypermutability.

PubMed Central

Slechta, E Susan; Liu, Jing; Andersson, Dan I; Roth, John R

2002-01-01

In the genetic system of Cairns and Foster, a nongrowing population of an E. coli lac frameshift mutant appears to specifically accumulate Lac(+) revertants when starved on medium including lactose (adaptive mutation). This behavior has been attributed to stress-induced general mutagenesis in a subpopulation of starved cells (the hypermutable state model). We have suggested that, on the contrary, stress has no direct effect on mutability but favors only growth of cells that amplify their leaky mutant lac region (the amplification mutagenesis model). Selection enhances reversion primarily by increasing the mutant lac copy number within each developing clone on the selection plate. The observed general mutagenesis is attributed to a side effect of growth with an amplification-induction of SOS by DNA fragments released from a tandem array of lac copies. Here we show that the S. enterica version of the Cairns system shows SOS-dependent general mutagenesis and behaves in every way like the original E. coli system. In both systems, lac revertants are mutagenized during selection. Eliminating the 35-fold increase in mutation rate reduces revertant number only 2- to 4-fold. This discrepancy is due to continued growth of amplification cells until some clones manage to revert without mutagenesis solely by increasing their lac copy number. Reversion in the absence of mutagenesis is still dependent on RecA function, as expected if it depends on lac amplification (a recombination-dependent process). These observations support the amplification mutagenesis model. PMID:12136002

5' Rapid Amplification of cDNA Ends and Illumina MiSeq Reveals B Cell Receptor Features in Healthy Adults, Adults With Chronic HIV-1 Infection, Cord Blood, and Humanized Mice.

PubMed

Waltari, Eric; Jia, Manxue; Jiang, Caroline S; Lu, Hong; Huang, Jing; Fernandez, Cristina; Finzi, Andrés; Kaufmann, Daniel E; Markowitz, Martin; Tsuji, Moriya; Wu, Xueling

2018-01-01

Using 5' rapid amplification of cDNA ends, Illumina MiSeq, and basic flow cytometry, we systematically analyzed the expressed B cell receptor (BCR) repertoire in 14 healthy adult PBMCs, 5 HIV-1+ adult PBMCs, 5 cord blood samples, and 3 HIS-CD4/B mice, examining the full-length variable region of μ, γ, α, κ, and λ chains for V-gene usage, somatic hypermutation (SHM), and CDR3 length. Adding to the known repertoire of healthy adults, Illumina MiSeq consistently detected small fractions of reads with high mutation frequencies including hypermutated μ reads, and reads with long CDR3s. Additionally, the less studied IgA repertoire displayed similar characteristics to that of IgG. Compared to healthy adults, the five HIV-1 chronically infected adults displayed elevated mutation frequencies for all μ, γ, α, κ, and λ chains examined and slightly longer CDR3 lengths for γ, α, and λ. To evaluate the reconstituted human BCR sequences in a humanized mouse model, we analyzed cord blood and HIS-CD4/B mice, which all lacked the typical SHM seen in the adult reference. Furthermore, MiSeq revealed identical unmutated IgM sequences derived from separate cell aliquots, thus for the first time demonstrating rare clonal members of unmutated IgM B cells by sequencing.

HIV-1 Vif can directly inhibit apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G-mediated cytidine deamination by using a single amino acid interaction and without protein degradation.

PubMed

Santa-Marta, Mariana; da Silva, Frederico Aires; Fonseca, Ana Margarida; Goncalves, Joao

2005-03-11

The human apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G), also known as CEM-15, is a host-cell factor involved in innate resistance to retroviral infection. HIV-1 viral infectivity factor (Vif) protein was shown to protect the virus from APOBEC3G-mediated viral cDNA hypermutation. The mechanism proposed for protection of the virus by HIV-1 Vif is mediated by APOBEC3G degradation through ubiquitination and the proteasomal pathway. Here we show that in Escherichia coli the APOBEC3G-induced cytidine deamination is inhibited by expression of Vif without depletion of deaminase. Moreover, inhibition of deaminase-mediated bacterial hypermutation is dependent on a single amino acid substitution D128K that renders APOBEC3G resistant to Vif inhibition. This single amino acid was elegantly proven by other authors to determine species-specific sensitivity. Our results show that in bacteria this single amino acid substitution controls Vif-dependent blocking of APOBEC3G that is dependent on a strong protein interaction. The C-terminal region of Vif is responsible for this strong protein-protein interaction. In conclusion, our experiments suggest a complement to the model of Vif-induced degradation of APOBEC3G by bringing to relevance that deaminase inhibition can also result from a direct interaction with Vif protein.

Temporal contingency.

PubMed

Gallistel, C R; Craig, Andrew R; Shahan, Timothy A

2014-01-01

Contingency, and more particularly temporal contingency, has often figured in thinking about the nature of learning. However, it has never been formally defined in such a way as to make it a measure that can be applied to most animal learning protocols. We use elementary information theory to define contingency in such a way as to make it a measurable property of almost any conditioning protocol. We discuss how making it a measurable construct enables the exploration of the role of different contingencies in the acquisition and performance of classically and operantly conditioned behavior. Copyright © 2013 Elsevier B.V. All rights reserved.

A randomized study of contingency management and spirometric lung age for motivating smoking cessation among injection drug users.

PubMed

Drummond, Michael B; Astemborski, Jacquie; Lambert, Allison A; Goldberg, Scott; Stitzer, Maxine L; Merlo, Christian A; Rand, Cynthia S; Wise, Robert A; Kirk, Gregory D

2014-07-28

Even after quitting illicit drugs, tobacco abuse remains a major cause of morbidity and mortality in former injection drug users. An important unmet need in this population is to have effective interventions that can be used in the context of community based care. Contingency management, where a patient receives a monetary incentive for healthy behavior choices, and incorporation of individual counseling regarding spirometric "lung age" (the age of an average healthy individual with similar spirometry) have been shown to improve cessation rates in some populations. The efficacy of these interventions on improving smoking cessation rates has not been studied among current and former injection drug users. In a randomized, factorial design study, we recruited 100 active smokers from an ongoing cohort study of current and former injection drug users to assess the impact of contingency management and spirometric lung age on smoking cessation. The primary outcome was 6-month biologically-confirmed smoking cessation comparing contingency management, spirometric lung age or both to usual care. Secondary outcomes included differences in self-reported and biologically-confirmed cessation at interim visits, number of visits attended and quit attempts, smoking rates at interim visits, and changes in Fagerstrom score and self-efficacy. Six-month biologically-confirmed smoking cessations rates were 4% usual care, 0% lung age, 14% contingency management and 0% for combined lung age and contingency management (p = 0.13). There were no differences in secondary endpoints comparing the four interventions or when pooling the lung age groups. Comparing contingency management to non-contingency management, 6-month cessation rates were not different (7% vs. 2%; p = 0.36), but total number of visits with exhaled carbon monoxide-confirmed abstinence were higher for contingency management than non-contingency management participants (0.38 vs. 0.06; p = 0.03), and more contingency management participants showed reduction in their Fagerstrom score from baseline to follow-up (39% vs. 18%; p = 0.03). While lung age appeared ineffective, contingency management was associated with more short-term abstinence and lowered nicotine addiction. Contingency management may be a useful tool in development of effective tobacco cessation strategies among current and former injection drug users. Clinicaltrials.gov NCT01334736 (April 12, 2011).

25 CFR 39.504 - May schools carry over contingency funds to a subsequent fiscal year?

Code of Federal Regulations, 2012 CFR

2012-04-01

... 25 Indians 1 2012-04-01 2011-04-01 true May schools carry over contingency funds to a subsequent fiscal year? 39.504 Section 39.504 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION THE INDIAN SCHOOL EQUALIZATION PROGRAM Contingency Fund § 39.504 May schools carry over contingency funds to a subsequent fiscal year?...

25 CFR 39.504 - May schools carry over contingency funds to a subsequent fiscal year?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 25 Indians 1 2011-04-01 2011-04-01 false May schools carry over contingency funds to a subsequent fiscal year? 39.504 Section 39.504 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION THE INDIAN SCHOOL EQUALIZATION PROGRAM Contingency Fund § 39.504 May schools carry over contingency funds to a subsequent fiscal year?...

25 CFR 39.504 - May schools carry over contingency funds to a subsequent fiscal year?

Code of Federal Regulations, 2013 CFR

2013-04-01

... 25 Indians 1 2013-04-01 2013-04-01 false May schools carry over contingency funds to a subsequent fiscal year? 39.504 Section 39.504 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION THE INDIAN SCHOOL EQUALIZATION PROGRAM Contingency Fund § 39.504 May schools carry over contingency funds to a subsequent fiscal year?...

25 CFR 39.504 - May schools carry over contingency funds to a subsequent fiscal year?

Code of Federal Regulations, 2014 CFR

2014-04-01

... 25 Indians 1 2014-04-01 2014-04-01 false May schools carry over contingency funds to a subsequent fiscal year? 39.504 Section 39.504 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION THE INDIAN SCHOOL EQUALIZATION PROGRAM Contingency Fund § 39.504 May schools carry over contingency funds to a subsequent fiscal year?...

Defense Infrastructure: Actions Needed to Enhance Oversight of Construction Projects Supporting Military Contingency Operations

DTIC Science & Technology

2016-09-01

unneeded to support U.S. forces in the CENTCOM area of responsibility and in future contingencies worldwide. View GAO-16-406. For more information...DEFENSE INFRASTRUCTURE Actions Needed to Enhance Oversight of Construction Projects Supporting Military Contingency ...Actions Needed to Enhance Oversight of Construction Projects Supporting Military Contingency Operations Why GAO Did This Study For about 15 years, DOD

Contingency management for patients with dual disorders in intensive outpatient treatment for addiction.

PubMed

Kelly, Thomas M; Daley, Dennis C; Douaihy, Antoine B

2014-01-01

This quality improvement program evaluation investigated the effectiveness of contingency management for improving retention in treatment and positive outcomes among patients with dual disorders in intensive outpatient treatment for addiction. The effect of contingency management was explored among a group of 160 patients exposed to contingency management (n = 88) and not exposed to contingency management (no contingency management, n = 72) in a six-week partial hospitalization program. Patients referred to the partial hospitalization program for treatment of substance use and comorbid psychiatric disorders received diagnoses from psychiatrists and specialist clinicians according to the Diagnostic and Statistical Manual of the American Psychiatric Association. A unique application of the contingency management "fishbowl" method was used to improve the consistency of attendance at treatment sessions, which patients attended 5 days a week. Days attending treatment and drug-free days were the main outcome variables. Other outcomes of interest were depression, anxiety and psychological stress, coping ability, and intensity of drug cravings. Patients in the contingency management group attended more treatment days compared to patients in the no contingency management group; M = 16.2 days (SD = 10.0) versus M = 9.9 days (SD = 8.5), respectively; t = 4.2, df = 158, p <.001. No difference was found between the treatment groups on number of drug-free days. Psychological stress and drug craving were inversely associated with drug-free days in bivariate testing (r = -.18, p <.02; r = -.31, p <.001, respectively). Treatment days attended and drug craving were associated with drug-free days in multivariate testing (B =.05, SE =.01, β =.39, t = 4.9, p <.001; B = -.47; SE =.12, β = -.30, t = -3.9, p <.001, respectively; Adj. R(2) =.21). Days attending treatment partially mediated the relationship between exposure to contingency management and self-reported drug-free days. Contingency management is a valuable adjunct for increasing retention in treatment among patients with dual disorders in partial hospitalization treatment. Exposure to contingency management increases retention in treatment, which in turn contributes to increased drug-free days. Interventions for coping with psychological stress and drug cravings should be emphasized in intensive dual diagnosis group therapy.

A systems view of mother-infant face-to-face communication.

PubMed

Beebe, Beatrice; Messinger, Daniel; Bahrick, Lorraine E; Margolis, Amy; Buck, Karen A; Chen, Henian

2016-04-01

Principles of a dynamic, dyadic systems view of mother-infant face-to-face communication, which considers self- and interactive processes in relation to one another, were tested. The process of interaction across time in a large low-risk community sample at infant age 4 months was examined. Split-screen videotape was coded on a 1-s time base for communication modalities of attention, affect, orientation, touch, and composite facial-visual engagement. Time-series approaches generated self- and interactive contingency estimates in each modality. Evidence supporting the following principles was obtained: (a) Significant moment-to-moment predictability within each partner (self-contingency) and between the partners (interactive contingency) characterizes mother-infant communication. (b) Interactive contingency is organized by a bidirectional, but asymmetrical, process: Maternal contingent coordination with infant is higher than infant contingent coordination with mother. (c) Self-contingency organizes communication to a far greater extent than interactive contingency. (d) Self- and interactive contingency processes are not separate; each affects the other in communication modalities of facial affect, facial-visual engagement, and orientation. Each person's self-organization exists in a dynamic, homoeostatic (negative feedback) balance with the degree to which the person coordinates with the partner. For example, those individuals who are less facially stable are likely to coordinate more strongly with the partner's facial affect and vice versa. Our findings support the concept that the dyad is a fundamental unit of analysis in the investigation of early interaction. Moreover, an individual's self-contingency is influenced by the way the individual coordinates with the partner. Our results imply that it is not appropriate to conceptualize interactive processes without simultaneously accounting for dynamically interrelated self-organizing processes. (c) 2016 APA, all rights reserved).

A Systems View of Mother-Infant Face-to-Face Communication

PubMed Central

Beebe, Beatrice; Messinger, Daniel; Bahrick, Lorraine E.; Margolis, Amy; Buck, Karen A.; Chen, Henian

2016-01-01

Principles of a dynamic, dyadic systems view of mother-infant face-to-face communication, which considers self- and interactive processes in relation to one another, were tested. We examined the process of interaction across time in a large, low-risk community sample, at infant age 4 months. Split-screen videotape was coded on a 1-s time base for communication modalities of attention, affect, orientation, touch and composite facial-visual engagement. Time-series approaches generated self- and interactive contingency estimates in each modality. Evidence supporting the following principles was obtained: (1) Significant moment-to-moment predictability within each partner (self-contingency) and between the partners (interactive contingency) characterizes mother-infant communication. (2) Interactive contingency is organized by a bi-directional, but asymmetrical, process: maternal contingent coordination with infant is higher than infant contingent coordination with mother. (3) Self-contingency organizes communication to a far greater extent than interactive contingency. (4) Self-and interactive contingency processes are not separate; each affects the other, in communication modalities of facial affect, facial-visual engagement, and orientation. Each person’s self-organization exists in a dynamic, homoeostatic (negative feedback) balance with the degree to which the person coordinates with the partner. For example, those individuals who are less facially stable are likely to coordinate more strongly with the partner’s facial affect; and vice-versa. Our findings support the concept that the dyad is a fundamental unit of analysis in the investigation of early interaction. Moreover, an individual’s self-contingency is influenced by the way the individual coordinates with the partner. Our results imply that it is not appropriate to conceptualize interactive processes without simultaneously accounting for dynamically inter-related self-organizing processes. PMID:26882118

Resurgence of instrumental behavior after an abstinence contingency.

PubMed

Bouton, Mark E; Schepers, Scott T

2014-06-01

In resurgence, an extinguished instrumental behavior (R1) recovers when a behavior that has replaced it (R2) is also extinguished. The phenomenon may be relevant to understanding relapse that can occur after the termination of "contingency management" treatments, in which an unwanted behavior (e.g., substance abuse) is reduced by reinforcing an alternative behavior. When reinforcement is discontinued, the unwanted behavior might resurge. However, unlike most resurgence experiments, contingency management treatments also introduce a negative contingency, in which reinforcers are not delivered unless the client has abstained from the unwanted behavior. In two experiments with rats, we therefore examined the effects of adding a negative "abstinence" contingency to the resurgence design. During response elimination, R2 was not reinforced unless R1 had not been emitted for a minimum period of time (45, 90, or 135 s). In both experiments, adding such a contingency to simple R1 extinction reduced, but did not eliminate, resurgence. In Experiment 2, we found the same effect in a yoked group that could earn reinforcers for R2 at the same points in time as the negative-contingency group, but without the requirement to abstain from R1. Thus, the negative contingency per se did not contribute to the reduction in resurgence. These results suggest that the contingency reduced resurgence by making reinforcers more difficult to earn and more widely spaced in time. This could have allowed the animal to learn that R1 was extinguished in the "context" of infrequent reinforcement-a context more like that of resurgence testing. The results are thus consistent with a contextual (renewal) account of resurgence. The method might provide a better model of relapse after termination of a contingency management treatment.

14 CFR 431.39 - Mission rules, procedures, contingency plans, and checklists.

Code of Federal Regulations, 2012 CFR

2012-01-01

... mission rules, procedures, checklists, emergency plans, and contingency abort plans, if any, that ensure..., procedures, checklists, emergency plans, and contingency abort plans must be contained in a safety directive...

14 CFR 431.39 - Mission rules, procedures, contingency plans, and checklists.

Code of Federal Regulations, 2014 CFR

2014-01-01

... mission rules, procedures, checklists, emergency plans, and contingency abort plans, if any, that ensure..., procedures, checklists, emergency plans, and contingency abort plans must be contained in a safety directive...

14 CFR 431.39 - Mission rules, procedures, contingency plans, and checklists.

Code of Federal Regulations, 2013 CFR

2013-01-01

... mission rules, procedures, checklists, emergency plans, and contingency abort plans, if any, that ensure..., procedures, checklists, emergency plans, and contingency abort plans must be contained in a safety directive...

Contingency Theories of Leadership: A Study.

ERIC Educational Resources Information Center

Saha, Sunhir K.

1979-01-01

Some of the major contingency theories of leadership are reviewed; some results from the author's study of Fiedler's contingency model are reported; and some thoughts for the future of leadership research are provided. (Author/MLF)

Extended child and caregiver benefits of behavior-based child contingency learning games.

