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Sample records for accent syndrome fas

  1. Transient foreign accent syndrome

    PubMed Central

    Bhandari, Hanul Srinivas

    2011-01-01

    Foreign accent syndrome (FAS) is a poorly understood and studied syndrome as it is indeed a rare entity. Since its first description in 1907 by French neurologist Pierre Marie involving a patient who presented with an Alsatian accent, there are approximately only 60 cases reported in the literature. The majority of such cases of FAS have been secondary to cerebrovascular accidents. Of the cases in the literature, none report such a transitory nature of FAS. In this particular case, a 55-year-old male presented with a foreign accent. This FAS was triggered by ischemia and was reversed after a seizure, the first reported in the literature. PMID:22674099

  2. Intonation in Neurogenic Foreign Accent Syndrome

    ERIC Educational Resources Information Center

    Kuschmann, Anja; Lowit, Anja; Miller, Nick; Mennen, Ineke

    2012-01-01

    Foreign accent syndrome (FAS) is a motor speech disorder in which changes to segmental as well as suprasegmental aspects lead to the perception of a foreign accent in speech. This paper focuses on one suprasegmental aspect, namely that of intonation. It provides an in-depth analysis of the intonation system of four speakers with FAS with the aim…

  3. Perception of Foreign Accent Syndrome Speech and Its Relation to Segmental Characteristics

    ERIC Educational Resources Information Center

    Dankovicova, Jana; Hunt, Claire

    2011-01-01

    Foreign accent syndrome (FAS) is an acquired neurogenic disorder characterized by altered speech that sounds foreign-accented. This study presents a British subject perceived to speak with an Italian (or Greek) accent after a brainstem (pontine) stroke. Native English listeners rated the strength of foreign accent and impairment they perceived in…

  4. Two French-Speaking Cases of Foreign Accent Syndrome: An Acoustic-Phonetic Analysis

    ERIC Educational Resources Information Center

    Roy, Johanna-Pascale; Macoir, Joel; Martel-Sauvageau, Vincent; Boudreault, Carol-Ann

    2012-01-01

    Foreign accent syndrome (FAS) is an acquired neurologic disorder in which an individual suddenly and unintentionally speaks with an accent which is perceived as being different from his/her usual accent. This study presents an acoustic-phonetic description of two Quebec French-speaking cases. The first speaker presents a perceived accent shift to…

  5. Phonological and Phonetic Marking of Information Status in Foreign Accent Syndrome

    ERIC Educational Resources Information Center

    Kuschmann, Anja; Lowit, Anja

    2012-01-01

    Background: Foreign Accent Syndrome (FAS) is a motor speech disorder in which a variety of segmental and suprasegmental errors lead to the perception of a new accent in speech. Whilst changes in intonation have been identified to contribute considerably to the perceived alteration in accent, research has rarely focused on how these changes impact…

  6. Acoustic and Perceptual Correlates of Foreign Accent Syndrome with Manic Etiology: A Case Study

    ERIC Educational Resources Information Center

    Lewis, Skye; Ball, Laura J.; Kitten, Suzanna

    2013-01-01

    In foreign accent syndrome (FAS), changes in articulation and prosody cause listeners to perceive the speaker as "foreign-sounding." Fewer than 100 cases of FAS have been described in the literature; commonly associated with brain damage, only a handful of these have been analyzed with respect to acoustic measures. Acoustic and…

  7. Is Language a Factor in the Perception of Foreign Accent Syndrome?

    PubMed

    Jose, Linda; Read, Jennifer; Miller, Nick

    2016-06-01

    Neurogenic foreign accent syndrome (FAS) is diagnosed when listeners perceive speech associated with motor speech impairments as foreign rather than disordered. Speakers with foreign accent syndrome typically have aphasia. It remains unclear how far language changes might contribute to the perception of foreign accent syndrome independent of accent. Judges with and without training in language analysis rated orthographic transcriptions of speech from people with foreign accent syndrome, speech-language disorder and no foreign accent syndrome, foreign accent without neurological impairment and healthy controls on scales of foreignness, normalness and disorderedness. Control speakers were judged as significantly more normal, less disordered and less foreign than other groups. Foreign accent syndrome speakers' transcriptions consistently profiled most closely to those of foreign speakers and significantly different to speakers with speech-language disorder. On normalness and foreignness ratings there were no significant differences between foreign and foreign accent syndrome speakers. For disorderedness, foreign accent syndrome participants fell midway between foreign speakers and those with speech-language impairment only. Slower rate, more hesitations, pauses within and between utterances influenced judgments, delineating control scripts from others. Word-level syntactic and morphological deviations and reduced syntactic and semantic repertoire linked strongly with foreignness perceptions. Greater disordered ratings related to word fragments, poorly intelligible grammatical structures and inappropriate word selection. Language changes influence foreignness perception. Clinical and theoretical issues are addressed.

  8. Psychogenic Foreign Accent Syndrome: A New Case

    PubMed Central

    Keulen, Stefanie; Verhoeven, Jo; De Page, Louis; Jonkers, Roel; Bastiaanse, Roelien; Mariën, Peter

    2016-01-01

    This paper presents the case of a 33-year-old, right-handed, French-speaking Belgian lady who was involved in a car accident as a pedestrian. Six months after the incident she developed a German/Flemish-like accent. The patient's medical history, the onset of the FAS and the possible psychological causes of the accent change are analyzed. Relevant neuropsychological, neurolinguistic, and psychodiagnostic test results are presented and discussed. The psychodiagnostic interview and testing will receive special attention, because these have been underreported in previous FAS case reports. Furthermore, an accent rating experiment was carried out in order to assess the foreign quality of the patient's speech. Pre- and post-morbid spontaneous speech samples were analyzed phonetically to identify the pronunciation characteristics associated with this type of FAS. Several findings were considered essential in the diagnosis of psychogenic FAS: the psychological assessments as well as the clinical interview confirmed the presence of psychological problems, while neurological damage was excluded by means of repeated neuroimaging and neurological examinations. The type and nature of the speech symptoms and the accent fluctuations associated with the patient's psychological state cannot be explained by a neurological disorder. Moreover, the indifference of the patient toward her condition may also suggest a psychogenic etiology, as the opposite is usually observed in neurogenic FAS patients. PMID:27148003

  9. Multidisciplinary assessment and diagnosis of conversion disorder in a patient with foreign accent syndrome.

    PubMed

    Jones, Harrison N; Story, Tyler J; Collins, Timothy A; Dejoy, Daniel; Edwards, Christopher L

    2011-01-01

    Multiple reports have described patients with disordered articulation and prosody, often following acute aphasia, dysarthria, or apraxia of speech, which results in the perception by listeners of a foreign-like accent. These features led to the term foreign accent syndrome (FAS), a speech disorder with perceptual features that suggest an indistinct, non-native speaking accent. Also correctly known as psuedoforeign accent, the speech does not typically match a specific foreign accent, but is rather a constellation of speech features that result in the perception of a foreign accent by listeners. The primary etiologies of FAS are cerebrovascular accidents or traumatic brain injuries which affect cortical and subcortical regions critical to expressive speech and language production. Far fewer cases of FAS associated with psychiatric conditions have been reported. We will present the clinical history, neurological examination, neuropsychological assessment, cognitive-behavioral and biofeedback assessments, and motor speech examination of a patient with FAS without a known vascular, traumatic, or infectious precipitant. Repeated multidisciplinary examinations of this patient provided convergent evidence in support of FAS secondary to conversion disorder. We discuss these findings and their implications for evaluation and treatment of rare neurological and psychiatric conditions.

  10. Foreign Accent Syndrome, a Rare Presentation of Schizophrenia in a 34-Year-Old African American Female: A Case Report and Literature Review

    PubMed Central

    Asogwa, Kenneth; Nisenoff, Carolina; Okudo, Jerome

    2016-01-01

    Foreign Accent Syndrome (FAS) is a rare phenomenon where speech is characterized by a new accent to the patient's native language. More than 100 cases with the syndrome have been published, the majority of which were associated with observed insults of the speech center. Some other cases have been described without identifiable organic brain injury, especially in patients with psychiatric illness. This paper presents a patient with schizophrenia and FAS, without any evidence of organic brain injury. FAS recurred during psychotic exacerbation and did not reverse before transfer to a long-term psychiatric facility. The case is discussed in the context of a brief review of the syndrome. PMID:26925283

  11. Foreign Accent Syndrome As a Psychogenic Disorder: A Review

    PubMed Central

    Keulen, Stefanie; Verhoeven, Jo; De Witte, Elke; De Page, Louis; Bastiaanse, Roelien; Mariën, Peter

    2016-01-01

    In the majority of cases published between 1907 and 2014, FAS is due to a neurogenic etiology. Only a few reports about FAS with an assumed psychogenic origin have been published. The present article discusses the findings of a careful database search on psychogenic FAS. This review may be particularly relevant as it is the first to analyze the salient features of psychogenic FAS cases to date. This article hopes to pave the way for the view that psychogenic FAS is a cognate of neurogenic FAS. It is felt that this variant of FAS may have been underreported, as most of the psychogenic cases have been published after the turn of the century. This review may improve the diagnosis of the syndrome in clinical practice and highlights the importance of recognizing psychogenic FAS as an independent taxonomic entity. PMID:27199699