PubMed

Dunst, Carl J; Raab, Melinda; Trivette, Carol M; Wilson, Linda L; Hamby, Deborah W; Parkey, Cindy

2010-08-01

Findings from 2 studies of the relationship between response-contingent child behavior and child, caregiver-child, and caregiver behavior not directly associated with child contingency learning are described. The participants were 19 children with significant developmental delays and their mothers in 1 study and 22 children with significant developmental delays and their teachers in the second study. Caregivers engaged the children in learning games characterized by behavior-based contingencies for 15 weeks. Research staff observed the children and their caregivers in everyday routines and activities and rated child and caregiver behavior while the children and caregivers were not playing the games. Results from both studies showed that the degree of response-contingent responding during the games was related to child and caregiver behavior, not the focus of the contingency learning opportunities afforded the children. Implications for practice are described.

Body Image Concerns and Contingent Self-Esteem in Male and Female College Students

PubMed Central

Lee, Christine M.; Neighbors, Clayton; Larimer, Mary E.

2017-01-01

Body dissatisfaction in females, and to a lesser extent males, is associated with low self-esteem, depression, and eating disorders. This research examined gender as a moderator of the association between contingent self-esteem and body image concerns, including weight and muscularity. Participants included 359 (59.1% female) heavy drinking first-year U.S. undergraduate students who completed a survey assessing health-related risk behaviors. Hierarchical multiple regression was used to examine relations among gender, contingent self-esteem, and body image. Females reported higher levels of contingent self-esteem and greater concerns about their weight, although males reported a greater drive for muscularity. The relationship between contingent self-esteem and weight concerns was stronger among females, and for males, greater contingent self-esteem was associated with a greater drive for muscularity. PMID:28959088

Relationship contingency and sexual motivation in women: implications for sexual satisfaction.

PubMed

Sanchez, Diana T; Moss-Racusin, Corinne A; Phelan, Julie E; Crocker, Jennifer

2011-02-01

Deriving self-worth from romantic relationships (relationship contingency) may have implications for women's sexual motives in relationships. Because relationship contingency enhances motivation to sustain relationships to maintain positive self-worth, relationship contingent women may engage in sex to maintain and enhance their relationships (relational sex motives). Using structural equation modeling on Internet survey data from a convenience sample of 462 women in heterosexual and lesbian relationships, we found that greater relationship contingency predicted greater relational sex motives, which simultaneously predicted both sexual satisfaction and dissatisfaction via two distinct motivational states. Having sex to improve intimacy with one's partner was associated with greater sexual satisfaction and autonomy, while having sex to earn partner's approval was associated with sexual dissatisfaction and inhibition. While some differences exist between lesbian and heterosexual relationships, relationship contingency had sexual costs and benefits, regardless of relationship type.

Betting on the future: the virtues of contingent contracts.

PubMed

Bazerman, M H; Gillespie, J J

1999-01-01

It happens all the time. Two parties with common interests fail to reach an agreement--about a sale, a merger, a technology transfer--because they have different expectations about the future. They are both so confident in their prediction, or so suspicious of the other side's motives, that they refuse to compromise. Such impasses are hard to break through. Fortunately, they can often be avoided altogether by using a straightforward but frequently overlooked type of agreement called a contingent contract. The terms of a contingent contract are not finalized until the uncertain event in question--the contingency--takes place. In some areas of business, such as compensation, contingent contracts are common: a CEO's pay is tied to the company's stock price, for instance. But in many business negotiations, contingent contracts are either ignored or rejected out of hand. That's mistake, according to the authors. In an increasingly uncertain world, flexible contingent contracts can actually be more rational and less risky than rigid, traditional ones. In particular, contingent contracts offer six benefits: they enable a difference of opinion to become the basis of an agreement, not an obstacle to it; they cancel out the biases of negotiators; they level the playing field by reducing the impact of asymmetric information; they provide a means of uncovering deceitful dealings; they reduce risk by sharing it among parties; and they motivate parties to fulfill their promises. While contingent contracts are not appropriate in all instances, they are much more broadly applicable than managers may think.

Flexibility to contingency changes distinguishes habitual and goal-directed strategies in humans

PubMed Central

Keramati, Mehdi

2017-01-01

Decision-making in the real world presents the challenge of requiring flexible yet prompt behavior, a balance that has been characterized in terms of a trade-off between a slower, prospective goal-directed model-based (MB) strategy and a fast, retrospective habitual model-free (MF) strategy. Theory predicts that flexibility to changes in both reward values and transition contingencies can determine the relative influence of the two systems in reinforcement learning, but few studies have manipulated the latter. Therefore, we developed a novel two-level contingency change task in which transition contingencies between states change every few trials; MB and MF control predict different responses following these contingency changes, allowing their relative influence to be inferred. Additionally, we manipulated the rate of contingency changes in order to determine whether contingency change volatility would play a role in shifting subjects between a MB and MF strategy. We found that human subjects employed a hybrid MB/MF strategy on the task, corroborating the parallel contribution of MB and MF systems in reinforcement learning. Further, subjects did not remain at one level of MB/MF behaviour but rather displayed a shift towards more MB behavior over the first two blocks that was not attributable to the rate of contingency changes but rather to the extent of training. We demonstrate that flexibility to contingency changes can distinguish MB and MF strategies, with human subjects utilizing a hybrid strategy that shifts towards more MB behavior over blocks, consequently corresponding to a higher payoff. PMID:28957319

Flexibility to contingency changes distinguishes habitual and goal-directed strategies in humans.

PubMed

Lee, Julie J; Keramati, Mehdi

2017-09-01

Decision-making in the real world presents the challenge of requiring flexible yet prompt behavior, a balance that has been characterized in terms of a trade-off between a slower, prospective goal-directed model-based (MB) strategy and a fast, retrospective habitual model-free (MF) strategy. Theory predicts that flexibility to changes in both reward values and transition contingencies can determine the relative influence of the two systems in reinforcement learning, but few studies have manipulated the latter. Therefore, we developed a novel two-level contingency change task in which transition contingencies between states change every few trials; MB and MF control predict different responses following these contingency changes, allowing their relative influence to be inferred. Additionally, we manipulated the rate of contingency changes in order to determine whether contingency change volatility would play a role in shifting subjects between a MB and MF strategy. We found that human subjects employed a hybrid MB/MF strategy on the task, corroborating the parallel contribution of MB and MF systems in reinforcement learning. Further, subjects did not remain at one level of MB/MF behaviour but rather displayed a shift towards more MB behavior over the first two blocks that was not attributable to the rate of contingency changes but rather to the extent of training. We demonstrate that flexibility to contingency changes can distinguish MB and MF strategies, with human subjects utilizing a hybrid strategy that shifts towards more MB behavior over blocks, consequently corresponding to a higher payoff.

Pershing in Mexico: a case study in limited contingency operations

DTIC Science & Technology

2016-05-26

Pershing in Mexico: A Case Study in Limited Contingency Operations A Monograph by MAJ Timothy J. Lawrence United States Army School...DATE (00-MM-YYYY) REPORT TYPE 12. 31-03-2016 SAMS Monograph 4. TITLE AND SUBTITLE Pershing in Mexico: A Case Study in Limited Contingency Operations...Monograph Approval Page Name of Candidate: MAJ Timothy J. Lawrence Monograph Title: Pershing in Mexico: A Case Study in Limited Contingency Operations

Overseas Contingency Operations Funding: Background and Status

DTIC Science & Technology

2017-02-07

emergency” or “Overseas Contingency Operation/ Global War on Terror” (OCO/GWOT) requirement in annual agency budget requests—or both. Funds designated as...to be excluded from budget control limits. The BCA added the designation “Overseas Contingency Operation/ Global War on Terror” to the BBEDCA...been largely provided through supplemental appropriation acts or has been designated as an “emergency” or “overseas contingency operation/ global war on

Evaluating and Comparing the Effects of Group Contingencies on Mathematics Accuracy in a First-Grade Classroom: Class Average Criteria versus Unknown Small-Group Average Criteria

ERIC Educational Resources Information Center

Scott, Katelyn C.; Skinner, Christopher H.; Moore, Tara C.; McCurdy, Merilee; Ciancio, Dennis; Cihak, David F.

2017-01-01

An adapted alternating treatments design was used to evaluate and compare the effects of two group contingency interventions on mathematics assignment accuracy in an intact first-grade classroom. Both an interdependent contingency with class-average criteria (16 students) and a dependent contingency with criteria based on the average of a smaller,…

45 CFR 264.71 - What determines the amount of the provisional payment of contingency funds that will be made to a...

Code of Federal Regulations, 2010 CFR

2010-10-01

... payment of contingency funds that will be made to a State? 264.71 Section 264.71 Public Welfare... Requirements for the Contingency Fund? § 264.71 What determines the amount of the provisional payment of contingency funds that will be made to a State? We will make a provisional payment to a State that meets the...

Effects of contingent self-esteem on depressive symptoms and suicidal behavior.

PubMed

Lakey, Chad E; Hirsch, Jameson K; Nelson, Lyndsay A; Nsamenang, Sheri A

2014-01-01

Contingent self-esteem, or self-worth hinged upon successfully meeting standards or attaining goals, requires continual maintenance and validation. Despite the inherent instability that accompanies contingent self-esteem, relatively little is known about how it relates to markers of mental health. A sample of 371 college students completed measures of self-esteem, contingent self-esteem, suicidal behaviors, and depression. Individuals with fragile low self-esteem, described as highly contingent, reported greater depressive symptoms and suicidal behavior. Among those with secure high self-esteem, or high yet noncontingent, depression and suicide risk were markedly lower. Therapeutically promoting positive but noncontingent self-worth may reduce poor mental health outcomes.

Sample size, confidence, and contingency judgement.

PubMed

Clément, Mélanie; Mercier, Pierre; Pastò, Luigi

2002-06-01

According to statistical models, the acquisition function of contingency judgement is due to confidence increasing with sample size. According to associative models, the function reflects the accumulation of associative strength on which the judgement is based. Which view is right? Thirty university students assessed the relation between a fictitious medication and a symptom of skin discoloration in conditions that varied sample size (4, 6, 8 or 40 trials) and contingency (delta P = .20, .40, .60 or .80). Confidence was also collected. Contingency judgement was lower for smaller samples, while confidence level correlated inversely with sample size. This dissociation between contingency judgement and confidence contradicts the statistical perspective.

An analysis of contingency statements in a DRO procedure: A case report.

PubMed

Gerow, Stephanie; Rispoli, Mandy; Boles, Margot B; Neely, Leslie C

2015-06-01

To examine latency to criterion for reduction of challenging behaviour with and without stating a contingency statement immediately prior to a DRO procedure. An ABAC design in which A was baseline, B was used to evaluate the efficacy of a DRO procedure, and C was used to evaluate the efficacy of a DRO procedure with a contingency statement. The DRO with the contingency statement intervention was associated with a shorter latency to behaviour change than the DRO procedure without the contingency statement. These preliminary findings from this case study highlight the importance of examining the efficiency of behaviour change procedures. Directions for future research are provided.

Appendix F - Sample Contingency Plan

EPA Pesticide Factsheets

This sample Contingency Plan in Appendix F is intended to provide examples of contingency planning as a reference when a facility determines that the required secondary containment is impracticable, pursuant to 40 CFR §112.7(d).

Contingent Faculty as Nonideal Workers

ERIC Educational Resources Information Center

Kezar, Adrianna; Bernstein-Sierra, Samantha

2016-01-01

This chapter explores how contingent faculty address the issue of work and family and demonstrates the importance of understanding the diversity of contingent faculty experiences and of underemployment rather than notions of the ideal worker to explain their work lives.

Hypersensitivity to Contingent Behavior in Paranoia: A New Virtual Reality Paradigm.

PubMed

Fornells-Ambrojo, Miriam; Elenbaas, Maaike; Barker, Chris; Swapp, David; Navarro, Xavier; Rovira, Aitor; Sanahuja, Josep Maria Tomàs; Slater, Mel

2016-02-01

Contingency in interpersonal relationships is associated with the development of secure attachment and trust, whereas paranoia arises from the overattribution of negative intentions. We used a new virtual reality paradigm to experimentally investigate the impact of contingent behavior on trust along the paranoia continuum. Sixty-one healthy participants were randomly allocated to have a social interaction with a pleasant virtual human (avatar) programmed to be highly responsive or not (high/low contingency). Perceived trustworthiness and trusting behavior were assessed alongside control variables attachment and anxiety. Higher paranoia and dismissive attachment were associated with larger interpersonal distances. Unexpectedly, extremely paranoid individuals experienced the highly contingent avatar as more trustworthy than their low contingency counterpart. Higher dismissive attachment was also associated with more subjective trust in both conditions. Extreme paranoia is associated with hypersensitivity to noncontingent behavior, which might explain experiences of mistrust when others are not highly responsive in everyday social situations.

Contingency blindness: location-identity binding mismatches obscure awareness of spatial contingencies and produce profound interference in visual working memory.

PubMed

Fiacconi, Chris M; Milliken, Bruce

2012-08-01

The purpose of the present study was to highlight the role of location-identity binding mismatches in obscuring explicit awareness of a strong contingency. In a spatial-priming procedure, we introduced a high likelihood of location-repeat trials. Experiments 1, 2a, and 2b demonstrated that participants' explicit awareness of this contingency was heavily influenced by the local match in location-identity bindings. In Experiment 3, we sought to determine why location-identity binding mismatches produce such low levels of contingency awareness. Our results suggest that binding mismatches can interfere substantially with visual-memory performance. We attribute the low levels of contingency awareness to participants' inability to remember the critical location-identity binding in the prime on a trial-to-trial basis. These results imply a close interplay between object files and visual working memory.

Collectivists' contingency and autonomy as predictors of buffet preferences among Taiwanese adolescents.

PubMed

Chiou, Wen-Bin

2006-01-01

In a culture or society with high collectivism, contingent orientation and constrained autonomy are the prominent characteristics of adolescents' self-construal. This article examined whether Taiwanese adolescents' contingency and autonomy were associated with their prevalent preferences for buffet consumption. Findings in a panel survey indicated that contingency was positively correlated with adolescents' buffet preference, whereas autonomy was negatively correlated. Moreover, the results showed that adolescents' contingent orientation and perceived autonomy could predict their subsequent buffet preference over a half-year period. A laboratory experiment showed that adolescents who perceived lower autonomy exhibited greater preferences for buffet over the other diet consumption. In general, the results suggest that collectivist adolescents' contingency and autonomy were related to their trait-like preferences for buffet, and the state-like preferences for buffet were affected by their perceived levels of autonomy. Findings provide further insights into the impact of adolescents' self-construal on their diet consumption.

Fear expression and return of fear following threat instruction with or without direct contingency experience.

PubMed

Mertens, Gaëtan; Kuhn, Manuel; Raes, An K; Kalisch, Raffael; De Houwer, Jan; Lonsdorf, Tina B

2016-08-01

Prior research showed that mere instructions about the contingency between a conditioned stimulus (CS) and an unconditioned stimulus (US) can generate fear reactions to the CS. Little is known, however, about the extent to which actual CS-US contingency experience adds anything beyond the effect of contingency instructions. Our results extend previous studies on this topic in that it included fear potentiated startle as an additional dependent variable and examined return of fear (ROF) following reinstatement. We observed that CS-US pairings can enhance fear reactions beyond the effect of contingency instructions. Moreover, for all measures of fear, instructions elicited immediate fear reactions that could not be completely overridden by subsequent situational safety information. Finally, ROF following reinstatement for instructed CS+s was unaffected by actual experience. In summary, our results demonstrate the power of contingency instructions and reveal the additional impact of actual experience of CS-US pairings.

Identifying Contingency Requirements using Obstacle Analysis on an Unpiloted Aerial Vehicle

NASA Technical Reports Server (NTRS)

Lutz, Robyn R.; Nelson, Stacy; Patterson-Hine, Ann; Frost, Chad R.; Tal, Doron

2005-01-01

This paper describes experience using Obstacle Analysis to identify contingency requirements on an unpiloted aerial vehicle. A contingency is an operational anomaly, and may or may not involve component failure. The challenges to this effort were: ( I ) rapid evolution of the system while operational, (2) incremental autonomy as capabilities were transferred from ground control to software control and (3) the eventual safety-criticality of such systems as they begin to fly over populated areas. The results reported here are preliminary but show that Obstacle Analysis helped (1) identify new contingencies that appeared as autonomy increased; (2) identify new alternatives for handling both previously known and new contingencies; and (3) investigate the continued validity of existing software requirements for contingency handling. Since many mobile, intelligent systems are built using a development process that poses the same challenges, the results appear to have applicability to other similar systems.

The Dynamics of Germinal Centre Selection as Measured by Graph-Theoretical Analysis of Mutational Lineage Trees

PubMed Central

Dunn-Walters, Deborah K.; Belelovsky, Alex; Edelman, Hanna; Banerjee, Monica; Mehr, Ramit

2002-01-01

We have developed a rigorous graph-theoretical algorithm for quantifying the shape properties of mutational lineage trees. We show that information about the dynamics of hypermutation and antigen-driven clonal selection during the humoral immune response is contained in the shape of mutational lineage trees deduced from the responding clones. Age and tissue related differences in the selection process can be studied using this method. Thus, tree shape analysis can be used as a means of elucidating humoral immune response dynamics in various situations. PMID:15144020

Inactivation of the Mismatch Repair System in Pseudomonas aeruginosa Attenuates Virulence but Favors Persistence of Oropharyngeal Colonization in Cystic Fibrosis Mice▿

PubMed Central

Mena, Ana; Maciá, María D.; Borrell, Nuria; Moya, Bartolomé; de Francisco, Teresa; Pérez, José L.; Oliver, Antonio

2007-01-01

The inactivation of the mismatch repair (MMR) system of Pseudomonas aeruginosa modestly reduced in vitro fitness, attenuated virulence in murine models of acute systemic and respiratory infections, and decreased the initial oropharyngeal colonization potential. In contrast, the inactivation of the MMR system favored long-term persistence of oropharyngeal colonization in cystic fibrosis mice. These results may help in understanding the reasons for the low and high prevalences, respectively, of hypermutable P. aeruginosa strains in acute and chronic infections. PMID:17307847

A contingency-based approach to the etiology of 'disorganized' attachment: the 'flickering switch' hypothesis.

PubMed

Koós, O; Gergely, G

2001-01-01

The authors present a new approach to the etiology of disorganized attachment based on contingency detection theory. According to this view, the relevant common factor in parental maltreatment and unresolved loss that leads to disorganized attachment has to do with the type of "deviant contingency environment" that both of these conditions generate. In such environments, infants experience periods of being in control followed by periods of sudden loss of control over the caregiver's behavior. The authors hypothesize that this adversely affects the developmental unfolding of the infant's innate "contingency detection module" (Gergely & Watson, 1999), which normally involves a maturational shift around 3 months from an initial attention bias for perfectly contingent stimulation to an emerging preference for less-than-perfect social contingencies. The periodically changing controllability of abusive and dissociating "unresolved" attachment figures is hypothesized to block this process and to lead to the defensive fixation of a dysfunctional "flickering contingency switch" mechanism with two dominant and competing target positions (self-oriented vs. other-oriented). This results in the dissociative style of attention and behavioral organization characteristic of disorganized infant attachment. The authors summarize the preliminary results of an empirical study that provides support for this model in 6.5-month-old infants using a modified Still-Face situation (the Mirror Interaction Situation). The study demonstrates differential emotional and behavioral reactions to sudden loss of maternal contingency and a specific interest in exploring the perfectly contingent self-image in the mirror in infants who at 12 months become categorized as "disorganized" in the Strange Situation.

Role of contingency in striatal response to incentive in adolescents with anxiety.

PubMed

Benson, Brenda E; Guyer, Amanda E; Nelson, Eric E; Pine, Daniel S; Ernst, Monique

2015-03-01

This study examines the effect of contingency on reward function in anxiety. We define contingency as the aspect of a situation in which the outcome is determined by one's action-that is, when there is a direct link between one's action and the outcome of the action. Past findings in adolescents with anxiety or at risk for anxiety have revealed hypersensitive behavioral and neural responses to higher value rewards with correct performance. This hypersensitivity to highly valued (salient) actions suggests that the value of actions is determined not only by outcome magnitude, but also by the degree to which the outcome is contingent on correct performance. Thus, contingency and incentive value might each modulate reward responses in unique ways in anxiety. Using fMRI with a monetary reward task, striatal response to cue anticipation is compared in 18 clinically anxious and 20 healthy adolescents. This task manipulates orthogonally reward contingency and incentive value. Findings suggest that contingency modulates the neural response to incentive magnitude differently in the two groups. Specifically, during the contingent condition, right-striatal response tracks incentive value in anxious, but not healthy, adolescents. During the noncontingent condition, striatal response is bilaterally stronger to low than to high incentive in anxious adolescents, while healthy adolescents exhibit the expected opposite pattern. Both contingency and reward magnitude differentiate striatal activation in anxious versus healthy adolescents. These findings may reflect exaggerated concern about performance and/or alterations of striatal coding of reward value in anxious adolescents. Abnormalities in reward function in anxiety may have treatment implications.

A Reappraisal of Leadership Theory and Training.

ERIC Educational Resources Information Center

Owens, James

1981-01-01

Reviews and organizes modern leadership theories. Notes the research supporting the main thesis of contingency theory and that effective leadership style is contingent upon situational factors. Characteristics of management training based on the contingency approach are identified. (Author/MLF)

7 CFR 457.9 - Appropriation contingency.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 6 2010-01-01 2010-01-01 false Appropriation contingency. 457.9 Section 457.9 Agriculture Regulations of the Department of Agriculture (Continued) FEDERAL CROP INSURANCE CORPORATION, DEPARTMENT OF AGRICULTURE COMMON CROP INSURANCE REGULATIONS § 457.9 Appropriation contingency...

48 CFR 1318.201 - Contingency operation.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contingency operation. 1318.201 Section 1318.201 Federal Acquisition Regulations System DEPARTMENT OF COMMERCE CONTRACTING METHODS AND CONTRACT TYPES EMERGENCY ACQUISITIONS Emergency Acquisition Flexibilities 1318.201 Contingency...

Contingency Management for Patients with Dual Disorders in Intensive Outpatient Treatment for Addiction

PubMed Central

Daley, Dennis C.; Douaihy, Antoine B.

2014-01-01

Objective This project investigated the effectiveness of contingency management for improving retention in treatment and positive outcomes among patients with dual disorders in intensive outpatient treatment for addiction. Methods The effect of contingency management was explored among a group of 160 patients exposed to contingency management (n = 88) and not exposed to contingency management (no contingency management, n = 72) in a partial hospitalization program. Patients referred to the partial hospitalization program for treatment of substance use and comorbid psychiatric disorders were diagnosed by psychiatrists and specialist clinicians according to the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV-TR). A unique application of the contingency management “fishbowl” method was used in the to improve consistency of attendance at treatment sessions, which patients attended five days a week. Days attending treatment and drug-free days were the main outcome variables. Other outcomes of interest were depression, anxiety and psychological stress, coping ability, and intensity of drug cravings. Results Patients in the contingency management group attended more treatment days compared to patients in the no contingency management group; M = 16.2 days (SD = 10.0) vs. M = 9.9 days (SD = 8.5), respectively; t = 4.2, df = 158, p<.001. No difference was found between the treatment groups on number of drug-free days. Psychological stress and drug craving were inversely associated with drug-free days in bivariate testing (r =−.18, p<.02; r = −.31, p<.001 respectively). Treatment days attended and drug craving were associated with drug-free days in multivariate testing (B = .05, SE =.01, β = .39, t =4.9, p <.001; B = −.47 SE = .12, β = −.30, t =−3.9, p <.001; respectively; Adj. R2 = .21). Days attending treatment partially mediated the relationship between exposure to contingency management and self-reported drug-free days. Conclusions Contingency management is a valuable adjunct for increasing retention in treatment among patients with dual disorders in partial hospitalization treatment. Exposure to contingency management increases retention in treatment, which in turn contributes to increased drug-free days. Interventions for coping with psychological stress and drug cravings should be emphasized in intensive dual diagnosis group therapy. PMID:25392284

Visual perceptual learning by operant conditioning training follows rules of contingency.

PubMed

Kim, Dongho; Seitz, Aaron R; Watanabe, Takeo

2015-01-01

Visual perceptual learning (VPL) can occur as a result of a repetitive stimulus-reward pairing in the absence of any task. This suggests that rules that guide Conditioning, such as stimulus-reward contingency (e.g. that stimulus predicts the likelihood of reward), may also guide the formation of VPL. To address this question, we trained subjects with an operant conditioning task in which there were contingencies between the response to one of three orientations and the presence of reward. Results showed that VPL only occurred for positive contingencies, but not for neutral or negative contingencies. These results suggest that the formation of VPL is influenced by similar rules that guide the process of Conditioning.

Visual perceptual learning by operant conditioning training follows rules of contingency

PubMed Central

Kim, Dongho; Seitz, Aaron R; Watanabe, Takeo

2015-01-01

Visual perceptual learning (VPL) can occur as a result of a repetitive stimulus-reward pairing in the absence of any task. This suggests that rules that guide Conditioning, such as stimulus-reward contingency (e.g. that stimulus predicts the likelihood of reward), may also guide the formation of VPL. To address this question, we trained subjects with an operant conditioning task in which there were contingencies between the response to one of three orientations and the presence of reward. Results showed that VPL only occurred for positive contingencies, but not for neutral or negative contingencies. These results suggest that the formation of VPL is influenced by similar rules that guide the process of Conditioning. PMID:26028984

Natural history's hypothetical moments: narratives of contingency in Victorian culture.

PubMed

Choi, Tina Young

2009-01-01

This essay focuses on the ways in which works by Robert Chambers, Charles Darwin, and George Eliot encouraged readers to imagine the future as contingent. But where Chambers alludes to Charles Babbage's computational engine and the period's life insurance industry to hint at the role of contingency in natural history, Darwin insists on the importance of contingently determined outcomes to speciation. The "Origin" consistently exercises the reader's speculative energies by generating conditional statements, causal hypotheses, adn diverging alternatives. "Adam Bede" constitutes its characters' interior lives around the proliferation of such contingent narratives. To reflect on the future or on the past, these works suggest, demands a temporal, moral, and narrative complexity in one's thinking.

Overseas Contingency Operations: OMB and DOD Should Revise the Criteria for Determining Eligible Costs and Identify the Costs Likely to Endure Long Term

DTIC Science & Technology

2017-01-01

OVERSEAS CONTINGENCY OPERATIONS OMB and DOD Should Revise the Criteria for Determining Eligible Costs and Identify the... CONTINGENCY OPERATIONS OMB and DOD Should Revise the Criteria for Determining Eligible Costs and Identify the Costs Likely to Endure Long Term Why GAO...billion in funding for OCO. While DOD’s OCO budget request has included amounts for contingency operations primarily in Iraq and Afghanistan, more

Using Contingency Management Procedures to Reduce At-Risk Drinking in Heavy Drinkers

PubMed Central

Dougherty, Donald M.; Lake, Sarah L.; Hill-Kapturczak, Nathalie; Liang, Yuanyuan; Karns, Tara E.; Mullen, Jillian; Roache, John D.

2017-01-01

Background Treatments for alcohol use disorders typically have been abstinence-based, but harm reduction approaches that encourage drinkers to alter their drinking behavior to reduce the probability of alcohol-related consequences, have gained in popularity. The current study used a contingency management procedure to determine its effectiveness in reducing alcohol consumption among heavy drinkers. Methods Eighty non-treatment-seeking heavy drinkers (ages 21–54, M = 30.20) who did not meet diagnostic criteria for alcohol dependence participated in the study. The study had three phases: 1) an Observation phase (4 weeks) where participants drank normally; 2) a Contingency Management phase (12 weeks) where participants were paid $50 weekly for not exceeding low levels of alcohol consumption as measured by transdermal alcohol concentrations, < 0.03 g/dL; and 3) a Follow-up phase (12 weeks) where participants (n = 66) returned monthly for 3 months to self-report drinking after the contingencies were removed. Transdermal alcohol monitors were used to verify meeting contingency requirements; all other analyses were conducted on self-reported alcohol use. Results On average 42.3% of participants met the contingency criteria and were paid an average of $222 during the Contingency Management phase, with an average $1998 in total compensation throughout the study. Compared to the Observation phase, the percent of any self-reported drinking days significantly decreased from 59.9% to 40.0% in the Contingency Management and 32.0% in the Follow-up phases. The percent of self-reported heavy drinking days reported also significantly decreased from 42.4% in the Observation phase to 19.7% in the Contingency Management phase, which was accompanied by a significant increase in percent days of self-reported no (from 40.1% to 60.0%) and low level drinking (from 9.9% to 15.4%). Self-reported reductions in drinking either persisted, or became more pronounced, during the Follow-up phase. Conclusions Contingency management was associated with a reduction in self-reported episodes of heavy drinking among non-treatment-seeking heavy drinkers. These effects persisted even after incentives were removed, indicating the potential utility of contingency management as a therapeutic intervention to reduce harmful patterns of drinking. PMID:25833033

5 CFR 930.301 - Information systems security awareness training program.

Code of Federal Regulations, 2011 CFR

2011-01-01

... training in system/application life cycle management, risk management, and contingency planning. (4) Chief... security management, system/application life cycle management, risk management, and contingency planning..., risk management, and contingency planning. (b) Provide the Federal information systems security...

Proposed energy conservation contingency plan: emergency restrictions on advertising lighting. Authorities, need, rationale, and operation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

The emergency restrictions on advertising lighting proposed in Energy Conservation Contingency Plan No. 5 of 1977 are presented. A statement is given on the need for rationale and operation of the Contingency Plan.

49 CFR 1542.301 - Contingency plan.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Transportation Other Regulations Relating to Transportation (Continued) TRANSPORTATION SECURITY ADMINISTRATION, DEPARTMENT OF HOMELAND SECURITY CIVIL AVIATION SECURITY AIRPORT SECURITY Contingency Measures § 1542.301 Contingency plan. (a) Each airport operator required to have a security program under § 1542.103(a) and (b...

49 CFR 1542.301 - Contingency plan.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Transportation Other Regulations Relating to Transportation (Continued) TRANSPORTATION SECURITY ADMINISTRATION, DEPARTMENT OF HOMELAND SECURITY CIVIL AVIATION SECURITY AIRPORT SECURITY Contingency Measures § 1542.301 Contingency plan. (a) Each airport operator required to have a security program under § 1542.103(a) and (b...

49 CFR 1542.301 - Contingency plan.

Code of Federal Regulations, 2012 CFR

2012-10-01

... Transportation Other Regulations Relating to Transportation (Continued) TRANSPORTATION SECURITY ADMINISTRATION, DEPARTMENT OF HOMELAND SECURITY CIVIL AVIATION SECURITY AIRPORT SECURITY Contingency Measures § 1542.301 Contingency plan. (a) Each airport operator required to have a security program under § 1542.103(a) and (b...

49 CFR 1542.301 - Contingency plan.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Transportation Other Regulations Relating to Transportation (Continued) TRANSPORTATION SECURITY ADMINISTRATION, DEPARTMENT OF HOMELAND SECURITY CIVIL AVIATION SECURITY AIRPORT SECURITY Contingency Measures § 1542.301 Contingency plan. (a) Each airport operator required to have a security program under § 1542.103(a) and (b...

5 CFR 930.301 - Information systems security awareness training program.

Code of Federal Regulations, 2010 CFR

2010-01-01

... training in system/application life cycle management, risk management, and contingency planning. (4) Chief... security management, system/application life cycle management, risk management, and contingency planning..., risk management, and contingency planning. (b) Provide the Federal information systems security...

40 CFR 265.55 - Emergency coordinator.

Code of Federal Regulations, 2010 CFR

2010-07-01

... FACILITIES Contingency Plan and Emergency Procedures § 265.55 Emergency coordinator. At all times, there must... aspects of the facility's contingency plan, all operations and activities at the facility, the location... out the contingency plan. [Comment: The emergency coordinator's responsibilities are more fully...

Contingency Contractor Optimization Phase 3 Sustainment Third-Party Software List - Contingency Contractor Optimization Tool - Prototype

DOE Office of Scientific and Technical Information (OSTI.GOV)

Durfee, Justin David; Frazier, Christopher Rawls; Bandlow, Alisa

2016-05-01

The Contingency Contractor Optimization Tool - Prototype (CCOT-P) requires several third-party software packages. These are documented below for each of the CCOT-P elements: client, web server, database server, solver, web application and polling application.

Contingent and Alternative Work Arrangements, Defined.

ERIC Educational Resources Information Center

Polivka, Anne E.

1996-01-01

Discusses the definitions of contingent workers and alternative work arrangements used by the Bureau of Labor Statistics to analyze data, and presents aggregate estimates of the number of workers in each group. Discusses the overlap between contingent workers and workers in alternative arrangements. (Author/JOW)

9 CFR 2.134 - Contingency planning.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Contingency planning. 2.134 Section 2.134 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE ANIMAL WELFARE REGULATIONS Miscellaneous § 2.134 Contingency planning. (a) Dealers, exhibitors...

9 CFR 2.134 - Contingency planning.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Contingency planning. 2.134 Section 2.134 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE ANIMAL WELFARE REGULATIONS Miscellaneous § 2.134 Contingency planning. (a) Dealers, exhibitors...

Speaking rate effects on locus equation slope.

PubMed

Berry, Jeff; Weismer, Gary

2013-11-01

A locus equation describes a 1st order regression fit to a scatter of vowel steady-state frequency values predicting vowel onset frequency values. Locus equation coefficients are often interpreted as indices of coarticulation. Speaking rate variations with a constant consonant-vowel form are thought to induce changes in the degree of coarticulation. In the current work, the hypothesis that locus slope is a transparent index of coarticulation is examined through the analysis of acoustic samples of large-scale, nearly continuous variations in speaking rate. Following the methodological conventions for locus equation derivation, data pooled across ten vowels yield locus equation slopes that are mostly consistent with the hypothesis that locus equations vary systematically with coarticulation. Comparable analyses between different four-vowel pools reveal variations in the locus slope range and changes in locus slope sensitivity to rate change. Analyses across rate but within vowels are substantially less consistent with the locus hypothesis. Taken together, these findings suggest that the practice of vowel pooling exerts a non-negligible influence on locus outcomes. Results are discussed within the context of articulatory accounts of locus equations and the effects of speaking rate change.

Mini-Membrane Evaporator for Contingency Spacesuit Cooling

NASA Technical Reports Server (NTRS)

Makinen, Janice V.; Bue, Grant C.; Campbell, Colin; Petty, Brian; Craft, Jesse; Lynch, William; Wilkes, Robert; Vogel, Matthew

2015-01-01

The next-generation Advanced Extravehicular Mobility Unit (AEMU) Portable Life Support System (PLSS) is integrating a number of new technologies to improve reliability and functionality. One of these improvements is the development of the Auxiliary Cooling Loop (ACL) for contingency crewmember cooling. The ACL is a completely redundant, independent cooling system that consists of a small evaporative cooler--the Mini Membrane Evaporator (Mini-ME), independent pump, independent feedwater assembly and independent Liquid Cooling Garment (LCG). The Mini-ME utilizes the same hollow fiber technology featured in the full-sized AEMU PLSS cooling device, the Spacesuit Water Membrane Evaporator (SWME), but Mini-ME occupies only approximately 25% of the volume of SWME, thereby providing only the necessary crewmember cooling in a contingency situation. The ACL provides a number of benefits when compared with the current EMU PLSS contingency cooling technology, which relies upon a Secondary Oxygen Vessel; contingency crewmember cooling can be provided for a longer period of time, more contingency situations can be accounted for, no reliance on a Secondary Oxygen Vessel (SOV) for contingency cooling--thereby allowing a reduction in SOV size and pressure, and the ACL can be recharged-allowing the AEMU PLSS to be reused, even after a contingency event. The first iteration of Mini-ME was developed and tested in-house. Mini-ME is currently packaged in AEMU PLSS 2.0, where it is being tested in environments and situations that are representative of potential future Extravehicular Activities (EVA's). The second iteration of Mini-ME, known as Mini-ME2, is currently being developed to offer more heat rejection capability. The development of this contingency evaporative cooling system will contribute to a more robust and comprehensive AEMU PLSS.