  12. Perceptual Accent Rating and Attribution in Psychogenic FAS: Some Further Evidence Challenging Whitaker’s Operational Definition

    PubMed Central

    Keulen, Stefanie; Verhoeven, Jo; Bastiaanse, Roelien; Mariën, Peter; Jonkers, Roel; Mavroudakis, Nicolas; Paquier, Philippe

    2016-01-01

    A 40-year-old, non-aphasic, right-handed, and polyglot (L1: French, L2: Dutch, and L3: English) woman with a 12-year history of addiction to opiates and psychoactive substances, and clear psychiatric problems, presented with a foreign accent of sudden onset in L1. Speech evolved toward a mostly fluent output, despite a stutter-like behavior and a marked grammatical output disorder. The psychogenic etiology of the accent foreignness was construed based on the patient’s complex medical history and psychodiagnostic, neuropsychological, and neurolinguistic assessments. The presence of a foreign accent was affirmed by a perceptual accent rating and attribution experiment. It is argued that this patient provides additional evidence demonstrating the outdatedness of Whitaker’s (1982) definition of foreign accent syndrome, as only one of the four operational criteria was unequivocally applicable to our patient: her accent foreignness was not only recognized by her relatives and the medical staff but also by a group of native French-speaking laymen. However, our patient defied the three remaining criteria, as central nervous system damage could not conclusively be demonstrated, psychodiagnostic assessment raised the hypothesis of a conversion disorder, and the patient was a polyglot whose newly gained accent was associated with a range of foreign languages, which exceeded the ones she spoke. PMID:26973488

  13. Foreign accent syndrome: a multimodal evaluation in the search of neuroscience-driven treatments.

    PubMed

    Moreno-Torres, Ignacio; Berthier, Marcelo L; Del Mar Cid, Maria; Green, Cristina; Gutiérrez, Antonio; García-Casares, Natalia; Froudist Walsh, Seán; Nabrozidis, Alejandro; Sidorova, Julia; Dávila, Guadalupe; Carnero-Pardo, Cristóbal

    2013-02-01

    Foreign accent syndrome (FAS) is a rare condition which is placed in the mildest end of the spectrum of speech disorders. The impairment, not severe enough to elicit phonological errors, is associated with various alterations in the fine execution of speech sounds which cause the impression of foreignness. There is a growing interest in the study of linguistic and paralinguistic components, psychosocial aftermaths, and neural basis of FAS, but there are not yet neuroscience-driven treatments for this condition. A multimodal evaluation was conducted in a single patient with the aim of searching for clues which may assist to design neuroscience-driven therapies. The patient was a middle-aged bilingual woman who had chronic FAS. She had segmental deficits, abnormal production of linguistic and emotional prosody, impaired verbal communication, and reduced motivation and social engagement. Magnetic resonance imaging showed bilateral small lesions mainly affecting the left deep frontal operculum and dorsal anterior insula. Diffusion tensor tractography suggested disrupted left deep frontal operculum-anterior insula connectivity. Metabolic activity measured with positron emission tomography was primarily decreased in key components of networks implicated in planning and execution of speech production, cognitive control and emotional communication (Brodmann's areas 4/6/9/10/13/25/47, basal ganglia, and anterior cerebellar vermis). Compensatory increases of metabolic activity were found in cortical areas (left anterior cingulate gyrus, left superior temporal gyrus and right prefrontal cortex) associated with feedback and focal attention processes critical for monitoring and adjustment of verbal utterances. Moreover, bilateral structural and functional abnormalities probably interrupted the trajectory of the lateral and medial cholinergic pathways causing region-specific hypoactivity. The results from this study provide targets for further investigation and some clues to

  14. A Potential of sFasL in Preventing Gland Injury in Sjogren's Syndrome

    PubMed Central

    Wang, Ying; Yu, Bing

    2017-01-01

    Fas and its ligand FasL, members of tumor necrosis factor receptor superfamily, have been implicated in the process of cell apoptosis. FasL consists of two forms, membrane FasL (mFasL) and soluble FasL (sFasL). sFasL can be produced by mFasL cleaved by matrix metalloproteinases (MMP) and also reveals a role for binding to Fas which is expressed on cell surface. Although Fas/FasL axis has been implicated in a variety of diseases, its role in Sjogren's syndrome still remains ill defined. In this study, we investigated the potential of sFasL in the pathogenesis of Sjogren's syndrome (SS). We found that the serum levels of sFasL in SS patients were significantly lower than healthy subjects. Moreover, serum levels of sFasL in patients with mild disease activity were higher than patients with severe disease activity. There is a positive correlation of the serum level of sFasL with uptake index of parotid gland in our expectation. In addition, liver injury involvement in SS patients showed decreased level of sFasL. Furthermore, we here also observed that the protective cytokine IL-10 expression was positively correlated with sFasL expression. Thus, our results here suggest a potential of sFasL in maintaining gland organ homeostasis. PMID:28326325

  15. Mild Developmental Foreign Accent Syndrome and Psychiatric Comorbidity: Altered White Matter Integrity in Speech and Emotion Regulation Networks.

    PubMed

    Berthier, Marcelo L; Roé-Vellvé, Núria; Moreno-Torres, Ignacio; Falcon, Carles; Thurnhofer-Hemsi, Karl; Paredes-Pacheco, José; Torres-Prioris, María J; De-Torres, Irene; Alfaro, Francisco; Gutiérrez-Cardo, Antonio L; Baquero, Miquel; Ruiz-Cruces, Rafael; Dávila, Guadalupe

    2016-01-01

    Foreign accent syndrome (FAS) is a speech disorder that is defined by the emergence of a peculiar manner of articulation and intonation which is perceived as foreign. In most cases of acquired FAS (AFAS) the new accent is secondary to small focal lesions involving components of the bilaterally distributed neural network for speech production. In the past few years FAS has also been described in different psychiatric conditions (conversion disorder, bipolar disorder, and schizophrenia) as well as in developmental disorders (specific language impairment, apraxia of speech). In the present study, two adult males, one with atypical phonetic production and the other one with cluttering, reported having developmental FAS (DFAS) since their adolescence. Perceptual analysis by naïve judges could not confirm the presence of foreign accent, possibly due to the mildness of the speech disorder. However, detailed linguistic analysis provided evidence of prosodic and segmental errors previously reported in AFAS cases. Cognitive testing showed reduced communication in activities of daily living and mild deficits related to psychiatric disorders. Psychiatric evaluation revealed long-lasting internalizing disorders (neuroticism, anxiety, obsessive-compulsive disorder, social phobia, depression, alexithymia, hopelessness, and apathy) in both subjects. Diffusion tensor imaging (DTI) data from each subject with DFAS were compared with data from a group of 21 age- and gender-matched healthy control subjects. Diffusion parameters (MD, AD, and RD) in predefined regions of interest showed changes of white matter microstructure in regions previously related with AFAS and psychiatric disorders. In conclusion, the present findings militate against the possibility that these two subjects have FAS of psychogenic origin. Rather, our findings provide evidence that mild DFAS occurring in the context of subtle, yet persistent, developmental speech disorders may be associated with structural brain

  16. Mild Developmental Foreign Accent Syndrome and Psychiatric Comorbidity: Altered White Matter Integrity in Speech and Emotion Regulation Networks

    PubMed Central

    Berthier, Marcelo L.; Roé-Vellvé, Núria; Moreno-Torres, Ignacio; Falcon, Carles; Thurnhofer-Hemsi, Karl; Paredes-Pacheco, José; Torres-Prioris, María J.; De-Torres, Irene; Alfaro, Francisco; Gutiérrez-Cardo, Antonio L.; Baquero, Miquel; Ruiz-Cruces, Rafael; Dávila, Guadalupe

    2016-01-01

    Foreign accent syndrome (FAS) is a speech disorder that is defined by the emergence of a peculiar manner of articulation and intonation which is perceived as foreign. In most cases of acquired FAS (AFAS) the new accent is secondary to small focal lesions involving components of the bilaterally distributed neural network for speech production. In the past few years FAS has also been described in different psychiatric conditions (conversion disorder, bipolar disorder, and schizophrenia) as well as in developmental disorders (specific language impairment, apraxia of speech). In the present study, two adult males, one with atypical phonetic production and the other one with cluttering, reported having developmental FAS (DFAS) since their adolescence. Perceptual analysis by naïve judges could not confirm the presence of foreign accent, possibly due to the mildness of the speech disorder. However, detailed linguistic analysis provided evidence of prosodic and segmental errors previously reported in AFAS cases. Cognitive testing showed reduced communication in activities of daily living and mild deficits related to psychiatric disorders. Psychiatric evaluation revealed long-lasting internalizing disorders (neuroticism, anxiety, obsessive-compulsive disorder, social phobia, depression, alexithymia, hopelessness, and apathy) in both subjects. Diffusion tensor imaging (DTI) data from each subject with DFAS were compared with data from a group of 21 age- and gender-matched healthy control subjects. Diffusion parameters (MD, AD, and RD) in predefined regions of interest showed changes of white matter microstructure in regions previously related with AFAS and psychiatric disorders. In conclusion, the present findings militate against the possibility that these two subjects have FAS of psychogenic origin. Rather, our findings provide evidence that mild DFAS occurring in the context of subtle, yet persistent, developmental speech disorders may be associated with structural brain

  17. Fetal Alcohol Syndrome (FAS)--A Review.

    ERIC Educational Resources Information Center

    Holzman, Ian R.