Mini-Membrane Evaporator for Contingency Spacesuit Cooling

NASA Technical Reports Server (NTRS)

Makinen, Janice V.; Bue, Grant C.; Campbell, Colin; Craft, Jesse; Lynch, William; Wilkes, Robert; Vogel, Matthew

2014-01-01

The next-generation Advanced Extravehicular Mobility Unit (AEMU) Portable Life Support System (PLSS) is integrating a number of new technologies to improve reliability and functionality. One of these improvements is the development of the Auxiliary Cooling Loop (ACL) for contingency crewmember cooling. The ACL is a completely redundant, independent cooling system that consists of a small evaporative cooler--the Mini Membrane Evaporator (Mini-ME), independent pump, independent feedwater assembly and independent Liquid Cooling Garment (LCG). The Mini-ME utilizes the same hollow fiber technology featured in the full-sized AEMU PLSS cooling device, the Spacesuit Water Membrane Evaporator (SWME), but Mini-ME occupies only 25% of the volume of SWME, thereby providing only the necessary crewmember cooling in a contingency situation. The ACL provides a number of benefits when compared with the current EMU PLSS contingency cooling technology, which relies upon a Secondary Oxygen Vessel; contingency crewmember cooling can be provided for a longer period of time, more contingency situations can be accounted for, no reliance on a Secondary Oxygen Vessel (SOV) for contingency cooling--thereby allowing a reduction in SOV size and pressure, and the ACL can be recharged-allowing the AEMU PLSS to be reused, even after a contingency event. The first iteration of Mini-ME was developed and tested in-house. Mini-ME is currently packaged in AEMU PLSS 2.0, where it is being tested in environments and situations that are representative of potential future Extravehicular Activities (EVA's). The second iteration of Mini-ME, known as Mini- ME2, is currently being developed to offer more heat rejection capability. The development of this contingency evaporative cooling system will contribute to a more robust and comprehensive AEMU PLSS.

A randomized controlled trial of contingency management for psycho-stimulant use in community mental health outpatients with co-occurring serious mental illness

PubMed Central

McDonell, Michael G.; Srebnik, Debra; Angelo, Frank; McPherson, Sterling; Lowe, Jessica M.; Sugar, Andrea; Short, Robert A.; Roll, John M.; Ries, Richard K.

2014-01-01

Objective The primary objective of this study was to determine if contingency management was associated with increased stimulant drug abstinence in community mental health outpatients with serious mental illness and stimulant dependence. Secondary objectives were to determine if contingency management was associated with reductions in use of other substances, psychiatric symptoms, HIV-risk behavior, and inpatient service utilization. Method A randomized controlled design compared outcomes of 176 outpatients with serious mental illness and stimulant dependence. Participants were randomized to three months of contingency management for stimulant abstinence plus treatment-as-usual or treatment-as-usual with reinforcement for study participation only. Urine drug tests, self-report, clinician-report, and service utilization outcomes were assessed during three-month treatment and three-month follow-up periods. Results While participants in the contingency management condition were less likely to complete the treatment period (n=38; 42%) than those assigned to the control condition (n=55; 65%), X2(1)=9.8, p=0.02; those assigned to the contingency management condition were 2.4 (CI=1.9-3.0) times more likely to submit a stimulant-negative urine test during treatment. Participants assigned to contingency management experienced significantly lower levels of alcohol use, injection drug use, psychiatric symptoms, and were five times less likely than those assigned to the control condition to be admitted for psychiatric hospitalization, X2(1)=5.4, p=0.02. Contingency management participants reported significantly fewer days of stimulant drug use, relative to controls during the three-month follow-up. Conclusions When added to treatment-as-usual, contingency management is associated with large reductions in stimulant, injection drug, and alcohol use. Reductions in psychiatric symptoms and hospitalizations were important secondary benefits. PMID:23138961

Resurgence of instrumental behavior after an abstinence contingency

PubMed Central

Bouton, Mark E.; Schepers, Scott T.

2014-01-01

In resurgence, an extinguished instrumental behavior (R1) recovers when a behavior that replaced it (R2) is also extinguished. The phenomenon may be relevant to understanding relapse that can occur after the termination of “contingency management” treatments, in which unwanted behavior (e.g., substance abuse) is reduced by reinforcing alternative behavior. When reinforcement is discontinued, the unwanted behavior might resurge. However, unlike most resurgence experiments, contingency management treatments also introduce a negative contingency in which reinforcers are not delivered unless the client has abstained from the unwanted behavior. Two experiments with rats therefore examined the effects of adding a negative “abstinence” contingency to the resurgence design. During response elimination, R2 was not reinforced unless R1 had not been emitted for a minimum period of time (45, 90, or 135 s). In both experiments, adding such a contingency to simple R1 extinction reduced, but did not eliminate, resurgence. Experiment 2 found the same effect in a yoked group that could earn reinforcers for R2 at the same points in time, but without the requirement to abstain from R1. Thus, the negative contingency per se did not contribute. Results suggest that the contingency reduced resurgence by making reinforcers more difficult to earn and more widely spaced in time. This could have allowed the animal to learn that R1 was extinguished in the “context” of infrequent reinforcement—a context more like that of resurgence testing. The results are thus consistent with a contextual (renewal) account of resurgence. The method might provide a better model of relapse after termination of a contingency management treatment. PMID:24366673

A randomized controlled trial of ethyl glucuronide-based contingency management for outpatients with co-occurring alcohol use disorders and serious mental illness

PubMed Central

McDonell, Michael G.; Leickly, Emily; McPherson, Sterling; Skalisky, Jordan; Srebnik, Debra; Angelo, Frank; Vilardaga, Roger; Nepom, Jenny R.; Roll, John M.; Ries, Richard K.

2017-01-01

Objective To determine if a contingency management intervention using the ethyl glucuronide (EtG) alcohol biomarker resulted in increased alcohol abstinence in outpatients with co-occurring serious mental illnesses. Secondary objectives were to determine if contingency management was associated with changes in heavy drinking, treatment attendance, drug use, cigarette smoking, psychiatric symptoms, and HIV-risk behavior. Method Seventy-nine (37% female, 44% non-white) outpatients with serious mental illness and alcohol dependence receiving treatment as usual completed a 4-week observation period and were randomized to 12-weeks of contingency management for EtG-negative urine samples and addiction treatment attendance, or reinforcement only for study participation. Contingency management included the variable magnitude of reinforcement “prize draw” procedure contingent on EtG-negative samples (<150 ng/mL) three times a week and weekly gift cards for outpatient treatment attendance. Urine EtG, drug test, and self-report outcomes were assessed during the 12-week intervention and 3-month follow-up periods. Results Contingency management participants were 3.1 times (95% CI: 2.2, 4.5) more likely to submit an EtG-negative urine test during the 12-week intervention period, attaining nearly 1.5 weeks of additional abstinence relative to controls. Contingency management participants had significantly lower mean EtG levels, reported less drinking and fewer heavy drinking episodes, and were more likely to submit stimulant-negative urine and smoking-negative breath samples, relative to controls. Differences in self-reported alcohol use were maintained at the 3-month follow-up. Conclusions This is the first randomized trial utilizing an accurate and validated biomarker (EtG) to demonstrate the efficacy of contingency management for alcohol dependence in outpatients with serious mental illness. PMID:28135843

Affective Modulation of Cognitive Control is Determined by Performance-Contingency and Mediated by Ventromedial Prefrontal and Cingulate Cortex

PubMed Central

King, Joseph A.; Korb, Franziska M.; Krebs, Ruth M.; Notebaert, Wim; Egner, Tobias

2013-01-01

Cognitive control requires a fine balance between stability, the protection of an on-going task-set, and flexibility, the ability to update a task-set in line with changing contingencies. It is thought that emotional processing modulates this balance, but results have been equivocal regarding the direction of this modulation. Here, we tested the hypothesis that a crucial determinant of this modulation is whether affective stimuli represent performance-contingent or task-irrelevant signals. Combining functional magnetic resonance imaging with a conflict task-switching paradigm, we contrasted the effects of presenting negative- and positive-valence pictures on the stability/flexibility trade-off in humans, depending on whether picture presentation was contingent on behavioral performance. Both the behavioral and neural expressions of cognitive control were modulated by stimulus valence and performance contingency: in the performance-contingent condition, cognitive flexibility was enhanced following positive pictures, whereas in the nonperformance-contingent condition, positive stimuli promoted cognitive stability. The imaging data showed that, as anticipated, the stability/flexibility trade-off per se was reflected in differential recruitment of dorsolateral frontoparietal and striatal regions. In contrast, the affective modulation of stability/flexibility shifts was mirrored, unexpectedly, by neural responses in ventromedial prefrontal and posterior cingulate cortices, core nodes of the “default mode” network. Our results demonstrate that the affective modulation of cognitive control depends on the performance contingency of the affect-inducing stimuli, and they document medial default mode regions to mediate the flexibility-promoting effects of performance-contingent positive affect, thus extending recent work that recasts these regions as serving a key role in on-task control processes. PMID:24155301

A Randomized Controlled Trial of Ethyl Glucuronide-Based Contingency Management for Outpatients With Co-Occurring Alcohol Use Disorders and Serious Mental Illness.

PubMed

McDonell, Michael G; Leickly, Emily; McPherson, Sterling; Skalisky, Jordan; Srebnik, Debra; Angelo, Frank; Vilardaga, Roger; Nepom, Jenny R; Roll, John M; Ries, Richard K

2017-04-01

The authors examined whether a contingency management intervention using the ethyl glucuronide (EtG) alcohol biomarker resulted in increased alcohol abstinence in outpatients with co-occurring serious mental illnesses. Secondary objectives were to determine whether contingency management was associated with changes in heavy drinking, treatment attendance, drug use, cigarette smoking, psychiatric symptoms, and HIV-risk behavior. Seventy-nine (37% female, 44% nonwhite) outpatients with serious mental illness and alcohol dependence receiving treatment as usual completed a 4-week observation period and were randomly assigned to 12 weeks of contingency management for EtG-negative urine samples and addiction treatment attendance, or reinforcement only for study participation. Contingency management included the variable magnitude of reinforcement "prize draw" procedure contingent on EtG-negative samples (<150 ng/mL) three times a week and weekly gift cards for outpatient treatment attendance. Urine EtG, drug test, and self-report outcomes were assessed during the 12-week intervention and 3-month follow-up periods. Contingency management participants were 3.1 times (95% CI=2.2-4.5) more likely to submit an EtG-negative urine test during the 12-week intervention period, attaining nearly 1.5 weeks of additional alcohol abstinence compared with controls. Contingency management participants had significantly lower mean EtG levels, reported less drinking and fewer heavy drinking episodes, and were more likely to submit stimulant-negative urine and smoking-negative breath samples, compared with controls. Differences in self-reported alcohol use were maintained at the 3-month follow-up. This is the first randomized trial utilizing an accurate and validated biomarker (EtG) to demonstrate the efficacy of contingency management for alcohol dependence in outpatients with serious mental illness.

Getting help quickly: older people and community worker perspectives of contingency planning for falls management.

PubMed

Charlton, Kimberly; Murray, Carolyn M; Kumar, Saravana

2018-01-01

Older people living in the community need to plan for getting help quickly if they have a fall. In this paper planning for falls is referred to as contingency planning and is not a falls prevention strategy but rather a falls management strategy. This research explored the perspectives of older people and community workers (CWs) about contingency planning for a fall. Using a qualitative descriptive approach, participants were recruited through a community agency that supports older people. In-depth interviews were conducted with seven older people (67-89 years of age) and a focus group was held with seven workers of mixed disciplines from the same agency. Older people who hadn't fallen were included but were assumed to be at risk of falls because they were in receipt of services. Thematic analysis and concept mapping combined the data from the two participant groups. Four themes including preconceptions about planning ahead for falling, a fall changes perception, giving, and receiving advice about contingency plans and what to do about falling. Both CWs and older people agree contingency planning requires understanding of individual identity and circumstances. CWs have limited knowledge about contingency planning and may be directive, informative, or conservative. Implications for Rehabilitation Falls can result in serious consequences for older people. There is an evidence-practice gap as availability of and access to contingency planning does not necessarily mean older people will use it in a falls emergency. Older people prefer community workers to be directive or informative about contingency planning options but they do want choice and control. Increased community workers knowledge of, and collaborative decision-making about, contingency planning may promote patient-centered services and assist in closing the evidence-practice gap.

Two-trait-locus linkage analysis: A powerful strategy for mapping complex genetic traits

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schork, N.J.; Boehnke, M.; Terwilliger, J.D.

1993-11-01

Nearly all diseases mapped to date follow clear Mendelian, single-locus segregation patterns. In contrast, many common familial diseases such as diabetes, psoriasis, several forms of cancer, and schizophrenia are familial and appear to have a genetic component but do not exhibit simple Mendelian transmission. More complex models are required to explain the genetics of these important diseases. In this paper, the authors explore two-trait-locus, two-marker-locus linkage analysis in which two trait loci are mapped simultaneously to separate genetic markers. The authors compare the utility of this approach to standard one-trait-locus, one-marker-locus linkage analysis with and without allowance for heterogeneity. Themore » authors also compare the utility of the two-trait-locus, two-marker-locus analysis to two-trait-locus, one-marker-locus linkage analysis. For common diseases, pedigrees are often bilineal, with disease genes entering via two or more unrelated pedigree members. Since such pedigrees often are avoided in linkage studies, the authors also investigate the relative information content of unilineal and bilineal pedigrees. For the dominant-or-recessive and threshold models that the authors consider, the authors find that two-trait-locus, two-marker-locus linkage analysis can provide substantially more linkage information, as measured by expected maximum lod score, than standard one-trait-locus, one-marker-locus methods, even allowing for heterogeneity, while, for a dominant-or-dominant generating model, one-locus models that allow for heterogeneity extract essentially as much information as the two-trait-locus methods. For these three models, the authors also find that bilineal pedigrees provide sufficient linkage information to warrant their inclusion in such studies. The authors discuss strategies for assessing the significance of the two linkages assumed in two-trait-locus, two-marker-locus models. 37 refs., 1 fig., 4 tabs.« less

The influence of the number of relevant causes on the processing of covariation information in causal reasoning.

PubMed

Kim, Kyungil; Markman, Arthur B; Kim, Tae Hoon

2016-11-01

Research on causal reasoning has focused on the influence of covariation between candidate causes and effects on causal judgments. We suggest that the type of covariation information to which people attend is affected by the task being performed. For this, we manipulated the test questions for the evaluation of contingency information and observed its influence on both contingency learning and subsequent causal selections. When people select one cause related to an effect, they focus on conditional contingencies assuming the absence of alternative causes. When people select two causes related to an effect, they focus on conditional contingencies assuming the presence of alternative causes. We demonstrated this use of contingency information in four experiments.

Mother-infant interaction during the first 3 months: the emergence of culture-specific contingency patterns.

PubMed

Kärtner, Joscha; Keller, Heidi; Yovsi, Relindis D

2010-01-01

This study analyzed German and Nso mothers' auditory, proximal, and visual contingent responses to their infants' nondistress vocalizations in postnatal Weeks 4, 6, 8, 10, and 12. Visual contingency scores increased whereas proximal contingency scores decreased over time for the independent (German urban middle-class, N = 20) but not the interdependent sociocultural context (rural Nso farmers, N = 24). It seems, therefore, that culture-specific differences in the modal patterns of contingent responsiveness emerge during the 2nd and 3rd months of life. This differential development was interpreted as the result of the interplay between maturational processes associated with the 2-month shift that are selectively integrated and reinforced in culture-specific mother-infant interaction.

Programming a randomized dependent group contingency and common stimuli to promote durable behavior change.

PubMed

Cariveau, Tom; Kodak, Tiffany

2017-01-01

Low levels of academic engagement may impede students' acquisition of skills. Intervening on student behavior using group contingencies may be a feasible way to increase academic engagement during group instruction. The current study examined the effect of a randomized dependent group contingency on levels of academic engagement for second-grade participants receiving small-group reading and writing instruction. The results showed that a randomized dependent group contingency increased the academic engagement of primary participants and several of the other participants during small-group instruction. The findings also showed that high levels of academic engagement were maintained when common stimuli were present and the dependent group contingency was withdrawn. © 2016 Society for the Experimental Analysis of Behavior.

Contingencies and metacontingencies: Toward a synthesis of behavior analysis and cultural materialism

PubMed Central

Glenn, Sigrid S.

1988-01-01

A synthesis of cultural materialism and behavior analysis might increase the scientific and technological value of both fields. Conceptual and substantive relations between the two fields show important similarities, particularly with regard to the causal role of the environment in behavioral and cultural evolution. Key concepts in Marvin Harris's cultural materialist theories are outlined. A distinction is made between contingencies at the behavioral level of analysis (contingencies of reinforcement) and contingencies at the cultural level of analysis (metacontingencies). Relations between the two kinds of contingencies are explored in cultural practices from paleolithic to industrial sociocultural systems. A synthesis of these two fields may offer the opportunity to resolve serious problems currently facing modern cultures. PMID:22478011

A look-ahead probabilistic contingency analysis framework incorporating smart sampling techniques

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Yousu; Etingov, Pavel V.; Ren, Huiying

2016-07-18

This paper describes a framework of incorporating smart sampling techniques in a probabilistic look-ahead contingency analysis application. The predictive probabilistic contingency analysis helps to reflect the impact of uncertainties caused by variable generation and load on potential violations of transmission limits.