    1982-01-01

    At least 30 percent of newborn children of alcoholic mothers are affected severely by the fetal alcohol syndrome and 40-45 percent show some stigmata. Risks to offspring of mothers who drink occasionally or binge drink are not clear, but the danger is probably greatest in the first trimester of pregnancy. (CMG)

  18. FAS Haploinsufficiency Caused by Extracellular Missense Mutations Underlying Autoimmune Lymphoproliferative Syndrome.

    PubMed

    de Bielke, María Gabriela Simesen; Perez, Laura; Yancoski, Judith; Oliveira, João Bosco; Danielian, Silvia

    2015-11-01

    Mutations in the FAS gene are the most common cause of Autoimmune Lymphoproliferative Syndrome (ALPS), and the majority of them affect the intracellular domain of FAS protein, particularly the region termed death domain. However, approximately one third of these mutations affect the extracellular region of FAS and most are stop codons, with very few missense changes having been described to date. We previously described 7 patients with a FAS missense extracellular mutation, C107Y, two in homozygozity and 5 in heterozygosity. We investigated here the mechanistic effects of this mutation and observed that the homozygous patients did not show any FAS surface expression, while the heterozygous patients had diminished receptor expression. Aiming to understand why a missense mutation was abolishing receptor expression, we analyzed intracellular FAS protein trafficking using fluorescent fusion proteins of wild type FAS, two missense extracellular mutants (FAS-C107Y and FAS-C104Y) and one missense change localized in the intracellular region, FAS-D260E. The FAS-C107Y and FAS-C104Y mutants failed to reach the cell surface, being retained at the endoplasmic reticulum, unlike the WT or the FAS-D260E which were clearly expressed at the plasma membrane. These results support haploinsufficiency as the underlying mechanism involved in the pathogenesis of ALPS caused by extracellular FAS missense mutations.

  19. Differential regulation of miR-146a/FAS and miR-21/FASLG axes in autoimmune lymphoproliferative syndrome due to FAS mutation (ALPS-FAS).

    PubMed

    Marega, Lia Furlaneto; Teocchi, Marcelo Ananias; Dos Santos Vilela, Maria Marluce

    2016-08-01

    Most cases of autoimmune lymphoproliferative syndrome (ALPS) have an inherited genetic defect involving apoptosis-related genes of the FAS pathway. MicroRNAs (miRNAs) are a class of small non-coding regulatory RNAs playing a role in the control of gene expression. This is the first report on miRNAs in ALPS patients. We studied a mother and son carrying the same FAS cell surface death receptor (FAS) mutation, but with only the son manifesting the signs and symptoms of ALPS-FAS. The aim was to analyse, by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), the peripheral blood mononuclear cells (PBMC) relative expression of miR-146a and miR-21, including their passenger strands and respective targets (FAS and FASLG). In comparison with healthy matched control individuals, miR-21-3p was over-expressed significantly (P = 0·0313) in the son, with no significant change in the expression of miR-146a, miR-146a-3p and miR-21. In contrast, the mother had a slight under-expression of the miR-146a pair and miR-21-3p (P = 0·0625). Regarding the miRNA targets, FAS was up-regulated markedly for the mother (P = 0·0078), but down-regulated for the son (P = 0·0625), while FASLG did not have any significant alteration. Taken together, our finding clearly suggests a role of the miR-146a/FAS axis in ALPS-FAS variable expressivity in which FAS haploinsufficiency seems to be compensated only in the mother who had the miR-146a pair down-regulated. As only the son had the major clinical manifestations of ALPS-FAS, miR-21-3p should be investigated as playing a critical role in ALPS physiopathology, including the development of lymphoma.

  20. Diagnosis of autoimmune lymphoproliferative syndrome caused by FAS deficiency in adults.

    PubMed

    Lambotte, Olivier; Neven, Bénédicte; Galicier, Lionel; Magerus-Chatinet, Aude; Schleinitz, Nicolas; Hermine, Olivier; Meyts, Isabelle; Picard, Capucine; Godeau, Bertrand; Fischer, Alain; Rieux-Laucat, Frédéric

    2013-03-01

    A diagnosis of autoimmune lymphoproliferative syndrome caused by FAS deficiency during adulthood is unusual. We analyzed 17 cases of autoimmune lymphoproliferative syndrome caused by FAS deficiency diagnosed during adulthood in French reference centers for hereditary immunodeficiencies and for immune cytopenias. Twelve of the 17 patients had developed their first symptoms during childhood. The diagnosis of autoimmune lymphoproliferative syndrome had been delayed for a variety of reasons, including unusual clinical manifestations, late referral to a reference center, and the occurrence of somatic FAS mutations. The 5 other patients presented their first symptoms after the age of 16 years. In these patients, three germline heterozygous FAS mutations were predicted to be associated with haploinsufficiency and a somatic event on the second FAS allele was observed in 2 cases. Autoimmune lymphoproliferative syndrome may well be diagnosed in adulthood. The occurrence of additional genetic events may account for the delayed disease onset.

  1. Developmental Foreign Accent Syndrome: Report of a New Case

    PubMed Central

    Keulen, Stefanie; Mariën, Peter; Wackenier, Peggy; Jonkers, Roel; Bastiaanse, Roelien; Verhoeven, Jo

    2016-01-01

    This paper presents the case of a 17-year-old right-handed Belgian boy with developmental FAS and comorbid developmental apraxia of speech (DAS). Extensive neuropsychological and neurolinguistic investigations demonstrated a normal IQ but impaired planning (visuo-constructional dyspraxia). A Tc-99m-ECD SPECT revealed a significant hypoperfusion in the prefrontal and medial frontal regions, as well as in the lateral temporal regions. Hypoperfusion in the right cerebellum almost reached significance. It is hypothesized that these clinical findings support the view that FAS and DAS are related phenomena following impairment of the cerebro-cerebellar network. PMID:27014011

  2. Autoimmune lymphoproliferative syndrome due to somatic FAS mutation (ALPS-sFAS) combined with a germline caspase-10 (CASP10) variation.

    PubMed

    Martínez-Feito, Ana; Melero, Josefa; Mora-Díaz, Sergio; Rodríguez-Vigil, Carmen; Elduayen, Ramón; González-Granado, Luis I; Pérez-Méndez, Dolores; Sánchez-Zapardiel, Elena; Ruiz-García, Raquel; Menchén, Miguela; Díaz-Madroñero, Josefa; Paz-Artal, Estela; Del Orbe-Barreto, Rafael; Riñón, Marta; Allende, Luis M

    2016-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency caused by impaired Fas/FasL-mediated apoptosis of lymphocytes and is characterized by chronic nonmalignant or benign lymphoproliferation, autoimmune manifestations and expansion of double negative (DN) T-cells (TCRαβ+CD4-CD8-). Most cases of ALPS are associated with germline (ALPS-FAS) or somatic (ALPS-sFAS) heterozygous FAS mutations or a combination of both. Here we report three unrelated patients with ALPS-sFAS. Only one of them showed impaired Fas function in PHA-activated T-cells. In this patient, the genetic analysis of the caspase-10 gene (CASP10) identified a heterozygous germline change in exon 9 (c.1337A>G) causing Y446C substitution in the caspase-10 protein. In addition, this patient had a dysregulated T- and B-cell phenotype; circulating lymphocytes showed expansion of T effector memory CD45RA+ (TEMRA) CD4 T-cells, effector memory CD8 T-cells, CD21(low) B-cells and reduced memory switched B-cells. Additionally, this patient showed altered expression in T-cells of several molecules that change during differentiation from naïve to effector cells (CD27, CD95, CD57 and perforin). Molecular alterations in genes of the Fas pathway are necessary for the development of ALPS and this syndrome could be influenced by the concurrent effect of other mutations hitting different genes involved in Fas or related pathways.

  3. Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome.

    PubMed

    Dowdell, Kennichi C; Niemela, Julie E; Price, Susan; Davis, Joie; Hornung, Ronald L; Oliveira, João Bosco; Puck, Jennifer M; Jaffe, Elaine S; Pittaluga, Stefania; Cohen, Jeffrey I; Fleisher, Thomas A; Rao, V Koneti

    2010-06-24

    Autoimmune lymphoproliferative syndrome (ALPS) is characterized by childhood onset of lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, elevated numbers of double-negative T (DNT) cells, and increased risk of lymphoma. Most cases of ALPS are associated with germline mutations of the FAS gene (type Ia), whereas some cases have been noted to have a somatic mutation of FAS primarily in their DNT cells. We sought to determine the proportion of patients with somatic FAS mutations among a group of our ALPS patients with no detectable germline mutation and to further characterize them. We found more than one-third (12 of 31) of the patients tested had somatic FAS mutations, primarily involving the intracellular domain of FAS resulting in loss of normal FAS signaling. Similar to ALPS type Ia patients, the somatic ALPS patients had increased DNT cell numbers and elevated levels of serum vitamin B(12), interleukin-10, and sFAS-L. These data support testing for somatic FAS mutations in DNT cells from ALPS patients with no detectable germline mutation and a similar clinical and laboratory phenotype to that of ALPS type Ia. These findings also highlight the potential role for somatic mutations in the pathogenesis of nonmalignant and/or autoimmune hematologic conditions in adults and children.

  4. Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease.

    PubMed

    Nabhani, Schafiq; Ginzel, Sebastian; Miskin, Hagit; Revel-Vilk, Shoshana; Harlev, Dan; Fleckenstein, Bernhard; Hönscheid, Andrea; Oommen, Prasad T; Kuhlen, Michaela; Thiele, Ralf; Laws, Hans-Jürgen; Borkhardt, Arndt; Stepensky, Polina; Fischer, Ute

    2015-09-01

    Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20-30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand-deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor-component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon γ production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease.

  5. FAS haploinsufficiency is a common disease mechanism in the human autoimmune lymphoproliferative syndrome.

    PubMed

    Kuehn, Hye Sun; Caminha, Iusta; Niemela, Julie E; Rao, V Koneti; Davis, Joie; Fleisher, Thomas A; Oliveira, João B

    2011-05-15

    The autoimmune lymphoproliferative syndrome (ALPS) is characterized by early-onset lymphadenopathy, splenomegaly, immune cytopenias, and an increased risk for B cell lymphomas. Most ALPS patients harbor mutations in the FAS gene, which regulates lymphocyte apoptosis. These are commonly missense mutations affecting the intracellular region of the protein and have a dominant-negative effect on the signaling pathway. However, analysis of a large cohort of ALPS patients revealed that ∼30% have mutations affecting the extracellular region of FAS, and among these, 70% are nonsense, splice site, or insertions/deletions with frameshift for which no dominant-negative effect would be expected. We evaluated the latter patients to understand the mechanism(s) by which these mutations disrupted the FAS pathway and resulted in clinical disease. We demonstrated that most extracellular-region FAS mutations induce low FAS expression due to nonsense-mediated RNA decay or protein instability, resulting in defective death-inducing signaling complex formation and impaired apoptosis, although to a lesser extent as compared with intracellular mutations. The apoptosis defect could be corrected by FAS overexpression in vitro. Our findings define haploinsufficiency as a common disease mechanism in ALPS patients with extracellular FAS mutations.

  6. Autoimmune lymphoproliferative syndrome (ALPS) in a patient with a new germline Fas gene mutation.

    PubMed

    Del-Rey, Manuel J; Manzanares, Javier; Bosque, Alberto; Aguiló, Juan I; Gómez-Rial, José; Roldan, Ernesto; Serrano, Antonio; Anel, Alberto; Paz-Artal, Estela; Allende, Luis M

    2007-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder characterized by chronic lymphoproliferation, autoimmune manifestations and expansion of TCRalphabeta+CD4-CD8- lymphocytes. The main pathogenic factor is a defective Fas-mediated apoptosis generally caused by mutations in the Fas gene. This report describes a new heterozygous Fas gene mutation in a boy with clinical and immunological features of ALPS. In vitro, T-cell blasts from the patient are completely resistant to the effects on the anti-Fas cytotoxic mAb CH-11, they also have a higher proliferation rate than T cells from healthy donors, while PHA-induced AICD is normal. The location of the mutation (I246S) found in the intracytoplasmic death domain, and the conservation of that residue in four different species from human suggest that I246 is an essential amino acid for Fas function. The patient has inherited the mutation from his father who also shows defective Fas-mediated apoptosis but the clinical and immunological manifestations are much less severe. These results provide evidence that the penetrance of genetic defects in Fas is variable and that other factors may influence the phenotype of the disease.

  7. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations.

    PubMed

    Price, Susan; Shaw, Pamela A; Seitz, Amy; Joshi, Gyan; Davis, Joie; Niemela, Julie E; Perkins, Katie; Hornung, Ronald L; Folio, Les; Rosenberg, Philip S; Puck, Jennifer M; Hsu, Amy P; Lo, Bernice; Pittaluga, Stefania; Jaffe, Elaine S; Fleisher, Thomas A; Rao, V Koneti; Lenardo, Michael J

    2014-03-27

    Autoimmune lymphoproliferative syndrome (ALPS) presents in childhood with nonmalignant lymphadenopathy and splenomegaly associated with a characteristic expansion of mature CD4 and CD8 negative or double negative T-cell receptor αβ(+) T lymphocytes. Patients often present with chronic multilineage cytopenias due to autoimmune peripheral destruction and/or splenic sequestration of blood cells and have an increased risk of B-cell lymphoma. Deleterious heterozygous mutations in the FAS gene are the most common cause of this condition, which is termed ALPS-FAS. We report the natural history and pathophysiology of 150 ALPS-FAS patients and 63 healthy mutation-positive relatives evaluated in our institution over the last 2 decades. Our principal findings are that FAS mutations have a clinical penetrance of <60%, elevated serum vitamin B12 is a reliable and accurate biomarker of ALPS-FAS, and the major causes of morbidity and mortality in these patients are the overwhelming postsplenectomy sepsis and development of lymphoma. With longer follow-up, we observed a significantly greater relative risk of lymphoma than previously reported. Avoiding splenectomy while controlling hypersplenism by using corticosteroid-sparing treatments improves the outcome in ALPS-FAS patients. This trial was registered at www.clinicaltrials.gov as #NCT00001350.

  8. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations

    PubMed Central

    Price, Susan; Shaw, Pamela A.; Seitz, Amy; Joshi, Gyan; Davis, Joie; Niemela, Julie E.; Perkins, Katie; Hornung, Ronald L.; Folio, Les; Rosenberg, Philip S.; Puck, Jennifer M.; Hsu, Amy P.; Lo, Bernice; Pittaluga, Stefania; Jaffe, Elaine S.; Fleisher, Thomas A.; Lenardo, Michael J.

    2014-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) presents in childhood with nonmalignant lymphadenopathy and splenomegaly associated with a characteristic expansion of mature CD4 and CD8 negative or double negative T-cell receptor αβ+ T lymphocytes. Patients often present with chronic multilineage cytopenias due to autoimmune peripheral destruction and/or splenic sequestration of blood cells and have an increased risk of B-cell lymphoma. Deleterious heterozygous mutations in the FAS gene are the most common cause of this condition, which is termed ALPS-FAS. We report the natural history and pathophysiology of 150 ALPS-FAS patients and 63 healthy mutation-positive relatives evaluated in our institution over the last 2 decades. Our principal findings are that FAS mutations have a clinical penetrance of <60%, elevated serum vitamin B12 is a reliable and accurate biomarker of ALPS-FAS, and the major causes of morbidity and mortality in these patients are the overwhelming postsplenectomy sepsis and development of lymphoma. With longer follow-up, we observed a significantly greater relative risk of lymphoma than previously reported. Avoiding splenectomy while controlling hypersplenism by using corticosteroid-sparing treatments improves the outcome in ALPS-FAS patients. This trial was registered at www.clinicaltrials.gov as #NCT00001350. PMID:24398331

  9. Fetal Alcohol Syndrome (FAS), Fetal Alcohol Effects (FAE): Implications For Rural Classrooms.

    ERIC Educational Resources Information Center

    Schenck, Rosalie; And Others

    This report reviews literature on the effects of maternal alcohol consumption on the fetus and the resulting impact on the learning abilities and behavior of children born with fetal alcohol syndrome (FAS). Recent reports indicate that an estimated 73 percent of infants are exposed to alcohol before birth, resulting in varying degrees of learning…

  10. Lethal familial fetal akinesia sequence (FAS) with distinct neuropathological pattern: type III lissencephaly syndrome.

    PubMed

    Encha Razavi, F; Larroche, J C; Roume, J; Gonzales, M; Kondo, H C; Mulliez, N

    1996-03-01

    We report on a distinct pattern of primary central nervous system (CNS) degeneration affecting neuronal survival in the brain and spinal cord in 5 fetuses with fetal akinesia sequence (FAS). This neuropathological pattern is characteristic of a lethal entity that we propose calling type III lissencephaly syndrome. Parental consanguinity and the recurrence in sibs support a genetic cause. The mechanism of neuronal death is not yet understood; abnormal apoptosis and/or deficiency in neurotropic factors may be considered possible causes.