Temporal Contingency as an Independent Component of Parenting Behavior.

ERIC Educational Resources Information Center

Keller, Heidi; Lohaus, Arnold; Volker, Susanne; Cappenberg, Martina; Chasiotis, Athanasios

1999-01-01

Examined relationship between temporal contingency of maternal behavior and interactional quality. Found that although prompt responding was typical, the existence of individual differences indicated that this tendency was expressed in different communicative channels. The relationship between contingency and ratings of interactional quality was…

48 CFR 2132.770 - Insurance premium payments and special contingency reserve.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Insurance premium payments... GENERAL CONTRACTING REQUIREMENTS CONTRACT FINANCING Contract Funding 2132.770 Insurance premium payments and special contingency reserve. Insurance premium payments and a special contingency reserve are made...

48 CFR 2132.770 - Insurance premium payments and special contingency reserve.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 6 2011-10-01 2011-10-01 false Insurance premium payments... GENERAL CONTRACTING REQUIREMENTS CONTRACT FINANCING Contract Funding 2132.770 Insurance premium payments and special contingency reserve. Insurance premium payments and a special contingency reserve are made...

The Dependence Structure of Conditional Probabilities in a Contingency Table

ERIC Educational Resources Information Center

Joarder, Anwar H.; Al-Sabah, Walid S.

2002-01-01

Conditional probability and statistical independence can be better explained with contingency tables. In this note some special cases of 2 x 2 contingency tables are considered. In turn an interesting insight into statistical dependence as well as independence of events is obtained.

75 FR 54773 - Approval and Promulgation of Air Quality Implementation Plans; Minnesota; Carbon Monoxide (CO...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-09

.... Monitoring Network and Verification of Continued Attainment 4. Contingency Plan 5. Conformity Determination... Continued Attainment, Contingency Plan, and Conformity Determinations Under Limited Maintenance Plans. These.../Verification of Continued Attainment, Contingency Plan, and Conformity Determination Under Limited Maintenance...

A Primer on Improving Contingent Faculty Conditions

ERIC Educational Resources Information Center

McGrew, Heidi; Untener, Joe

2010-01-01

Challenges associated with the increasing use of contingent faculty appointments in American higher education are mounting. The AAUP and other professional groups have identified several major problems: (1) unacceptable conditions and compensation for contingent faculty members; (2) poor learning outcomes for students; and (3) the potential…

75 FR 53268 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-31

... relations, Penalties, Reporting and recordkeeping requirements, Superfund, Water pollution control, Water... and Hazardous Substances Pollution Contingency Plan; National Priorities List: Deletion of the..., as amended, is an appendix of the National Oil and Hazardous Substances Pollution Contingency Plan...

40 CFR 109.6 - Coordination.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., LOCAL AND REGIONAL OIL REMOVAL CONTINGENCY PLANS § 109.6 Coordination. For the purposes of coordination, the contingency plans of State and local governments should be developed and implemented in consultation with private interests. A copy of any oil removal contingency plan developed by State and local...

The Effectiveness of Gaze-Contingent Control in Computer Games.

PubMed

Orlov, Paul A; Apraksin, Nikolay

2015-01-01

Eye-tracking technology and gaze-contingent control in human-computer interaction have become an objective reality. This article reports on a series of eye-tracking experiments, in which we concentrated on one aspect of gaze-contingent interaction: Its effectiveness compared with mouse-based control in a computer strategy game. We propose a measure for evaluating the effectiveness of interaction based on "the time of recognition" the game unit. In this article, we use this measure to compare gaze- and mouse-contingent systems, and we present the analysis of the differences as a function of the number of game units. Our results indicate that performance of gaze-contingent interaction is typically higher than mouse manipulation in a visual searching task. When tested on 60 subjects, the results showed that the effectiveness of gaze-contingent systems over 1.5 times higher. In addition, we obtained that eye behavior stays quite stabile with or without mouse interaction. © The Author(s) 2015.

Influences of Source - Item Contingency and Schematic Knowledge on Source Monitoring: Tests of the Probability-Matching Account

PubMed Central

Bayen, Ute J.; Kuhlmann, Beatrice G.

2010-01-01

The authors investigated conditions under which judgments in source-monitoring tasks are influenced by prior schematic knowledge. According to a probability-matching account of source guessing (Spaniol & Bayen, 2002), when people do not remember the source of information, they match source guessing probabilities to the perceived contingency between sources and item types. When they do not have a representation of a contingency, they base their guesses on prior schematic knowledge. The authors provide support for this account in two experiments with sources presenting information that was expected for one source and somewhat unexpected for another. Schema-relevant information about the sources was provided at the time of encoding. When contingency perception was impeded by dividing attention, participants showed schema-based guessing (Experiment 1). Manipulating source - item contingency also affected guessing (Experiment 2). When this contingency was schema-inconsistent, it superseded schema-based expectations and led to schema-inconsistent guessing. PMID:21603251

Contingencies of self-worth and social-networking-site behavior.

PubMed

Stefanone, Michael A; Lackaff, Derek; Rosen, Devan

2011-01-01

Social-networking sites like Facebook enable people to share a range of personal information with expansive groups of "friends." With the growing popularity of media sharing online, many questions remain regarding antecedent conditions for this behavior. Contingencies of self-worth afford a more nuanced approach to variable traits that affect self-esteem, and may help explain online behavior. A total of 311 participants completed an online survey measuring such contingencies and typical behaviors on Facebook. First, exploratory factor analyses revealed an underlying structure to the seven dimensions of self-worth. Public-based contingencies explained online photo sharing (β = 0.158, p < 0.01), while private-based contingencies demonstrated a negative relationship with time online (β = -0.186, p < 0.001). Finally, the appearance contingency for self-worth had the strongest relationship with the intensity of online photo sharing (β = 0.242), although no relationship was evident for time spent managing profiles.

A Mobile Element in mutS Drives Hypermutation in a Marine Vibrio

PubMed Central

Chu, Nathaniel D.; Clarke, Sean A.; Timberlake, Sonia; Polz, Martin F.; Grossman, Alan D.

2017-01-01

ABSTRACT Bacteria face a trade-off between genetic fidelity, which reduces deleterious mistakes in the genome, and genetic innovation, which allows organisms to adapt. Evidence suggests that many bacteria balance this trade-off by modulating their mutation rates, but few mechanisms have been described for such modulation. Following experimental evolution and whole-genome resequencing of the marine bacterium Vibrio splendidus 12B01, we discovered one such mechanism, which allows this bacterium to switch to an elevated mutation rate. This switch is driven by the excision of a mobile element residing in mutS, which encodes a DNA mismatch repair protein. When integrated within the bacterial genome, the mobile element provides independent promoter and translation start sequences for mutS—different from the bacterium’s original mutS promoter region—which allow the bacterium to make a functional mutS gene product. Excision of this mobile element rejoins the mutS gene with host promoter and translation start sequences but leaves a 2-bp deletion in the mutS sequence, resulting in a frameshift and a hypermutator phenotype. We further identified hundreds of clinical and environmental bacteria across Betaproteobacteria and Gammaproteobacteria that possess putative mobile elements within the same amino acid motif in mutS. In a subset of these bacteria, we detected excision of the element but not a frameshift mutation; the mobile elements leave an intact mutS coding sequence after excision. Our findings reveal a novel mechanism by which one bacterium alters its mutation rate and hint at a possible evolutionary role for mobile elements within mutS in other bacteria. PMID:28174306

DNA polymerase ɛ and δ exonuclease domain mutations in endometrial cancer

PubMed Central

Church, David N.; Briggs, Sarah E.W.; Palles, Claire; Domingo, Enric; Kearsey, Stephen J.; Grimes, Jonathon M.; Gorman, Maggie; Martin, Lynn; Howarth, Kimberley M.; Hodgson, Shirley V.; Kaur, Kulvinder; Taylor, Jenny; Tomlinson, Ian P.M.

2013-01-01

Accurate duplication of DNA prior to cell division is essential to suppress mutagenesis and tumour development. The high fidelity of eukaryotic DNA replication is due to a combination of accurate incorporation of nucleotides into the nascent DNA strand by DNA polymerases, the recognition and removal of mispaired nucleotides (proofreading) by the exonuclease activity of DNA polymerases δ and ɛ, and post-replication surveillance and repair of newly synthesized DNA by the mismatch repair (MMR) apparatus. While the contribution of defective MMR to neoplasia is well recognized, evidence that faulty DNA polymerase activity is important in cancer development has been limited. We have recently shown that germline POLE and POLD1 exonuclease domain mutations (EDMs) predispose to colorectal cancer (CRC) and, in the latter case, to endometrial cancer (EC). Somatic POLE mutations also occur in 5–10% of sporadic CRCs and underlie a hypermutator, microsatellite-stable molecular phenotype. We hypothesized that sporadic ECs might also acquire somatic POLE and/or POLD1 mutations. Here, we have found that missense POLE EDMs with good evidence of pathogenic effects are present in 7% of a set of 173 endometrial cancers, although POLD1 EDMs are uncommon. The POLE mutations localized to highly conserved residues and were strongly predicted to affect proofreading. Consistent with this, POLE-mutant tumours were hypermutated, with a high frequency of base substitutions, and an especially large relative excess of G:C>T:A transversions. All POLE EDM tumours were microsatellite stable, suggesting that defects in either DNA proofreading or MMR provide alternative mechanisms to achieve genomic instability and tumourigenesis. PMID:23528559

Somatic hypermutation and antigen-driven selection of B cells are altered in autoimmune diseases.

PubMed

Zuckerman, Neta S; Hazanov, Helena; Barak, Michal; Edelman, Hanna; Hess, Shira; Shcolnik, Hadas; Dunn-Walters, Deborah; Mehr, Ramit

2010-12-01

B cells have been found to play a critical role in the pathogenesis of several autoimmune (AI) diseases. A common feature amongst many AI diseases is the formation of ectopic germinal centers (GC) within the afflicted tissue or organ, in which activated B cells expand and undergo somatic hypermutation (SHM) and antigen-driven selection on their immunoglobulin variable region (IgV) genes. However, it is not yet clear whether these processes occurring in ectopic GCs are identical to those in normal GCs. The analysis of IgV mutations has aided in revealing many aspects concerning B cell expansion, mutation and selection in GC reactions. We have applied several mutation analysis methods, based on lineage tree construction, to a large set of data, containing IgV productive and non-productive heavy and light chain sequences from several different tissues, to examine three of the most profoundly studied AI diseases - Rheumatoid Arthritis (RA), Multiple Sclerosis (MS) and Sjögren's Syndrome (SS). We have found that RA and MS sequences exhibited normal mutation spectra and targeting motifs, but a stricter selection compared to normal controls, which was more apparent in RA. SS sequence analysis results deviated from normal controls in both mutation spectra and indications of selection, also showing differences between light and heavy chain IgV and between different tissues. The differences revealed between AI diseases and normal control mutation patterns may result from the different microenvironmental influences to which ectopic GCs are exposed, relative to those in normal secondary lymphoid tissues. Copyright © 2010 Elsevier Ltd. All rights reserved.

Analysis of IgV gene mutations in B cell chronic lymphocytic leukaemia according to antigen-driven selection identifies subgroups with different prognosis and usage of the canonical somatic hypermutation machinery.

PubMed

Degan, Massimo; Bomben, Riccardo; Bo, Michele Dal; Zucchetto, Antonella; Nanni, Paola; Rupolo, Maurizio; Steffan, Agostino; Attadia, Vincenza; Ballerini, Pier Ferruccio; Damiani, Daniela; Pucillo, Carlo; Poeta, Giovanni Del; Colombatti, Alfonso; Gattei, Valter

2004-07-01

Cases of B-cell chronic lymphocytic leukaemia (B-CLL) with mutated (M) IgV(H) genes have a better prognosis than unmutated (UM) cases. We analysed the IgV(H) mutational status of B-CLL according to the features of a canonical somatic hypermutation (SHM) process, correlating this data with survival. In a series of 141 B-CLLs, 124 cases were examined for IgV(H) gene per cent mutations and skewing of replacement/silent mutations in the framework/complementarity-determining regions as evidence of antigen-driven selection; this identified three B-CLL subsets: significantly mutated (sM), with evidence of antigen-driven selection, not significantly mutated (nsM) and UM, without such evidence and IgV(H) gene per cent mutations above or below the 2% cut-off. sM B-CLL patients had longer survival within the good prognosis subgroup that had more than 2% mutations of IgV(H) genes. sM, nsM and UM B-CLL were also characterized for the biased usage of IgV(H) families, intraclonal IgV(H) gene diversification, preference of mutations to target-specific nucleotides or hotspots, and for the expression of enzymes involved in SHM (translesion DNA polymerase zeta and eta and activation-induced cytidine deaminase). These findings indicate the activation of a canonical SHM process in nsM and sM B-CLLs and underscore the role of the antigen in defining the specific clinical and biological features of B-CLL.

Activation-induced cytidine deaminase (AID)-dependent somatic hypermutation requires a splice isoform of the serine/arginine-rich (SR) protein SRSF1

PubMed Central

Kanehiro, Yuichi; Todo, Kagefumi; Negishi, Misaki; Fukuoka, Junji; Gan, Wenjian; Hikasa, Takuya; Kaga, Yoshiaki; Takemoto, Masayuki; Magari, Masaki; Li, Xialu; Manley, James L.; Ohmori, Hitoshi; Kanayama, Naoki

2012-01-01

Somatic hypermutation (SHM) of Ig variable region (IgV) genes requires both IgV transcription and the enzyme activation-induced cytidine deaminase (AID). Identification of a cofactor responsible for the fact that IgV genes are much more sensitive to AID-induced mutagenesis than other genes is a key question in immunology. Here, we describe an essential role for a splice isoform of the prototypical serine/arginine-rich (SR) protein SRSF1, termed SRSF1-3, in AID-induced SHM in a DT40 chicken B-cell line. Unexpectedly, we found that SHM does not occur in a DT40 line lacking SRSF1-3 (DT40-ASF), although it is readily detectable in parental DT40 cells. Strikingly, overexpression of AID in DT40-ASF cells led to a large increase in nonspecific (off-target) mutations. In contrast, introduction of SRSF1-3, but not SRSF1, into these cells specifically restored SHM without increasing off-target mutations. Furthermore, we found that SRSF1-3 binds preferentially to the IgV gene and inhibits processing of the Ig transcript, providing a mechanism by which SRSF1-3 makes the IgV gene available for AID-dependent SHM. SRSF1 not only acts as an essential splicing factor but also regulates diverse aspects of mRNA metabolism and maintains genome stability. Our findings, thus, define an unexpected and important role for SRSF1, particularly for its splice variant, in enabling AID to function specifically on its natural substrate during SHM. PMID:22232677

Activation-induced cytidine deaminase (AID)-dependent somatic hypermutation requires a splice isoform of the serine/arginine-rich (SR) protein SRSF1.

PubMed

Kanehiro, Yuichi; Todo, Kagefumi; Negishi, Misaki; Fukuoka, Junji; Gan, Wenjian; Hikasa, Takuya; Kaga, Yoshiaki; Takemoto, Masayuki; Magari, Masaki; Li, Xialu; Manley, James L; Ohmori, Hitoshi; Kanayama, Naoki

2012-01-24

Somatic hypermutation (SHM) of Ig variable region (IgV) genes requires both IgV transcription and the enzyme activation-induced cytidine deaminase (AID). Identification of a cofactor responsible for the fact that IgV genes are much more sensitive to AID-induced mutagenesis than other genes is a key question in immunology. Here, we describe an essential role for a splice isoform of the prototypical serine/arginine-rich (SR) protein SRSF1, termed SRSF1-3, in AID-induced SHM in a DT40 chicken B-cell line. Unexpectedly, we found that SHM does not occur in a DT40 line lacking SRSF1-3 (DT40-ASF), although it is readily detectable in parental DT40 cells. Strikingly, overexpression of AID in DT40-ASF cells led to a large increase in nonspecific (off-target) mutations. In contrast, introduction of SRSF1-3, but not SRSF1, into these cells specifically restored SHM without increasing off-target mutations. Furthermore, we found that SRSF1-3 binds preferentially to the IgV gene and inhibits processing of the Ig transcript, providing a mechanism by which SRSF1-3 makes the IgV gene available for AID-dependent SHM. SRSF1 not only acts as an essential splicing factor but also regulates diverse aspects of mRNA metabolism and maintains genome stability. Our findings, thus, define an unexpected and important role for SRSF1, particularly for its splice variant, in enabling AID to function specifically on its natural substrate during SHM.

Discrimination of germline V genes at different sequencing lengths and mutational burdens: A new tool for identifying and evaluating the reliability of V gene assignment.

PubMed

Zhang, Bochao; Meng, Wenzhao; Prak, Eline T Luning; Hershberg, Uri

2015-12-01

Immune repertoires are collections of lymphocytes that express diverse antigen receptor gene rearrangements consisting of Variable (V), (Diversity (D) in the case of heavy chains) and Joining (J) gene segments. Clonally related cells typically share the same germline gene segments and have highly similar junctional sequences within their third complementarity determining regions. Identifying clonal relatedness of sequences is a key step in the analysis of immune repertoires. The V gene is the most important for clone identification because it has the longest sequence and the greatest number of sequence variants. However, accurate identification of a clone's germline V gene source is challenging because there is a high degree of similarity between different germline V genes. This difficulty is compounded in antibodies, which can undergo somatic hypermutation. Furthermore, high-throughput sequencing experiments often generate partial sequences and have significant error rates. To address these issues, we describe a novel method to estimate which germline V genes (or alleles) cannot be discriminated under different conditions (read lengths, sequencing errors or somatic hypermutation frequencies). Starting with any set of germline V genes, this method measures their similarity using different sequencing lengths and calculates their likelihood of unambiguous assignment under different levels of mutation. Hence, one can identify, under different experimental and biological conditions, the germline V genes (or alleles) that cannot be uniquely identified and bundle them together into groups of specific V genes with highly similar sequences. Copyright © 2015 Elsevier B.V. All rights reserved.