  11. A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats.

    PubMed

    Aberdein, Danielle; Munday, John S; Gandolfi, Barbara; Dittmer, Keren E; Malik, Richard; Garrick, Dorian J; Lyons, Leslie A

    2017-02-01

    British shorthair (BSH) kittens in multiple litters died as a result of a severe non-neoplastic lymphoproliferative disease that showed many similarities with human autoimmune lymphoproliferative syndrome (ALPS). Human ALPS is caused by inherited defects in FAS-mediated lymphocyte apoptosis and the possibility of similar defects was investigated in BSH cats. The whole genomes of two affected kittens were sequenced and compared to 82 existing cat genomes. Both BSH kittens had homozygous insertions of an adenine within exon 3 of the FAS-ligand gene. The resultant frameshift and premature stop codon were predicted to result in a severely truncated protein that is unlikely to be able to activate FAS. Three additional affected BSH kittens were homozygous for the variant, while 11 of 16 unaffected, but closely related, BSH cats were heterozygous for the variant. All BSH cats in the study were from a population with significant inbreeding. The variant was not identified in a further survey of 510 non-BSH cats. Identification of a genetic defect in the FAS-mediated apoptosis pathway confirms that the lymphoproliferative disease in BSH cats fulfills the diagnostic criteria for ALPS in humans. These results will enable the development of a genetic test to detect BSH carrier animals.

  12. Somatic loss of heterozygosity, but not haploinsufficiency alone, leads to full-blown autoimmune lymphoproliferative syndrome in 1 of 12 family members with FAS start codon mutation.

    PubMed

    Hauck, Fabian; Magerus-Chatinet, Aude; Vicca, Stephanie; Rensing-Ehl, Anne; Roesen-Wolff, Angela; Roesler, Joachim; Rieux-Laucat, Frédéric

    2013-04-01

    We describe a family with 12 members carrying a heterozygous germline FAS c.3G>T start codon mutation leading to FAS haploinsufficiency. One patient had autoimmune lymphoproliferative syndrome (ALPS), one had recovered from ALPS, and ten mutation-positive relatives (MPRs) were healthy. FAS-mediated apoptosis and surface expression of FAS in single-positive T cells were lower for MPRs but did not discriminate between them and the ALPS patient. However, double-negative (DN) T cells of the ALPS patient had no FAS expression due to somatic loss of heterozygosity. Our results in this kindred suggest that FAS haploinsufficiency does not cause ALPS-FAS, but that modifying genetic events are crucial for its pathogenesis. FAS surface expression on DN T cells should be assessed routinely and FAS haploinsufficient patients should be followed as its potential for lymphomagenesis is not well defined and a second hit might occur later on.

  13. FAS-L, IL-10, and double-negative CD4- CD8- TCR alpha/beta+ T cells are reliable markers of autoimmune lymphoproliferative syndrome (ALPS) associated with FAS loss of function.

    PubMed

    Magerus-Chatinet, Aude; Stolzenberg, Marie-Claude; Loffredo, Maria S; Neven, Bénédicte; Schaffner, Catherine; Ducrot, Nicolas; Arkwright, Peter D; Bader-Meunier, Brigitte; Barbot, José; Blanche, Stéphane; Casanova, Jean-Laurent; Debré, Marianne; Ferster, Alina; Fieschi, Claire; Florkin, Benoit; Galambrun, Claire; Hermine, Olivier; Lambotte, Olivier; Solary, Eric; Thomas, Caroline; Le Deist, Francoise; Picard, Capucine; Fischer, Alain; Rieux-Laucat, Frédéric

    2009-03-26

    Autoimmune lymphoproliferative syndrome (ALPS) is characterized by splenomegaly, lymphadenopathy, hypergammaglobulinemia, accumulation of double-negative TCRalphabeta(+) CD4(-)CD8(-) T cells (DNT cells), and autoimmunity. Previously, DNT cell detection and a functional defect of T cells in a FAS-induced apoptosis test in vitro had been used for ALPS diagnosis. However, a functional defect can also be detected in mutation-positive relatives (MPRs) who remain free of any ALPS-related disease. In contrast, lymphocytes from patients carrying a somatic mutation of FAS exhibit normal sensitivity to FAS-induced apoptosis in vitro. We assessed the soluble FAS-L concentration in the plasma of ALPS patients carrying FAS mutations. Overall, we showed that determination of the FAS-L represents, together with the IL-10 concentration and the DNT cell percentage, a reliable tool for the diagnosis of ALPS.

  14. FAS Gene Copy Numbers are Associated with Susceptibility to Behçet Disease and VKH Syndrome in Han Chinese.

    PubMed

    Yu, Hongsong; Luo, Le; Wu, Lili; Zheng, Minming; Zhang, Lijun; Liu, Yunjia; Li, Hua; Cao, Qingfeng; Kijlstra, Aize; Yang, Peizeng

    2015-11-01

    Previous studies have identified that disturbed apoptosis was involved in the pathogenesis of Behçet disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome. This study aims to investigate whether copy number variations of apoptosis-related genes, including FAS, CASPASE8, CASPASE3, and BCL2, are associated with BD and VKH syndrome in Han Chinese. A two-stage association study was performed in 1,014 BD patients, 1,051 VKH syndrome patients, and 2,076 healthy controls. TaqMan(®) Copy Number Assays and real-time PCR were performed. The first-stage study showed that increased frequency of high FAS copy number (>2) was found in BD (P = 1.05 × 10(-3) ) and VKH syndrome (P = 2.56 × 10(-3) ). Replication and combined study confirmed the association of high copy number (>2) of FAS with BD (P = 3.35 × 10(-8) ) and VKH syndrome (P = 9.77 × 10(-8) ). A significant upregulated mRNA expression of FAS was observed in anti-CD3/CD28 antibodies-stimulated CD4(+) T cells from individuals carrying a high gene copy number (>2) as compared to normal diploid 2 copy number carriers (P = 0.004). Moreover, the mRNA expression of FAS both in active patients with BD and VKH syndrome was significantly higher than that in controls (P = 0.001 and P = 0.007, respectively). Our findings suggest that a high copy number of FAS gene confers risk for BD and VKH syndrome.

  15. Bone marrow findings in autoimmune lymphoproliferative syndrome with germline FAS mutation.

    PubMed

    Xie, Yi; Pittaluga, Stefania; Price, Susan; Raffeld, Mark; Hahn, Jamie; Jaffe, Elaine S; Rao, V Koneti; Maric, Irina

    2017-02-01

    Autoimmune lymphoproliferative syndrome is a rare genetic disorder characterized by defective FAS-mediated apoptosis, autoimmune disease, accumulation of mature T-cell receptor alpha/beta positive, CD4 and CD8 double-negative T cells and increased risk of lymphoma. Despite frequent hematologic abnormalities, literature is scarce regarding the bone marrow pathology in autoimmune lymphoproliferative syndrome. We retrospectively reviewed 3l bone marrow biopsies from a cohort of 240 patients with germline FAS mutations. All biopsies were performed for the evaluation of cytopenias or to rule out lymphoma. Clinical information was collected and morphological, immunohistochemical, flow cytometric and molecular studies were performed. Bone marrow lymphocytosis was the predominant feature, present in 74% (23/31) of biopsies. The lymphoid cells showed several different patterns of infiltration, most often forming aggregates comprising T cells in 15 cases, B cells in one and a mixture of T and B cells in the other seven cases. Double-negative T cells were detected by immunohistochemistry in the minority of cases (10/31; 32%); significantly, all but one of these cases had prominent double-negative T-lymphoid aggregates, which in four cases diffusely replaced the marrow space. One case showed features of Rosai-Dorfman disease, containing scattered S-100(+) cells with emperipolesis and double-negative T cells. No clonal B or T cells were detected by polymerase chain reaction in any evaluated cases. Classical Hodgkin lymphoma was identified in three cases. Our results demonstrate that infiltrates of T cells, or rarely B cells, can be extensive in patients with autoimmune lymphoproliferative syndrome, mimicking lymphoma. A multi-modality approach, integrating clinical, histological, immunohistochemical as well as other ancillary tests, can help avoid this diagnostic pitfall. This study is registered at Clinicaltrials.gov ID # NCT00001350.

  16. Bone marrow findings in autoimmune lymphoproliferative syndrome with germline FAS mutation

    PubMed Central

    Xie, Yi; Pittaluga, Stefania; Price, Susan; Raffeld, Mark; Hahn, Jamie; Jaffe, Elaine S.; Rao, V. Koneti; Maric, Irina

    2017-01-01

    Autoimmune lymphoproliferative syndrome is a rare genetic disorder characterized by defective FAS-mediated apoptosis, autoimmune disease, accumulation of mature T-cell receptor alpha/beta positive, CD4 and CD8 double-negative T cells and increased risk of lymphoma. Despite frequent hematologic abnormalities, literature is scarce regarding the bone marrow pathology in autoimmune lymphoproliferative syndrome. We retrospectively reviewed 3l bone marrow biopsies from a cohort of 240 patients with germline FAS mutations. All biopsies were performed for the evaluation of cytopenias or to rule out lymphoma. Clinical information was collected and morphological, immunohistochemical, flow cytometric and molecular studies were performed. Bone marrow lymphocytosis was the predominant feature, present in 74% (23/31) of biopsies. The lymphoid cells showed several different patterns of infiltration, most often forming aggregates comprising T cells in 15 cases, B cells in one and a mixture of T and B cells in the other seven cases. Double-negative T cells were detected by immunohistochemistry in the minority of cases (10/31; 32%); significantly, all but one of these cases had prominent double-negative T-lymphoid aggregates, which in four cases diffusely replaced the marrow space. One case showed features of Rosai-Dorfman disease, containing scattered S-100+ cells with emperipolesis and double-negative T cells. No clonal B or T cells were detected by polymerase chain reaction in any evaluated cases. Classical Hodgkin lymphoma was identified in three cases. Our results demonstrate that infiltrates of T cells, or rarely B cells, can be extensive in patients with autoimmune lymphoproliferative syndrome, mimicking lymphoma. A multi-modality approach, integrating clinical, histological, immunohistochemical as well as other ancillary tests, can help avoid this diagnostic pitfall. This study is registered at Clinicaltrials.gov ID # NCT00001350 PMID:27846610