Hypermutation signature reveals a slippage and realignment model of translesion synthesis by Rev3 polymerase in cisplatin-treated yeast.

PubMed

Segovia, Romulo; Shen, Yaoqing; Lujan, Scott A; Jones, Steven J M; Stirling, Peter C

2017-03-07

Gene-gene or gene-drug interactions are typically quantified using fitness as a readout because the data are continuous and easily measured in high throughput. However, to what extent fitness captures the range of other phenotypes that show synergistic effects is usually unknown. Using Saccharomyces cerevisiae and focusing on a matrix of DNA repair mutants and genotoxic drugs, we quantify 76 gene-drug interactions based on both mutation rate and fitness and find that these parameters are not connected. Independent of fitness defects, we identified six cases of synthetic hypermutation, where the combined effect of the drug and mutant on mutation rate was greater than predicted. One example occurred when yeast lacking RA D1 were exposed to cisplatin, and we characterized this interaction using whole-genome sequencing. Our sequencing results indicate mutagenesis by cisplatin in rad1 Δ cells appeared to depend almost entirely on interstrand cross-links at GpCpN motifs. Interestingly, our data suggest that the following base on the template strand dictates the addition of the mutated base. This result differs from cisplatin mutation signatures in XPF-deficient Caenorhabditis elegans and supports a model in which translesion synthesis polymerases perform a slippage and realignment extension across from the damaged base. Accordingly, DNA polymerase ζ activity was essential for mutagenesis in cisplatin-treated rad1 Δ cells. Together these data reveal the potential to gain new mechanistic insights from nonfitness measures of gene-drug interactions and extend the use of mutation accumulation and whole-genome sequencing analysis to define DNA repair mechanisms.

Molecular genetic heterogeneity in undifferentiated endometrial carcinomas.

PubMed

Rosa-Rosa, Juan M; Leskelä, Susanna; Cristóbal-Lana, Eva; Santón, Almudena; López-García, Ma Ángeles; Muñoz, Gloria; Pérez-Mies, Belen; Biscuola, Michele; Prat, Jaime; Esther, Oliva E; Soslow, Robert A; Matias-Guiu, Xavier; Palacios, Jose

2016-11-01

Undifferentiated and dedifferentiated endometrial carcinomas are rare and highly aggressive subtypes of uterine cancer, not well characterized at a molecular level. To investigate whether dedifferentiated carcinomas carry molecular genetic alterations similar to those of pure undifferentiated carcinomas, and to gain insight into the pathogenesis of these tumors, we selected a cohort of 18 undifferentiated endometrial carcinomas, 8 of them with a well-differentiated endometrioid carcinoma component (dedifferentiated endometrioid carcinomas), and studied them by immunohistochemistry and massive parallel and Sanger sequencing. Whole-exome sequencing of the endometrioid and undifferentiated components, as well as normal myometrium, was also carried out in one case. According to The Cancer Genome Atlas classification, we distributed 95% of the undifferentiated carcinomas in this series as follows: (a) hypermutated tumors with loss of any mismatch repair protein expression and microsatellite instability (eight cases, 45%); (b) ultramutated carcinomas carrying mutations in the exonuclease domain of POLE (two cases, 11%); (c) high copy number alterations (copy-number high) tumors group exhibiting only TP53 mutations and high number of alterations detected by FISH (two cases, 11%); and (d) low copy number alterations (copy-number low) tumors with molecular alterations typical of endometrioid endometrial carcinomas (five cases, 28%). Two of the latter cases, however, also had TP53 mutations and higher number of alterations detected by FISH and could have progressed to a copy-number high phenotype. Most dedifferentiated carcinomas belonged to the hypermutated group, whereas pure undifferentiated carcinomas shared molecular genetic alterations with copy-number low or copy-number high tumors. These results indicate that undifferentiated and dedifferentiated endometrial carcinomas are molecularly heterogeneous tumors, which may have prognostic value.

Molecular genetic heterogeneity in undifferentiated endometrial carcinomas

PubMed Central

Rosa-Rosa, J.M.; Leskelä, S.; Cristóbal-Lana, E.; Santón, A.; López-García, M.A.; Muñoz, G.; Pérez-Mies, B.; Biscuola, M; Prat, J.; Oliva, E.; Soslow, R.A.; Matias-Guiu, X.; Palacios, J.

2017-01-01

Undifferentiated and dedifferentiated endometrial carcinomas are rare and highly aggressive subtypes of uterine cancer, not well characterized at a molecular level. To investigate whether dedifferentiated carcinomas carry molecular genetic alterations similar to those of pure undifferentiated carcinomas, and to gain insight into the pathogenesis of these tumours, we selected a cohort of 18 undifferentiated endometrial carcinomas, 8 of them with a well differentiated endometrioid carcinoma component (dedifferentiated endometrioid carcinomas), and studied them by immunohistochemistry and massive parallel and Sanger sequencing. Whole exome sequencing of the endometrioid and undifferentiated components as well as normal myometrium, was also carried out in one case. According to The Cancer Genome Atlas classification, we distributed 95% of the undifferentiated carcinomas in this series as follows: a) hypermutated tumours with loss of any mismatch repair protein expression and microsatellite instability (eight cases, 45%); b) ultramutated carcinomas carrying mutations in the exonuclease domain of POLE (two cases, 11%); c) high copy number alterations (copy-number high) tumours group exhibiting only TP53 mutations and high number of alterations detected by FISH (two cases, 11%) ; and d) low copy number alterations (copy-number low) tumours with molecular alterations typical of endometrioid endometrial carcinomas (five cases, 28%). Two of the latter cases, however, also had TP53 mutations and higher number of alterations detected by FISH and could have progressed to a copy-number high phenotype. Most dedifferentiated carcinomas belonged to the hypermutated group whereas pure undifferentiated carcinomas shared molecular genetic alterations with copy-number low or copy-number high tumours. These results indicate that undifferentiated and dedifferentiated endometrial carcinomas are molecularly heterogeneous tumours, which may have prognostic value. PMID:27491810

Integrating multiple immunogenetic data sources for feature extraction and mining somatic hypermutation patterns: the case of "towards analysis" in chronic lymphocytic leukaemia.

PubMed

Kavakiotis, Ioannis; Xochelli, Aliki; Agathangelidis, Andreas; Tsoumakas, Grigorios; Maglaveras, Nicos; Stamatopoulos, Kostas; Hadzidimitriou, Anastasia; Vlahavas, Ioannis; Chouvarda, Ioanna

2016-06-06

Somatic Hypermutation (SHM) refers to the introduction of mutations within rearranged V(D)J genes, a process that increases the diversity of Immunoglobulins (IGs). The analysis of SHM has offered critical insight into the physiology and pathology of B cells, leading to strong prognostication markers for clinical outcome in chronic lymphocytic leukaemia (CLL), the most frequent adult B-cell malignancy. In this paper we present a methodology for integrating multiple immunogenetic and clinocobiological data sources in order to extract features and create high quality datasets for SHM analysis in IG receptors of CLL patients. This dataset is used as the basis for a higher level integration procedure, inspired form social choice theory. This is applied in the Towards Analysis, our attempt to investigate the potential ontogenetic transformation of genes belonging to specific stereotyped CLL subsets towards other genes or gene families, through SHM. The data integration process, followed by feature extraction, resulted in the generation of a dataset containing information about mutations occurring through SHM. The Towards analysis performed on the integrated dataset applying voting techniques, revealed the distinct behaviour of subset #201 compared to other subsets, as regards SHM related movements among gene clans, both in allele-conserved and non-conserved gene areas. With respect to movement between genes, a high percentage movement towards pseudo genes was found in all CLL subsets. This data integration and feature extraction process can set the basis for exploratory analysis or a fully automated computational data mining approach on many as yet unanswered, clinically relevant biological questions.

Turning negative memories around: Contingency versus devaluation techniques.

PubMed

Dibbets, Pauline; Lemmens, Anke; Voncken, Marisol

2018-09-01

It is assumed that fear responses can be altered by changing the contingency between a conditioned stimulus (CS) and an unconditioned stimulus (US), or by devaluing the present mental representation of the US. The aim of the present study was to compare the efficacy of contingency- and devaluation-based intervention techniques on the diminishment in - and return of fear. We hypothesized that extinction (EXT, contingency-based) would outperform devaluation-based techniques regarding contingency measures, but that devaluation-based techniques would be most effective in reducing the mental representation of the US. Additionally, we expected that incorporations of the US during devaluation would result in less reinstatement of the US averseness. Healthy participants received a fear conditioning paradigm followed by one of three interventions: extinction (EXT, contingency-based), imagery rescripting (ImRs, devaluation-based) or eye movement desensitization and reprocessing (EMDR, devaluation-based). A reinstatement procedure and test followed the next day. EXT was indeed most successful in diminishing contingency-based US expectancies and skin conductance responses (SCRs), but all interventions were equally successful in reducing the averseness of the mental US representation. After reinstatement EXT showed lowest expectancies and SCRs; no differences were observed between the conditions concerning the mental US representation. A partial reinforcement schedule was used, resulting in a vast amount of contingency unaware participants. Additionally, a non-clinical sample was used, which may limit the generalizability to clinical populations. EXT is most effective in reducing conditioned fear responses. Copyright © 2018 Elsevier Ltd. All rights reserved.

Procedures for Establishing a Contingency Managed Classroom.

ERIC Educational Resources Information Center

Westinghouse Learning Corp., Albuquerque, NM. Behavior Systems Div.

This manual for classroom teachers is designed to teach the application of contingency contracting procedures in the typical instructional setting. A "contingency contract" is an agreement between teacher and student whereby the student, upon demonstration of specific task achievement, receives a reward: permission to participate in a "reinforcing…

Understanding the Growth of Contingent Faculty

ERIC Educational Resources Information Center

McNaughtan, Jon; García, Hugo A.; Nehls, Kim

2017-01-01

This chapter presents demographic characteristics of contingent faculty across and within higher education sectors. The descriptive data provide insight into how each sector's hiring patterns have changed over the past 30 years. Results indicate that regardless of institutional type, the role of contingent faculty has increased and will likely…

40 CFR 304.12 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., 42 U.S.C. 9601, or the National Oil and Hazardous Substances Pollution Contingency Plan, 40 CFR part... any party, and any attorney of record for any of the foregoing persons. (h) National Contingency Plan or NCP means the National Oil and Hazardous Substances Pollution Contingency Plan, developed under...

A Comparison of Group-Oriented Contingencies for Addition Fluency

ERIC Educational Resources Information Center

Gross, Thomas J.; Duhon, Gary J.; Shutte, Greg; Rowland, Julie E.

2016-01-01

Math fact fluency is critical for understanding complex mathematics. Explicit timing interventions have shown promise for improving math fluency, and they may benefit from being paired with group-oriented contingencies. Further, investigations of independent and dependent group-oriented contingencies would help to identify their relative…

Effects of Mother-Infant Social Interactions on Infants' Subsequent Contingency Task Performance.

ERIC Educational Resources Information Center

Dunham, Philip; Dunham, Frances

1990-01-01

Infants participated in a nonsocial contingency task immediately after a social interaction with their mothers. The amount of time mothers and infants spent in a state of vocal turn-taking predicted individual differences in infants' subsequent performance on the contingency task. (PCB)

77 FR 11519 - Commission Information Collection Activities; Comment Request; Extension

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-27

... collection, FERC-585, Reporting of Electric Energy shortages and Contingency Plans under PURPA. DATES... shortages and Contingency Plans under PURPA. OMB Control No.: 1902-0138. Type of Request: Three-year... Energy Shortages and Contingency Plans under PURPA'', is used by the Commission to implement the...

Contingency Contractor Optimization Phase 3 Sustainment Database Design Document - Contingency Contractor Optimization Tool - Prototype

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frazier, Christopher Rawls; Durfee, Justin David; Bandlow, Alisa

The Contingency Contractor Optimization Tool – Prototype (CCOT-P) database is used to store input and output data for the linear program model described in [1]. The database allows queries to retrieve this data and updating and inserting new input data.

40 CFR 51.152 - Contingency plans.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 2 2012-07-01 2012-07-01 false Contingency plans. 51.152 Section 51.152 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS REQUIREMENTS... emergency agencies and news media. (c) Each plan for a Priority IA and II region must include a contingency...

40 CFR 51.152 - Contingency plans.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 2 2014-07-01 2014-07-01 false Contingency plans. 51.152 Section 51.152 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS REQUIREMENTS... emergency agencies and news media. (c) Each plan for a Priority IA and II region must include a contingency...

40 CFR 51.152 - Contingency plans.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 2 2011-07-01 2011-07-01 false Contingency plans. 51.152 Section 51.152 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS REQUIREMENTS... emergency agencies and news media. (c) Each plan for a Priority IA and II region must include a contingency...

40 CFR 51.152 - Contingency plans.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 2 2013-07-01 2013-07-01 false Contingency plans. 51.152 Section 51.152 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS REQUIREMENTS... emergency agencies and news media. (c) Each plan for a Priority IA and II region must include a contingency...

10 CFR Appendix C to Part 73 - Nuclear Power Plant Safeguards Contingency Plans

Code of Federal Regulations, 2010 CFR

2010-01-01

.... Licensee's Organizational Structure for Contingency Responses—A delineation of the organization's chain of.... The following topics must be addressed: a. Organizational Structure. The safeguards contingency plan... individual, group, or organizational entity responsible for each decision and action. The goals of licensee...

75 FR 1269 - Dried Prunes Produced in California; Decreased Assessment Rate

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-11

... rate was possible due to significant decreases in operating expenses and contingencies, and a... and for contingencies. Most of the Committee's expenses reflect its portion of the joint..., $11,780 for operating expenses, and $15,908 for contingencies. In comparison, budgeted expenses for...

Training Eye-Pointing Behavior in a Nonabulatory Profoundly Mentally Retarded Child Using Contingent Vibratory Stimulation.

ERIC Educational Resources Information Center

Zucker, Stanley H.; And Others

1980-01-01

Contingent vibration was used to train a precommunication response in a spastic/quadriplegic profoundly mentally retarded boy (age 11). The results indicated an increase in the S's eye pointing behavior subsequent to the administration of response contingent vibration. (Author)

78 FR 65210 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-31

..., Intergovernmental relations, Penalties, Reporting and recordkeeping requirements, Superfund, Water pollution control...] National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List: Deletion of the... Substances Pollution Contingency Plan (NCP). The EPA and the State of California, through the California...

76 FR 50164 - National Oil and Hazardous Substance Pollution Contingency Plan National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-12

..., Reporting and recordkeeping requirements, Superfund, Water pollution control, Water supply. Authority: 33 U... and Hazardous Substance Pollution Contingency Plan National Priorities List: Deletion of the Pasley..., as amended, is an Appendix of the National Oil and Hazardous Substances Pollution Contingency Plan...

40 CFR 264.55 - Emergency coordinator.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Contingency Plan and Emergency Procedures § 264.55 Emergency coordinator. At all times, there must be at least...'s contingency plan, all operations and activities at the facility, the location and characteristics... addition, this person must have the authority to commit the resources needed to carry out the contingency...

Contingent Imitation Increases Verbal Interaction in Children with Autism Spectrum Disorders

ERIC Educational Resources Information Center

Ishizuka, Yuka; Yamamoto, Jun-ichi

2016-01-01

Several studies have suggested that contingent adult imitation increase nonverbal communication, such as attention and proximity to adults, in children with autism spectrum disorders. However, few studies have shown the effect of contingent imitation on verbal communication. This study examined whether children with autism were able to promote…

30 CFR 582.26 - Contingency Plan.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 30 Mineral Resources 2 2014-07-01 2014-07-01 false Contingency Plan. 582.26 Section 582.26 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE OPERATIONS IN THE OUTER... as part of its request for approval of a Delineation, Testing, or Mining Plan. The Contingency Plan...

30 CFR 282.26 - Contingency Plan.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 30 Mineral Resources 2 2011-07-01 2011-07-01 false Contingency Plan. 282.26 Section 282.26 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, REGULATION, AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR... Mining Plan. The Contingency Plan shall comply with the requirements of § 282.28(e) of this part. (b) The...

30 CFR 582.26 - Contingency Plan.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 30 Mineral Resources 2 2013-07-01 2013-07-01 false Contingency Plan. 582.26 Section 582.26 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE OPERATIONS IN THE OUTER... as part of its request for approval of a Delineation, Testing, or Mining Plan. The Contingency Plan...

30 CFR 582.26 - Contingency Plan.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 30 Mineral Resources 2 2012-07-01 2012-07-01 false Contingency Plan. 582.26 Section 582.26 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE OPERATIONS IN THE OUTER... as part of its request for approval of a Delineation, Testing, or Mining Plan. The Contingency Plan...

Dissociating Contingency Awareness and Conditioned Attitudes: Evidence of Contingency-Unaware Evaluative Conditioning

ERIC Educational Resources Information Center

Hutter, Mandy; Sweldens, Steven; Stahl, Christoph; Unkelbach, Christian; Klauer, Karl Christoph

2012-01-01

Whether human evaluative conditioning can occur without contingency awareness has been the subject of an intense and ongoing debate for decades, troubled by a wide array of methodological difficulties. Following recent methodological innovations, the available evidence currently points to the conclusion that evaluative conditioning effects do not…

The Role of Relational Information in Contingent Capture

ERIC Educational Resources Information Center

Becker, Stefanie I.; Folk, Charles L.; Remington, Roger W.

2010-01-01

On the contingent capture account, top-down attentional control settings restrict involuntary attentional capture to items that match the features of the search target. Attention capture is involuntary, but contingent on goals and intentions. The observation that only target-similar items can capture attention has usually been taken to show that…

33 CFR 385.28 - Operating Manuals.

Code of Federal Regulations, 2010 CFR

2010-07-01

... natural system; (vii) Include a drought contingency plan as required by § 222.5(i)(5) of this chapter and Engineer Regulation ER 1110-2-1941 “Drought Contingency Plans” that is consistent with the Water Rights... events, as well as by including a drought contingency plan. (A) Emergency deviations. Examples of some...

33 CFR 385.28 - Operating Manuals.

Code of Federal Regulations, 2013 CFR

2013-07-01

... natural system; (vii) Include a drought contingency plan as required by § 222.5(i)(5) of this chapter and Engineer Regulation ER 1110-2-1941 “Drought Contingency Plans” that is consistent with the Water Rights... events, as well as by including a drought contingency plan. (A) Emergency deviations. Examples of some...

33 CFR 385.28 - Operating Manuals.

Code of Federal Regulations, 2012 CFR

2012-07-01

... natural system; (vii) Include a drought contingency plan as required by § 222.5(i)(5) of this chapter and Engineer Regulation ER 1110-2-1941 “Drought Contingency Plans” that is consistent with the Water Rights... events, as well as by including a drought contingency plan. (A) Emergency deviations. Examples of some...

33 CFR 385.28 - Operating Manuals.

Code of Federal Regulations, 2011 CFR

2011-07-01

... natural system; (vii) Include a drought contingency plan as required by § 222.5(i)(5) of this chapter and Engineer Regulation ER 1110-2-1941 “Drought Contingency Plans” that is consistent with the Water Rights... events, as well as by including a drought contingency plan. (A) Emergency deviations. Examples of some...

33 CFR 385.28 - Operating Manuals.

Code of Federal Regulations, 2014 CFR

2014-07-01

... natural system; (vii) Include a drought contingency plan as required by § 222.5(i)(5) of this chapter and Engineer Regulation ER 1110-2-1941 “Drought Contingency Plans” that is consistent with the Water Rights... events, as well as by including a drought contingency plan. (A) Emergency deviations. Examples of some...

40 CFR 300.210 - Federal contingency plans.

Code of Federal Regulations, 2010 CFR

2010-07-01

... contingency plans under the national response system: The National Contingency Plan, RCPs, and ACPs. These... discharge under § 300.324, and to mitigate or prevent a substantial threat of such a discharge, from a vessel, offshore facility, or onshore facility operating in or near the area. (2) The areas of...

26 CFR 1.1275-4 - Contingent payment debt instruments.

Code of Federal Regulations, 2010 CFR

2010-04-01

... issued for money or publicly traded property and paragraph (c) of this section applies to a contingent payment debt instrument that is issued for nonpublicly traded property. Paragraph (d) of this section....1273-2 (e.g., a contingent payment debt instrument that is issued for money or publicly traded property...

40 CFR 264.52 - Content of contingency plan.

Code of Federal Regulations, 2012 CFR

2012-07-01

... waste management provisions that are sufficient to comply with the requirements of this part. The owner... that the plan be based on the National Response Team's Integrated Contingency Plan Guidance (“One Plan”). When modifications are made to non-RCRA provisions in an integrated contingency plan, the changes do...

Better off Jobless? Scarring Effects of Contingent Employment in Japan

ERIC Educational Resources Information Center

Yu, Wei-hsin

2012-01-01

Previous research fails to address whether contingent employment benefits individuals' careers more than the alternative they often face: being without a job. Using work history data from Japan, this study shows that accepting a contingent job delays individuals' transition to standard employment more than remaining jobless. Moreover, having a…

40 CFR 265.51 - Purpose and implementation of contingency plan.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 25 2010-07-01 2010-07-01 false Purpose and implementation of contingency plan. 265.51 Section 265.51 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... contingency plan must be designed to minimize hazards to human health or the environment from fires...

Interdependent Group Contingency Management for Cocaine-Dependent Methadone Maintenance Patients

ERIC Educational Resources Information Center

Kirby, Kimberly C.; Kerwin, MaryLouise E.; Carpenedo, Carolyn M.; Rosenwasser, Beth J.; Gardner, Robert S.

2008-01-01

Contingency management (CM) for drug abstinence has been applied to individuals independently even when delivered in groups. We developed a group CM intervention in which the behavior of a single, randomly selected, anonymous individual determined reinforcement delivery for the entire group. We also compared contingencies placed only on cocaine…

Frequency, Contingency and Online Processing of Multiword Sequences: An Eye-Tracking Study

ERIC Educational Resources Information Center

Yi, Wei; Lu, Shiyi; Ma, Guojie

2017-01-01

Frequency and contingency are two primary statistical factors that drive the acquisition and processing of language. This study explores the role of phrasal frequency and contingency (the co-occurrence probability/statistical association of the constituent words in multiword sequences) during online processing of multiword sequences. Meanwhile, it…

A Contingency Framework for Listening to the Dying

ERIC Educational Resources Information Center

Vora, Erika; Vora, Ariana

2008-01-01

Listening to the dying poses special challenges. This paper proposes a contingency framework for describing and assessing various circumstances when listening to the dying. It identifies current approaches to listening, applies the contingency framework toward effectively listening to the dying, and proposes a new type of listening called…

77 FR 46009 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-02

... and Hazardous Substances Pollution Contingency Plan; National Priorities List: Partial Deletion of the... Substances Pollution Contingency Plan (NCP). The EPA and the State of Maine, through the Maine Department of... preclude future actions under Superfund. This partial deletion pertains to all Site media (including soil...

76 FR 58404 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-21

... and Hazardous Substances Pollution Contingency Plan; National Priorities List: Partial Deletion of the..., as amended, is an appendix of the National Oil and Hazardous Substances Pollution Contingency Plan... opportunities for investigation and soil remediation, if the Program's Work Group determines that lead in...

76 FR 11350 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-02

... and Hazardous Substances Pollution Contingency Plan; National Priorities List: Partial Deletion of the... appendix of the National Oil and Hazardous Substances Pollution Contingency Plan (NCP). This partial deletion pertains to the soil and ground water associated with the northern 62-acre parcel. After this...

77 FR 31215 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-25

... and Hazardous Substances Pollution Contingency Plan; National Priorities List: Partial Deletion of the... National Oil and Hazardous Substances Pollution Contingency Plan (NCP). This partial deletion pertains to the surface soil, unsaturated subsurface soil, surface water and sediments of Operable Unit (OU) 1...

Collectivists' Contingency and Autonomy as Predictors of Buffet Preferences among Taiwanese Adolescents

ERIC Educational Resources Information Center

Chiou, Wen-Bin

2006-01-01

In a culture or society with high collectivism, contingent orientation and constrained autonomy are the prominent characteristics of adolescents' self-construal. This article examined whether Taiwanese adolescents' contingency and autonomy were associated with their prevalent preferences for buffet consumption. Findings in a panel survey indicated…

76 FR 18136 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-01

... and Hazardous Substances Pollution Contingency Plan; National Priorities List: Deletion of the Norwood... amended, is an appendix of the National Oil and Hazardous Substances Pollution Contingency Plan (NCP). The... we view this as a noncontroversial revision and anticipate no adverse comment. We have explained our...

75 FR 54821 - National Oil and Hazardous Substance Pollution Contingency Plan; National Priorities List; Intent...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-09

... and Hazardous Substance Pollution Contingency Plan; National Priorities List; Intent for Partial... amended, is an Appendix of the National Oil and Hazardous Substances Pollution Contingency Plan (NCP). The... Superfund Site without prior Notice of Intent for Partial Deletion because EPA views this as a...

76 FR 32115 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-03

... and Hazardous Substances Pollution Contingency Plan; National Priorities List: Intent To Delete the... Substances Pollution Contingency Plan (NCP). The EPA and the State of Delaware, through the Delaware... Delete because EPA views this as a noncontroversial revision and anticipates no adverse comment. We have...

78 FR 69360 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-19

...] National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List: Partial... and Hazardous Substances Pollution Contingency Plan (NCP). The EPA and the State of California... Corp Air Station Superfund Site without prior Notice of Intent for Partial Deletion because EPA views...

78 FR 44512 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-24

... and Hazardous Substances Pollution Contingency Plan; National Priorities List: Deletion of the Sola... Pollution Contingency Plan (NCP). The EPA and the State of California, through the Regional Water Quality...., Inc. Superfund Site without prior Notice of Intent to Delete because we view this as a...

76 FR 20605 - National Oil and Hazardous Substance Pollution Contingency Plan National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-13

... and Hazardous Substance Pollution Contingency Plan National Priorities List: Deletion of the... Substances Pollution Contingency Plan (NCP). EPA and the State of Michigan, through the Michigan Department... Delete because we view this as a noncontroversial revision and anticipate no adverse comment. We have...

78 FR 11620 - National Oil and Hazardous Substances Pollution Contingency Plan National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-19

... and Hazardous Substances Pollution Contingency Plan National Priorities List: Deletion of the Kerr... Substances Pollution Contingency Plan (NCP). EPA and the State of Illinois, through the Illinois... because we view this as a noncontroversial revision and anticipate no adverse comment. We have explained...

76 FR 51316 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-18

... and Hazardous Substances Pollution Contingency Plan; National Priorities List: Deletion of the... Contingency Plan (NCP). The EPA and the Commonwealth of Puerto Rico, through the Puerto Rico Environmental... Site without prior Notice of Intent to Delete because we view this as a noncontroversial revision and...

78 FR 45167 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-26

... and Hazardous Substances Pollution Contingency Plan; National Priorities List: Deletion of the Cannon... Substances Pollution Contingency Plan (NCP). The EPA and the State of Massachusetts, through the...), Superfund Site without prior Notice of Intent to Delete because we view this as a noncontroversial revision...

75 FR 43115 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-23

... and Hazardous Substances Pollution Contingency Plan; National Priorities List: Intent to Partially..., as amended, is an appendix of the National Oil and Hazardous Substances Pollution Contingency Plan... Intent for Partial Deletion because EPA views this as a noncontroversial revision and anticipates no...

78 FR 45905 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-30

... and Hazardous Substances Pollution Contingency Plan; National Priorities List: Deletion of the Craig... Substances Pollution Contingency Plan (NCP). The EPA and the Commonwealth of Pennsylvania, through the... Craig Farm Drum Superfund Site without prior Notice of Intent to Delete because we view this as a...

18 CFR 375.303 - Delegations to the Director of the Office of Electric Reliability.

Code of Federal Regulations, 2010 CFR

2010-04-01

... uncontested contingency plans regarding shortages of electric energy or capacity, circumstances which may result in such shortages, and accommodations of any such shortages or circumstances, if said contingency... Commission, if the filings comply with the terms of the waivers; (ii) Reject a contingency plan regarding...

76 FR 45484 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-29

... and Hazardous Substances Pollution Contingency Plan; National Priorities List: Notice of Intent for..., as amended, is an appendix of the National Oil and Hazardous Substances Pollution Contingency Plan... PBL Superfund Site without prior Notice of Intent for Deletion because EPA views this as a...

78 FR 47267 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-05

... and Hazardous Substances Pollution Contingency Plan; National Priorities List: Deletion of the... Contingency Plan (NCP). The EPA and the State of Oklahoma, through the Oklahoma Department of Environmental... without prior Notice of Intent to Delete because we view this as a noncontroversial revision and...

77 FR 67783 - National Oil and Hazardous Substance Pollution Contingency Plan National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-14

... and Hazardous Substance Pollution Contingency Plan National Priorities List: Deletion of the Waste... and Hazardous Substances Pollution Contingency Plan (NCP). EPA and the State of Michigan, through the...-Holland Lagoons Superfund Site without prior Notice of Intent to Delete because we view this as a...

Towards a Balanced Account of Autism Etiology

ERIC Educational Resources Information Center

Hall, Genae A.

2004-01-01

Drash and Tudor describe six sets of reinforcement contingencies which may be present in the environments of some children eventually diagnosed with autism and suggest that these contingencies account for the etiology of "autistic" behaviors. Nevertheless, merely observing such contingencies in the environments of these children is insufficient to…

Conditions for Contingent Instructors Engaged in the Scholarship of Teaching and Learning

ERIC Educational Resources Information Center

Vander Kloet, Marie; Frake-Mistak, Mandy; McGinn, Michelle K.; Caldecott, Marion; Aspenlieder, Erin D.; Beres, Jacqueline L.; Fukuzawa, Sherry; Cassidy, Alice; Gill, Apryl

2017-01-01

An increasingly large number of courses in Canadian postsecondary institutions are taught by contingent instructors who hold full- or part-time positions for contractually limited time periods. Despite strong commitments to advancing teaching and learning, the labour and employment conditions for contingent instructors affect the incentives and…

78 FR 63099 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-23

..., Superfund, Water pollution control, Water supply. Dated: September 26, 2013. Judith A. Enck, Regional...] National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List: Deletion of the... Pollution Contingency Plan (NCP). The EPA and the State of New York, through the Department of Environmental...

CW-FIT: Group Contingency Effects across the Day

ERIC Educational Resources Information Center

Wills, Howard P.; Iwaszuk, Wendy M.; Kamps, Debra; Shumate, Emily

2014-01-01

This study explored the effects of a group-contingency intervention on student behavior across academic instructional periods. Research suggests group contingencies are evidence-based practices, yet calls for investigation to determine the best conditions and groups suited for this type of intervention. CW-FIT (Class-Wide Function-related…

Collegiate contingencies

PubMed Central

Lamal, P. A.; Rakos, Richard F.; Greenspoon, Joel

2000-01-01

We discuss contemporary trends and developments that affect colleges and universities and describe several central contingencies that have given rise to, maintain, and operate in response to these trends and developments. We identify the differential impacts of these contingencies on faculty, students, and administrators in various types of higher education institutions. These contingencies are sources of conflict between and among these three groups within the academy that, we argue, cause significant instability in contemporary academe. We discuss prominent domains of this dis-equilibrium and propose several general interventions to address the sources of the instability. PMID:22478348

The effects of modeling contingencies in the treatment of food selectivity in children with autism.

PubMed

Fu, Sherrene B; Penrod, Becky; Fernand, Jonathan K; Whelan, Colleen M; Griffith, Kristin; Medved, Shannon

2015-11-01

The current study investigated the effectiveness of stating and modeling contingencies in increasing food consumption for two children with food selectivity. Results suggested that stating and modeling a differential reinforcement (DR) contingency for food consumption was effective in increasing consumption of two target foods for one child, and stating and modeling a DR plus nonremoval of the spoon contingency was effective in increasing consumption of the remaining food for the first child and all target foods for the second child. © The Author(s) 2015.

Skype me! Socially contingent interactions help toddlers learn language.

PubMed

Roseberry, Sarah; Hirsh-Pasek, Kathy; Golinkoff, Roberta M

2014-01-01

Language learning takes place in the context of social interactions, yet the mechanisms that render social interactions useful for learning language remain unclear. This study focuses on whether social contingency might support word learning. Toddlers aged 24-30 months (N = 36) were exposed to novel verbs in one of three conditions: live interaction training, socially contingent video training over video chat, and noncontingent video training (yoked video). Results suggest that children only learned novel verbs in socially contingent interactions (live interactions and video chat). This study highlights the importance of social contingency in interactions for language learning and informs the literature on learning through screen media as the first study to examine word learning through video chat technology. © 2013 The Authors. Child Development © 2013 Society for Research in Child Development, Inc.

Masculinity impediments: Internalized masculinity contributes to healthcare avoidance in men and women.

PubMed

Himmelstein, Mary S; Sanchez, Diana T

2016-07-01

Gender beliefs contribute to men's healthcare avoidance, but little research examines these outcomes in women. This article models healthcare avoidance related to masculine contingencies of self-worth in men and women. Nested path modelling tested relationships between social role beliefs, masculine contingencies of self-worth, barriers to help seeking and avoidance of health care in university and non-university-student adult samples. Results indicated social role beliefs predicted masculine contingencies of self-worth in men but not in women. Regardless of gender, masculine contingencies of self-worth predicted barriers to help seeking, which predicted healthcare avoidance in both men and women. Thus, masculine contingencies of self-worth have downstream consequences for men and women through barriers to help seeking. © The Author(s) 2014.

Multiple effects of performance-contingent pay for wait-persons

PubMed Central

George, James T.; Hopkins, B. L.

1989-01-01

The owners of three restaurants requested help with the pay of waitpersons who were paid by the hour. The waitpersons asked for raises which the owners said they could not afford. This research changed the method of compensating waitpersons by making their pay contingent on dollars of food sold. Increased productivity and increased earnings per hour of work for all of the waitpersons followed the beginning of the performance-contingent pay. Most of the waitpersons also earned increased take-home pay when the performance-contingent pay began. There was little improvement in labor costs per dollar of food sold, a measure of benefit to the owners. The fact that benefits to workers occurred without benefits to owners is contrary to common views about the effects of performance-contingent pay. PMID:16795723

On the generality of the displaywide contingent orienting hypothesis: can a visual onset capture attention without top-down control settings for displaywide onset?

PubMed

Yeh, Su-Ling; Liao, Hsin-I

2010-10-01

The contingent orienting hypothesis (Folk, Remington, & Johnston, 1992) states that attentional capture is contingent on top-down control settings induced by task demands. Past studies supporting this hypothesis have identified three kinds of top-down control settings: for target-specific features, for the strategy to search for a singleton, and for visual features in the target display as a whole. Previously, we have found stimulus-driven capture by onset that was not contingent on the first two kinds of settings (Yeh & Liao, 2008). The current study aims to test the third kind: the displaywide contingent orienting hypothesis (Gibson & Kelsey, 1998). Specifically, we ask whether an onset stimulus can still capture attention in the spatial cueing paradigm when attentional control settings for the displaywide onset of the target are excluded by making all letters in the target display emerge from placeholders. Results show that a preceding uninformative onset cue still captured attention to its location in a stimulus-driven fashion, whereas a color cue captured attention only when it was contingent on the setting for displaywide color. These results raise doubts as to the generality of the displaywide contingent orienting hypothesis and help delineate the boundary conditions on this hypothesis. Copyright © 2010 Elsevier B.V. All rights reserved.