  17. Autoimmune lymphoproliferative syndrome (ALPS) caused by Fas (CD95) mutation mimicking sarcoidosis.

    PubMed

    Müllauer, Leonhard; Emhofer, Josef; Wohlfart, Sabine; Pichlhöfer, Bettina; Stary, Susanne; Ebetsberger, Georg; Mannhalter, Christine; Chott, Andreas

    2008-02-01

    Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder associated with defects in apoptosis, characterized by childhood onset of lymphadenopathy, splenomegaly, hyperimmunoglobulinemia, and autoimmune disease. ALPS is most frequently associated with a mutation in the cell death receptor Fas (CD95). Very rarely a mutation in caspase 10 is present. An increase of CD4/CD8 double negative T cells in the peripheral blood and lymph nodes is a feature characteristic of ALPS. Additionally, histiocytic proliferations resembling sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) were reported recently in patients with ALPS. In the rare cases with a caspase 10 mutation an accumulation of dendritic cells in lymphoid organs was noted. We describe a different, sarcoidosislike, histiocytic infiltration of lymph nodes that persisted for years in a girl, that was initially supposed to suffer from sarcoidosis, but was eventually diagnosed as ALPS, associated with a missense mutation in the intracellular death domain of Fas. This sarcoidosislike histologic picture extends the spectrum of histiocytic lymph node alterations observed in ALPS and alerts of a potential diagnostic pitfall.

  18. Literacy-Based Supports for Young Adults with FAS/FAE [Fetal Alcohol Syndrome/Fetal Alcohol Effects].

    ERIC Educational Resources Information Center

    Raymond, Margaret; Belanger, Joe

    During a 1-year period, a study investigated the contributions made by 3 literacy-based supports (support circles, cognitive compensatory tools, and cognitive enhancement tools) to the lives of 5 young adults, aged 16-34, with FAS/FAE (Fetal Alcohol Syndrome/Fetal Alcohol Effects). Four of the five subjects had IQs (intelligence quotients) above…

  19. Foreign-Accented Speech Perception Ratings: A Multifactorial Case Study

    ERIC Educational Resources Information Center

    Kraut, Rachel; Wulff, Stefanie

    2013-01-01

    Seventy-eight native English speakers rated the foreign-accented speech (FAS) of 24 international students enrolled in an Intensive English programme at a public university in Texas on degree of accent, comprehensibility and communicative ability. Variables considered to potentially impact listeners' ratings were the sex of the speaker, the first…

  20. Systemic autoimmunity and defective Fas ligand secretion in the absence of the Wiskott-Aldrich syndrome protein

    PubMed Central

    Nikolov, Nikolay P.; Shimizu, Masaki; Cleland, Sophia; Bailey, Daniel; Aoki, Joseph; Strom, Ted; Schwartzberg, Pamela L.; Candotti, Fabio

    2010-01-01

    Autoimmunity is a surprisingly common complication of primary immunodeficiencies, yet the molecular mechanisms underlying this clinical observation are not well understood. One widely known example is provided by Wiskott-Aldrich syndrome (WAS), an X-linked primary immunodeficiency disorder caused by mutations in the gene encoding the WAS protein (WASp) with a high incidence of autoimmunity in affected patients. WASp deficiency affects T-cell antigen receptor (TCR) signaling and T-cell cytokine production, but its role in TCR-induced apoptosis, one of the mechanisms of peripheral immunologic tolerance, has not been investigated. We find that WASp-deficient mice produce autoantibodies and develop proliferative glomerulonephritis with immune complex deposition as they age. We also find that CD4+ T lymphocytes from WASp-deficient mice undergo reduced apoptosis after restimulation through the TCR. While Fas-induced cell death is normal, WASp deficiency affects TCR-induced secretion of Fas ligand (FasL) and other components of secretory granules by CD4+ T cells. These results describe a novel role of WASp in regulating TCR-induced apoptosis and FasL secretion and suggest that WASp-deficient mice provide a good model for the study of autoimmune manifestations of WAS and the development of more specific therapies for these complications. PMID:20457871

  1. Agnosia for accents in primary progressive aphasia☆

    PubMed Central

    Fletcher, Phillip D.; Downey, Laura E.; Agustus, Jennifer L.; Hailstone, Julia C.; Tyndall, Marina H.; Cifelli, Alberto; Schott, Jonathan M.; Warrington, Elizabeth K.; Warren, Jason D.

    2013-01-01

    As an example of complex auditory signal processing, the analysis of accented speech is potentially vulnerable in the progressive aphasias. However, the brain basis of accent processing and the effects of neurodegenerative disease on this processing are not well understood. Here we undertook a detailed neuropsychological study of a patient, AA with progressive nonfluent aphasia, in whom agnosia for accents was a prominent clinical feature. We designed a battery to assess AA's ability to process accents in relation to other complex auditory signals. AA's performance was compared with a cohort of 12 healthy age and gender matched control participants and with a second patient, PA, who had semantic dementia with phonagnosia and prosopagnosia but no reported difficulties with accent processing. Relative to healthy controls, the patients showed distinct profiles of accent agnosia. AA showed markedly impaired ability to distinguish change in an individual's accent despite being able to discriminate phonemes and voices (apperceptive accent agnosia); and in addition, a severe deficit of accent identification. In contrast, PA was able to perceive changes in accents, phonemes and voices normally, but showed a relatively mild deficit of accent identification (associative accent agnosia). Both patients showed deficits of voice and environmental sound identification, however PA showed an additional deficit of face identification whereas AA was able to identify (though not name) faces normally. These profiles suggest that AA has conjoint (or interacting) deficits involving both apperceptive and semantic processing of accents, while PA has a primary semantic (associative) deficit affecting accents along with other kinds of auditory objects and extending beyond the auditory modality. Brain MRI revealed left peri-Sylvian atrophy in case AA and relatively focal asymmetric (predominantly right sided) temporal lobe atrophy in case PA. These cases provide further evidence for the

  2. Agnosia for accents in primary progressive aphasia.

    PubMed

    Fletcher, Phillip D; Downey, Laura E; Agustus, Jennifer L; Hailstone, Julia C; Tyndall, Marina H; Cifelli, Alberto; Schott, Jonathan M; Warrington, Elizabeth K; Warren, Jason D

    2013-08-01

    As an example of complex auditory signal processing, the analysis of accented speech is potentially vulnerable in the progressive aphasias. However, the brain basis of accent processing and the effects of neurodegenerative disease on this processing are not well understood. Here we undertook a detailed neuropsychological study of a patient, AA with progressive nonfluent aphasia, in whom agnosia for accents was a prominent clinical feature. We designed a battery to assess AA's ability to process accents in relation to other complex auditory signals. AA's performance was compared with a cohort of 12 healthy age and gender matched control participants and with a second patient, PA, who had semantic dementia with phonagnosia and prosopagnosia but no reported difficulties with accent processing. Relative to healthy controls, the patients showed distinct profiles of accent agnosia. AA showed markedly impaired ability to distinguish change in an individual's accent despite being able to discriminate phonemes and voices (apperceptive accent agnosia); and in addition, a severe deficit of accent identification. In contrast, PA was able to perceive changes in accents, phonemes and voices normally, but showed a relatively mild deficit of accent identification (associative accent agnosia). Both patients showed deficits of voice and environmental sound identification, however PA showed an additional deficit of face identification whereas AA was able to identify (though not name) faces normally. These profiles suggest that AA has conjoint (or interacting) deficits involving both apperceptive and semantic processing of accents, while PA has a primary semantic (associative) deficit affecting accents along with other kinds of auditory objects and extending beyond the auditory modality. Brain MRI revealed left peri-Sylvian atrophy in case AA and relatively focal asymmetric (predominantly right sided) temporal lobe atrophy in case PA. These cases provide further evidence for the

  3. The FAS Child: A Primer for Teachers.

    ERIC Educational Resources Information Center

    Wentz, Thomas L.; Larson, Julie

    1993-01-01

    This primer on fetal alcohol syndrome (FAS) distinguishes between the syndrome and fetal alcohol effects (FAE), offers a history of FAS, outlines medical criteria for diagnosis, rates of incidence, factors influencing incidence and severity, developmental stages of children with FAS, clinical features, and educational implications and approaches.…

  4. A novel homozygous Fas ligand mutation leads to early protein truncation, abrogation of death receptor and reverse signaling and a severe form of the autoimmune lymphoproliferative syndrome.