Using contingency management procedures to reduce at-risk drinking in heavy drinkers.

PubMed

Dougherty, Donald M; Lake, Sarah L; Hill-Kapturczak, Nathalie; Liang, Yuanyuan; Karns, Tara E; Mullen, Jillian; Roache, John D

2015-04-01

Treatments for alcohol use disorders typically have been abstinence based, but harm reduction approaches that encourage drinkers to alter their drinking behavior to reduce the probability of alcohol-related consequences, have gained in popularity. This study used a contingency management procedure to determine its effectiveness in reducing alcohol consumption among heavy drinkers. Eighty-two nontreatment-seeking heavy drinkers (ages 21 to 54, M = 30.20) who did not meet diagnostic criteria for alcohol dependence participated in the study. The study had 3 phases: (i) an Observation phase (4 weeks) where participants drank normally; (ii) a Contingency Management phase (12 weeks) where participants were paid $50 weekly for not exceeding low levels of alcohol consumption as measured by transdermal alcohol concentrations, <0.03 g/dl; and (iii) a Follow-up phase (12 weeks) where participants (n = 66) returned monthly for 3 months to self-report drinking after the contingencies were removed. Transdermal alcohol monitors were used to verify meeting contingency requirements; all other analyses were conducted on self-reported alcohol use. On average 42.3% of participants met the contingency criteria and were paid an average of $222 during the Contingency Management phase, with an average $1,998 in total compensation throughout the study. Compared to the Observation phase, the percent of any self-reported drinking days significantly decreased from 59.9 to 40.0% in the Contingency Management and 32.0% in the Follow-up phases. The percent of self-reported heavy drinking days reported also significantly decreased from 42.4% in the Observation phase to 19.7% in the Contingency Management phase, which was accompanied by a significant increase in percent days of self-reported no (from 40.1 to 60.0%) and low-level drinking (from 9.9 to 15.4%). Self-reported reductions in drinking either persisted, or became more pronounced, during the Follow-up phase. Contingency management was associated with a reduction in self-reported episodes of heavy drinking among nontreatment-seeking heavy drinkers. These effects persisted even after incentives were removed, indicating the potential utility of contingency management as a therapeutic intervention to reduce harmful patterns of drinking. Copyright © 2015 by the Research Society on Alcoholism.

High-resolution mapping of the x-linked hypohidrotic ectodermal dysplasia (EDA) locus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zonana, J.; Jones, M.; Litt, M.

1992-11-01

The X-linked hypohidrotic ectodermal dysplasia (EDA) locus has been previously localized to the subchromosomal region Xq11-q21.1. The authors have extended previous linkage studies and analyzed linkage between the EDA locus and 10 marker loci, including five new loci, in 41 families. Four of the marker loci showed no recombination with the EDA locus, and six other loci were also linked to the EDA locus with recombination fractions of .009-.075. Multipoint analysis gave support to the placement of the PGK1P1 locus proximal to the EDA locus and the DXS453 and PGK1 loci distal to EDA. Further ordering of the loci couldmore » be inferred from a human-rodent somatic cell hybrid derived from an affected female with EDA and an X;9 translocation and from studies of an affected male with EDA and a submicroscopic deletion. Three of the proximal marker loci, which showed no recombination with the EDA locus, when used in combination, were informative in 92% of females. The closely linked flanking polymorphic loci DXS339 and DXS453 had heterozygosites of 72% and 76%, respectively, and when used jointly, they were doubly informative in 52% of females. The human DXS732 locus was defined by a conserved mouse probe pcos169E/4 (DXCrc169 locus) that consegregates with the mouse tabby (Ta) locus, a potential homologue to the EDA locus. The absence of recombination between EDA and the DXSA732 locus lends support to the hypothesis that the DXCrc169 locus in the mouse and the DXS732 locus in humans may contain candidate sequences for the Ta and EDA genes, respectively. 36 refs., 1 fig., 5 tabs.« less

Cognitive functioning correlates of self-esteem and health locus of control in schizophrenia

PubMed Central

Wang, Chien-Shu; Wu, Jo Yung-Wei; Chang, Wei-Chung; Chuang, Shu-Ping

2013-01-01

Aim The study aimed to investigate the relationship among sociodemographic factors, neurocognitive factors, self-esteem, and health locus of control in patients diagnosed with schizophrenia. We examined the self-esteem, internal health locus of control, and external health locus of control through sociodemographic and neurocognitive factors. Methods Forty-six schizophrenic patients and 31 healthy residents from the community or hospital were recruited as the control group. All subjects participated in the self-esteem questionnaire, health locus of control questionnaire, and a series of neuropychological measures. Results Multiple regression analysis revealed that inhibition of attention and external health locus of control were predictors for self-esteem (r=−0.30, P<0.05; r=0.41, P<0.01); inhibition of attention and external health locus of control were contributors for internal health locus of control (r=−0.43, P<0.01; r=0.61, P<0.001); and education was related to external health locus of control (r=−0.31, P<0.05). Conclusion The current study integrated background characteristics and cognitive function to better understand the impact of self-esteem and health locus of control in schizophrenia. The findings indicated that inhibition of attention, external health locus of control, and education contributed to self-esteem, internal health locus of control and external health locus of control. However, the overall predicted variance accounted for by these predictors was small; thus, further research is necessary to examine imperative variables related with self-esteem and health locus of control in schizophrenia. PMID:24194641

An Analysis of Response-Contingent Learning Experiences for Young Children.

ERIC Educational Resources Information Center

Hanson, Marci J.; Hanline, Mary Frances

1985-01-01

Three children with severe and multiple disabilities (8-25 months old) were provided contingent learning experiences via electromechanical apparatus. Results indicated that all three children increased the frequency of the target behavior. The data are equivocal as to whether or not children showed an awareness of the response-contingent feedback.…

The Influence of Social Contingencies on Teacher Education Students Undertaking a Rural Internship

ERIC Educational Resources Information Center

Hemmings, Brian; Kay, Russell; Kerr, Ron

2011-01-01

Hughes (1999) categorised non-work demands such as domestic responsibilities and health of family members (including self) as social contingencies. A literature review on social contingencies, examined from a medical, nursing, and allied health standpoint, revealed that certain factors, especially related to financial matters, impact directly on…

75 FR 27986 - Electronic Filing System-Web (EFS-Web) Contingency Option

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-19

...] Electronic Filing System--Web (EFS-Web) Contingency Option AGENCY: United States Patent and Trademark Office... availability of its patent electronic filing system, Electronic Filing System--Web (EFS-Web) by providing a new contingency option when the primary portal to EFS-Web has an unscheduled outage. Previously, the entire EFS...

An Experimental Test of the Contingency Model of Leadership Effectiveness.

ERIC Educational Resources Information Center

Chemers, Martin M.; Skrzypek, George J.

The present experiment provided a test of Fiedler's (1967) Contingency Model of Leadership Effectiveness, i.e., the relationship of leader style to group effectiveness is mediated by situational demands. Thirty-two 4 man task groups composed of military academy cadets were run in the experiment. In accordance with the Contingency Model, leaders…

Efficacy and Maintenance of an Education Program for a Consumer Cooperative.

ERIC Educational Resources Information Center

Altus, Deborah E.; And Others

1993-01-01

This study examined the effects of contingency management on participation in an education program by new members of a student housing cooperative. With credit and fine contingencies in place, the percentage of participants completing study guides was five times higher than without the contingencies. Members continued to implement the program for…

Investigation of Contingency Patterns of Teachers' Scaffolding in Teaching and Learning Mathematics

ERIC Educational Resources Information Center

Anwar; Yuwono, Ipung; Irawan, Edy Bambang; As'ari, Abdur Rahman

2017-01-01

The purpose of this study is to investigate the patterns of scaffolding contingency in teaching and learning mathematics carried out by three teachers. Contingency patterns are obtained by examining the transcription from video recording of conversation fragments between teachers and students during the provision of scaffolding. The contingency…

Contingent Fees in Medical Malpractice Litigation—A Qualitative Assessment

PubMed Central

Ottensmeyer, David J.; Smith, Howard L.; Porter, James

1983-01-01

The medical profession has experienced high liability insurance premiums accompanied by widespread use of contingent fees in medical malpractice litigation. It is worthwhile, therefore, to assess qualitatively the merits of contingent fees, the evidence suggesting that they are associated with unjustified litigation and their implications for the medical and legal professions. PMID:6636743

Flexible Workstyles: A Look at Contingent Labor. Conference Summary.

ERIC Educational Resources Information Center

Women's Bureau (DOL), Washington, DC.

This report summarizes the presentations and discussions at a conference on contingent labor sponsored by the U.S. Department of Labor. The first two sections are introductory: (1) "Introduction to the Role of Contingent Labor" (Kathleen Christensen, Mary Murphree); and (2) "Between Now and the Year 2000: A Glimpse of the Workplace" (Jill Houghton…

40 CFR 109.5 - Development and implementation criteria for State, local and regional oil removal contingency plans.

Code of Federal Regulations, 2012 CFR

2012-07-01

... OIL REMOVAL CONTINGENCY PLANS § 109.5 Development and implementation criteria for State, local and regional oil removal contingency plans. Criteria for the development and implementation of State, local and... 40 Protection of Environment 23 2012-07-01 2012-07-01 false Development and implementation...

The Contingent Use of Trading Stamps in Reducing Truancy: A Case Report.

ERIC Educational Resources Information Center

Zweig, John T.; And Others

1979-01-01

A 13-year-old learning-disabled subject received a daily amount of trading stamps contingent on school attendance. Results showed a significant decrease in truancy from three to four days per week to less than one. A reversal design indicated that truancy could be controlled by the contingency procedure. (Author/GDC)

Effects of Behavior-Contingent and Fixed-Time Release Contingencies on Frequency and Duration of Therapeutic Restraint

ERIC Educational Resources Information Center

Luiselli, James K.; Pace, Gary M.; Dunn, Erin K.

2006-01-01

Reducing therapeutic restraint is a desirable outcome for programs that serve individuals who exhibit challenging behaviors. This study investigated the effects of modifying the criterion for release from therapeutic restraint on frequency and duration. Release from restraint was changed from a behavior-contingent criterion (restraint terminated…

78 FR 71448 - Regional Reliability Standard BAL-002-WECC-2-Contingency Reserve

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-29

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission 18 CFR Part 40 [Docket No. RM13-13-000; Order No. 789] Regional Reliability Standard BAL-002-WECC-2--Contingency Reserve AGENCY: Federal Energy..., and Tony Clark. Regional Reliability Standard BAL-002-WECC-2--Contingency Reserve Docket No. RM13-13...

77 FR 35873 - Approval, Disapproval and Promulgation of Air Quality Implementation Plan; Utah; Maintenance Plan...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-15

... change the maintenance plan's trigger for contingency measures. Instead of a defined trigger, the revised plan would allow the State to consider several factors in deciding whether contingency measures should... the maintenance plan, the State must commit to implement one or more contingency measures within a set...

Randomized Trial of Contingent Prizes versus Vouchers in Cocaine-Using Methadone Patients

ERIC Educational Resources Information Center

Petry, Nancy M.; Alessi, Sheila M.; Hanson, Tressa; Sierra, Sean

2007-01-01

Contingency management (CM) interventions frequently utilize vouchers as reinforcers, but a prize-based system is also efficacious. This study compared these approaches. Seventy-four cocaine-dependent methadone outpatients were randomly assigned to standard treatment (ST), ST plus a maximum of $585 in contingent vouchers, or ST plus an expected…

Contingency Is Not Enough: Social Context Guides Third-Party Attributions of Intentional Agency

ERIC Educational Resources Information Center

Beier, Jonathan S.; Carey, Susan

2014-01-01

Four experiments investigated whether infants and adults infer that a novel entity that interacts in a contingent, communicative fashion with an experimenter is itself an intentional agent. The experiments contrasted the hypothesis that such an inference follows from amodal representations of the contingent interaction alone with the hypothesis…

Task-Contingent Conscientiousness as a Unit of Personality at Work

ERIC Educational Resources Information Center

Minbashian, Amirali; Wood, Robert E.; Beckmann, Nadin

2010-01-01

The present study examined the viability of incorporating task-contingent units into the study of personality at work, using conscientiousness as an illustrative example. We used experience-sampling data from 123 managers to show that (a) momentary conscientiousness at work is contingent on the difficulty and urgency demands of the tasks people…

Work Group Communication Modes and the Assessment of Contingency and Situational Models of Leadership.

ERIC Educational Resources Information Center

Stech, Ernest L.

A study of coordination modes in work group communication was conducted to evaluate and expand leadership contingency models. A total of 106 people in classes and workshops on organizational communication completed seven questionnaires resulting in nine measures of six independent variables representing the following contingency factors from…

Contingent Faculty at For-Profit Institutions

ERIC Educational Resources Information Center

Proper, Eve

2017-01-01

Most instruction at for-profit institutions is conducted by contingency faculty. This chapter will examine who contingency faculty are and how they have helped for-profits be the fastest growing higher education sector for the last 20 years. This chapter will also examine how having a majority of part-time faculty may also have negative impacts,…

77 FR 28861 - Commission Information Collection Activities (FERC-585); Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-16

... Energy shortages and Contingency Plans under PURPA, to the Office of Management and Budget (OMB) for... Contingency Plans under PURPA. OMB Control No.: 1902-0138. Type of Request: Three-year extension of the FERC... Contingency Plans under PURPA'', is used by the Commission to implement the statutory provisions of section...

Voucher-Based Contingent Reinforcement of Smoking Abstinence among Methadone-Maintained Patients: A Pilot Study

ERIC Educational Resources Information Center

Dunn, Kelly E.; Sigmon, Stacey C.; Thomas, Colleen S.; Heil, Sarah H.; Higgins, Stephen T.

2008-01-01

This study evaluated the efficacy of a contingency management (CM) intervention to promote smoking cessation in methadone-maintained patients. Twenty participants, randomized into contingent (n = 10) or noncontingent (n = 10) experimental conditions, completed the 14-day study. Abstinence was determined using breath carbon monoxide and urine…

Baseline Response Levels Are a Nuisance in Infant Contingency Learning

ERIC Educational Resources Information Center

Millar, W. S.; Weir, Catherine

2015-01-01

The impact of differences in level of baseline responding on contingency learning in the first year was examined by considering the response acquisition of infants classified into baseline response quartiles. Whereas the three lower baseline groups showed the predicted increment in responding to a contingency, the highest baseline responders did…

Safe Schools: Unified Emergency Contingency Plan for Schools.

ERIC Educational Resources Information Center

Illinois State Police, Springfield.

This contingency plan is intended to stimulate emergency planning and provide an organizational tool for Illinois schools to use in the development of individual emergency plans. It may accommodate and complement a school's current contingency plan and will allow for the inclusion of additional material concerning school safety. It is intended as…

78 FR 45152 - Approval and Promulgation of Implementation Plans and Designation of Areas; North Carolina...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-26

... available control measures (RACM), a reasonable further progress (RFP) plan, \\2\\ contingency measures, a..., contingency measures, and other planning SIP revisions related to attainment of the standard were suspended as...,'' Memorandum from G. T. Helms, Chief, Ozone/Carbon Monoxide Programs Branch, April 30, 1992; 3. ``Contingency...

76 FR 69895 - Approval and Promulgation of Implementation Plans; California; 2008 San Joaquin Valley PM2.5

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-09

... Control District and the California Air Resources Board. Finally, it is disapproving the SIP's contingency... that SIP revision on July 29, 2011. EPA also proposed to disapprove the contingency measures provisions... also today disapproving the SIP's contingency measure provisions because they do not provide sufficient...

78 FR 48318 - Approval and Promulgation of Air Quality Implementation Plans; Texas; Victoria County, 1997 8...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-08

... submitted a revision to the contingency portion of the Maintenance Plan. These submitted SIP revisions are..., penalties, milestones, contingency plans, and motor vehicle emission budgets. Consequently, the Court's... illustrating how the area will continue in attainment of the 1997 ozone NAAQS and contingency measures. Our...

Contingency Contracting and Operant Behavior Change: An Exercise in Applied Behavior Analysis.

ERIC Educational Resources Information Center

Mann, Ronald A.

Until recently, the use of contingency contracting has been largely an issue of theory and discussion with little experimental research evidence gathered to support efficacy. Two major reasons for this problem are suggested and discussed: (1) the concept of contingency contracting has not been adequately defined nor its minimal requirements…

75 FR 47521 - National Oil and Hazardous Substance Pollution Contingency Plan; National Priorities List: Intent...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-06

... and Hazardous Substance Pollution Contingency Plan; National Priorities List: Intent To Delete the... appendix of the National Oil and Hazardous Substances Pollution Contingency Plan (NCP). The EPA and the... Corporation (Markhams) Superfund Site without prior notice of intent to delete because we view this as a...

76 FR 45483 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-29

... and Hazardous Substances Pollution Contingency Plan; National Priorities List: Notice of Intent for... Contingency Plan (NCP). The EPA and the State of Texas, through the Texas Commission on Environmental Quality... Notice of Deletion for SMPA Superfund Site without prior Notice of Intent for Deletion because EPA views...

78 FR 66325 - National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-05

...] National Oil and Hazardous Substances Pollution Contingency Plan; National Priorities List: Deletion of the... Substances Pollution Contingency Plan (NCP). The EPA and the State of South Carolina, through the South... because we view this as a noncontroversial revision and anticipate no adverse comment. We have explained...