    PubMed

    Nabhani, Schafiq; Hönscheid, Andrea; Oommen, Prasad T; Fleckenstein, Bernhard; Schaper, Jörg; Kuhlen, Michaela; Laws, Hans-Jürgen; Borkhardt, Arndt; Fischer, Ute

    2014-12-01

    We report a novel type of mutation in the death ligand FasL that was associated with a severe phenotype of the autoimmune lymphoproliferative syndrome in two patients. A frameshift mutation in the intracellular domain led to complete loss of FasL expression. Cell death signaling via its receptor and reverse signaling via its intracellular domain were completely abrogated. In vitro lymphocyte proliferation induced by weak T cell receptor stimulation could be blocked and cell death was induced by engagement of FasL in T cells derived from healthy individuals and a heterozygous carrier, but not in FasL-deficient patient derived cells. Expression of genes implicated in lymphocyte proliferation and activation (CCND1, NFATc1, NF-κB1) was increased in FasL-deficient T cells and could not be downregulated by FasL engagement as in healthy cells. Our data thus suggest, that deficiency in FasL reverse signaling may contribute to the clinical lymphoproliferative phenotype of ALPS.

  5. Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia.

    PubMed

    Martin, D A; Zheng, L; Siegel, R M; Huang, B; Fisher, G H; Wang, J; Jackson, C E; Puck, J M; Dale, J; Straus, S E; Peter, M E; Krammer, P H; Fesik, S; Lenardo, M J

    1999-04-13

    Heterozygous mutations in the CD95 (APO-1/Fas) receptor occur in most individuals with autoimmune lymphoproliferative syndrome (ALPS) and dominantly interfere with apoptosis by an unknown mechanism. We show that local or global alterations in the structure of the cytoplasmic death domain from nine independent ALPS CD95 death-domain mutations result in a failure to bind the FADD/MORT1 signaling protein. Despite heterozygosity for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association and a loss of caspase recruitment and activation after CD95 crosslinking. These data suggest that intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by disrupting death-domain interactions with the signaling protein FADD/MORT1.

  6. Deletion of receptor for advanced glycation end products exacerbates lymphoproliferative syndrome and lupus nephritis in B6-MRL Fas lpr/j mice.

    PubMed

    Goury, Antoine; Meghraoui-Kheddar, Aïda; Belmokhtar, Karim; Vuiblet, Vincent; Ortillon, Jeremy; Jaisson, Stéphane; Devy, Jerôme; Le Naour, Richard; Tabary, Thierry; Cohen, Jacques H M; Schmidt, Ann-Marie; Rieu, Philippe; Touré, Fatouma

    2015-04-15

    The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that interacts with advanced glycation end products, but also with C3a, CpG DNA oligonucleotides, and alarmin molecules such as HMGB1 to initiate a proinflammatory reaction. Systemic lupus erythematosus is an autoimmune disorder associated with the accumulation of RAGE ligands. We generated mice invalidated for RAGE in the lupus-prone B6-MRL Fas lpr/j background to determine the role of RAGE in the pathogenesis of systemic lupus erythematosus. We compared the phenotype of these mice with that of their wild-type and B6-MRL Fas lpr/j littermates. Lymphoproliferative syndrome, production of anti-dsDNA Abs, lupus nephritis, and accumulation of CD3(+)B220(+)CD4(-)CD8(-) autoreactive T cells (in the peripheral blood and the spleen) were significantly increased in B6-MRL Fas lpr/j RAGE(-/-) mice compared with B6-MRL Fas lpr/j mice (respectively p < 0.005, p < 0.05, p < 0.001, and p < 0.001). A large proportion of autoreactive T cells from B6-MRL Fas lpr/j mice expressed RAGE at their surface. Time course studies of annexin V expression revealed that autoreactive T cells in the spleen of B6-MRL Fas lpr/j-RAGE(-/-) mice exhibited a delay in apoptosis and expressed significantly less activated caspase 3 (39.5 ± 4.3%) than T cells in B6-MRL Fas lpr/j mice (65.5 ± 5.2%) or wild-type mice (75.3 ± 2.64%) (p = 0.02). We conclude that the deletion of RAGE in B6-MRL Fas lpr/j mice promotes the accumulation of autoreactive CD3(+)B220(+)CD4(-)CD8(-) T cells, therefore exacerbating lymphoproliferative syndrome, autoimmunity, and organ injury. This suggests that RAGE rescues the apoptosis of T lymphocytes when the death receptor Fas/CD95 is dysfunctional.

  7. Accent processing in dementia

    PubMed Central

    Hailstone, Julia C.; Ridgway, Gerard R.; Bartlett, Jonathan W.; Goll, Johanna C.; Crutch, Sebastian J.; Warren, Jason D.

    2012-01-01

    Accented speech conveys important nonverbal information about the speaker as well as presenting the brain with the problem of decoding a non-canonical auditory signal. The processing of non-native accents has seldom been studied in neurodegenerative disease and its brain basis remains poorly understood. Here we investigated the processing of non-native international and regional accents of English in cohorts of patients with Alzheimer's disease (AD; n=20) and progressive nonfluent aphasia (PNFA; n=6) in relation to healthy older control subjects (n=35). A novel battery was designed to assess accent comprehension and recognition and all subjects had a general neuropsychological assessment. Neuroanatomical associations of accent processing performance were assessed using voxel-based morphometry on MR brain images within the larger AD group. Compared with healthy controls, both the AD and PNFA groups showed deficits of non-native accent recognition and the PNFA group showed reduced comprehension of words spoken in international accents compared with a Southern English accent. At individual subject level deficits were observed more consistently in the PNFA group, and the disease groups showed different patterns of accent comprehension impairment (generally more marked for sentences in AD and for single words in PNFA). Within the AD group, grey matter associations of accent comprehension and recognition were identified in the anterior superior temporal lobe. The findings suggest that accent processing deficits may constitute signatures of neurodegenerative disease with potentially broader implications for understanding how these diseases affect vocal communication under challenging listening conditions. PMID:22664324

  8. Do metrical accents create illusory phenomenal accents?

    PubMed

    Repp, Bruno H

    2010-07-01

    In music that is perceived as metrically structured, events coinciding with the main beat are called metrically accented. Are these accents purely cognitive, or do they perhaps represent illusory increases in perceived loudness or duration, caused by heightened attention to main beats? In four separate tasks, musicians tried to detect a small actual increase or decrease in the loudness or duration of a single note in melodies comprising 12 notes. Musical notation prescribed a meter (6/8) implying a main beat coinciding with every third note. Effects of metrical accentuation on detection performance were found in all four tasks. However, they reflected primarily an increase in sensitivity to physical changes in main beat positions, likely to be due to enhanced attention. There was no evidence of biases indicating illusory phenomenal accents in those positions. By contrast, and independent of metrical structure, pitch accents due to pitch contour pivots were often mistaken for increases in loudness.

  9. Forced miR-146a expression causes autoimmune lymphoproliferative syndrome in mice via downregulation of Fas in germinal center B cells.

    PubMed

    Guo, Qiuye; Zhang, Jinjun; Li, Jingyi; Zou, Liyun; Zhang, Jinyu; Xie, Zunyi; Fu, Xiaolan; Jiang, Shan; Chen, Gang; Jia, Qingzhu; Li, Fei; Wan, Ying; Wu, Yuzhang

    2013-06-13

    By inhibiting target gene expression, microRNAs (miRNAs) play major roles in various physiological and pathological processes. miR-146a, a miRNA induced upon lipopolysaccharide (LPS) stimulation and virus infection, is also highly expressed in patients with immune disorders such as rheumatoid arthritis, Sjögren's syndrome, and psoriasis. Whether the high level of miR-146a contributes to any of these pathogenesis-related processes remains unknown. To elucidate the function of miR-146a in vivo, we generated a transgenic (TG) mouse line overexpressing miR-146a. Starting at an early age, these TG mice developed spontaneous immune disorders that mimicked human autoimmune lymphoproliferative syndrome (ALPS) with distinct manifestations, including enlarged spleens and lymph nodes, inflammatory infiltration in the livers and lungs, increased levels of double-negative T cells in peripheral blood, and increased serum immunoglobulin G levels. Moreover, with the adoptive transfer approach, we found that the B-cell population was the major etiological factor and that the expression of Fas, a direct target of miR-146a, was significantly dampened in TG germinal center B cells. These results indicate that miR-146a may be involved in the pathogenesis of ALPS by targeting Fas and may therefore serve as a novel therapeutic target.

  10. A Market of Accents

    ERIC Educational Resources Information Center

    Blommaert, Jan

    2009-01-01

    This paper describes the cultural semantics of internet courses in American accent. Such courses are offered by corporate providers to specific groups of customers: people in search of success in the globalized business environment. The core of such courses is an order of indexicality which stresses uniformity and homogeneity, producing an…

  11. Language Learners' Perceptions of Accent

    ERIC Educational Resources Information Center

    Scales, Julie; Wennerstrom, Ann; Richard, Dara; Wu, Su Hui

    2006-01-01

    This study analyzed the accent perceptions of a group of 37 English language learners and 10 American undergraduate students. Each subject listened to a one-minute passage read by four speakers with different accents of English: General American, British English, Chinese English, and Mexican English. Participants then attempted to identify the…

  12. Japanese Attitudes toward English Accents.

    ERIC Educational Resources Information Center

    Chiba, Reiko; And Others

    1995-01-01

    Examined the attitudes of 169 Japanese university students toward varieties of spoken English. Results found that the students with more instrumental motivation were more positive toward nonnative English accents than those with less instrumental motivation, and that the students' familiarity with accents had an influence on their acceptance of…

  13. Loss of regional accent after damage to the speech production network

    PubMed Central

    Berthier, Marcelo L.; Dávila, Guadalupe; Moreno-Torres, Ignacio; Beltrán-Corbellini, Álvaro; Santana-Moreno, Daniel; Roé-Vellvé, Núria; Thurnhofer-Hemsi, Karl; Torres-Prioris, María José; Massone, María Ignacia; Ruiz-Cruces, Rafael

    2015-01-01

    Lesion-symptom mapping studies reveal that selective damage to one or more components of the speech production network can be associated with foreign accent syndrome, changes in regional accent (e.g., from Parisian accent to Alsatian accent), stronger regional accent, or re-emergence of a previously learned and dormant regional accent. Here, we report loss of regional accent after rapidly regressive Broca’s aphasia in three Argentinean patients who had suffered unilateral or bilateral focal lesions in components of the speech production network. All patients were monolingual speakers with three different native Spanish accents (Cordobés or central, Guaranítico or northeast, and Bonaerense). Samples of speech production from the patient with native Córdoba accent were compared with previous recordings of his voice, whereas data from the patient with native Guaranítico accent were compared with speech samples from one healthy control matched for age, gender, and native accent. Speech samples from the patient with native Buenos Aires’s accent were compared with data obtained from four healthy control subjects with the same accent. Analysis of speech production revealed discrete slowing in speech rate, inappropriate long pauses, and monotonous intonation. Phonemic production remained similar to those of healthy Spanish speakers, but phonetic variants peculiar to each accent (e.g., intervocalic aspiration of /s/ in Córdoba accent) were absent. While basic normal prosodic features of Spanish prosody were preserved, features intrinsic to melody of certain geographical areas (e.g., rising end F0 excursion in declarative sentences intoned with Córdoba accent) were absent. All patients were also unable to produce sentences with different emotional prosody. Brain imaging disclosed focal left hemisphere lesions involving the middle part of the motor cortex, the post-central cortex, the posterior inferior and/or middle frontal cortices, insula, anterior putamen and

  14. The Role of Accent Salience and Joint Accent Structure in Meter Perception

    ERIC Educational Resources Information Center

    Ellis, Robert J.; Jones, Mari R.

    2009-01-01

    Previous research indicates that temporal accents (TAs; accents due to time changes) play a strong role in meter perception, but evidence favoring a role for melodic accents (MAs; accents due to pitch changes) is mixed. The authors claim that this mixed support for MAs is the result of a failure to control for accent salience and addressed this…

  15. Fetal Alcohol Syndrome

    MedlinePlus

    ... Conditions Frequently Asked Questions Español Condiciones Chinese Conditions Fetal Alcohol Syndrome Read in Chinese What is Fetal Alcohol Syndrome (FAS)? Fetal Alcohol Syndrome (FAS) describes changes in ...

  16. Cross-linguistic expression of contrastive accent: Clinical assessment in Spanish and English.

    PubMed

    Martínez-Castilla, Pastora; Peppé, Sue

    2010-11-01

    Well-documented Romance-Germanic differences in the use of accent in speech to convey information-structure and focus cause problems for the assessment of prosodic skills in populations with clinical disorders. The strategies for assessing the ability to use lexical and contrastive accent in English and Spanish are reviewed, and studies in the expression of contrastive accent in Spanish- and English-speaking typically-developing children are described. These studies used similar tasks requiring pre-final contrastive accent. Results were, however, strikingly different (English > Spanish). Using the same tasks, studies of English-speaking individuals with autism and Williams syndrome showed marked difficulty with the expression of contrastive stress, but the use of such tasks with Spanish speakers may merely reflect cross-linguistic differences. This study presents the methodology and results of these tasks, and suggests alternative methods of assessing the ability to discern and use contrastive accents in Spanish.

  17. Foreign accent strength and listener familiarity with an accent codetermine speed of perceptual adaptation.

    PubMed

    Witteman, Marijt J; Weber, Andrea; McQueen, James M

    2013-04-01

    We investigated how the strength of a foreign accent and varying types of experience with foreign-accented speech influence the recognition of accented words. In Experiment 1, native Dutch listeners with limited or extensive prior experience with German-accented Dutch completed a cross-modal priming experiment with strongly, medium, and weakly accented words. Participants with limited experience were primed by the medium and weakly accented words, but not by the strongly accented words. Participants with extensive experience were primed by all accent types. In Experiments 2 and 3, Dutch listeners with limited experience listened to a short story before doing the cross-modal priming task. In Experiment 2, the story was spoken by the priming task speaker and either contained strongly accented words or did not. Strongly accented exposure led to immediate priming by novel strongly accented words, while exposure to the speaker without strongly accented tokens led to priming only in the experiment's second half. In Experiment 3, listeners listened to the story with strongly accented words spoken by a different German-accented speaker. Listeners were primed by the strongly accented words, but again only in the experiment's second half. Together, these results show that adaptation to foreign-accented speech is rapid but depends on accent strength and on listener familiarity with those strongly accented words.

  18. The impact of phonetic dissimilarity on the perception of foreign accented speech

    NASA Astrophysics Data System (ADS)

    Weil, Shawn A.

    2003-10-01

    Non-normative speech (i.e., synthetic speech, pathological speech, foreign accented speech) is more difficult to process for native listeners than is normative speech. Does perceptual dissimilarity affect only intelligibility, or are there other costs to processing? The current series of experiments investigates both the intelligibility and time course of foreign accented speech (FAS) perception. Native English listeners heard single English words spoken by both native English speakers and non-native speakers (Mandarin or Russian). Words were chosen based on the similarity between the phonetic inventories of the respective languages. Three experimental designs were used: a cross-modal matching task, a word repetition (shadowing) task, and two subjective ratings tasks which measured impressions of accentedness and effortfulness. The results replicate previous investigations that have found that FAS significantly lowers word intelligibility. Furthermore, in FAS as well as perceptual effort, in the word repetition task, correct responses are slower to accented words than to nonaccented words. An analysis indicates that both intelligibility and reaction time are, in part, functions of the similarity between the talker's utterance and the listener's representation of the word.

  19. Attitudinal and Affective Response toward Accented English.

    ERIC Educational Resources Information Center

    Bresnahan, Mary Jiang; Ohashi, Rie; Liu, Wen Ying; Nebashi, Reiko; Shearman, Sachiyo Morinaga

    2002-01-01

    Evaluated attitudinal and affective responses toward accented English based on variation in role identity and intelligibility. American English was preferred; intelligible foreign accents resulted in more positive attitudes and affective responses compared to foreign accents that were unintelligible. Friends were viewed more positively compared to…

  20. Accent Identification by Adults with Aphasia

    ERIC Educational Resources Information Center

    Newton, Caroline; Burns, Rebecca; Bruce, Carolyn

    2013-01-01

    The UK is a diverse society where individuals regularly interact with speakers with different accents. Whilst there is a growing body of research on the impact of speaker accent on comprehension in people with aphasia, there is none which explores their ability to identify accents. This study investigated the ability of this group to identify the…

  1. ACTFL's Accent! on Promoting FL's.

    ERIC Educational Resources Information Center

    Accent on ACTFL, 1975

    1975-01-01

    This insert in "Accent on ACTFL" is devoted to ways of promoting the study of foreign languages. The first section is a comic book, "The Continuing Story of Captain Fore Lang," created as an assignment by education students. The comic points out several benefits of language study. The second section is a language-specific promotion focusing on…

  2. Intercultural Processes in Accented English

    ERIC Educational Resources Information Center

    Rivers, Damian J.

    2011-01-01

    This study assessed the attitudinal responses of 48 Japanese university students towards 10 accented English speech samples across nine evaluative criteria. Of the 10 samples, one was a Japanese-English speech sample (the intracultural familiar), seven were non-native-English samples originating from a variety of Asian countries (intercultural…

  3. Why Do Some People Have an Accent?

    ERIC Educational Resources Information Center

    Birner, Betty, Ed.

    This brochure explains in lay terms what an accent is and how it occurs, focusing on how learners of English-as-a-Second-language come to have what is perceived as an accent. It begins with an explanation of two kinds of accent: that of a non-native speaker and that of a speaker from a particular region in which a language is spoken. The second…

  4. Recognising English Accents in the Community: Omani Students' Accent Preferences and Perceptions of Nativeness

    ERIC Educational Resources Information Center

    Buckingham, Louisa

    2015-01-01

    Previous research has revealed that although EFL students may claim to prefer British/US accents they often have difficulty identifying them, especially when such accents may differ from "standard" accents presented in ELT materials. In the Gulf, English is widely used as a lingua franca or as a second language by the large expatriate…

  5. Shibboleth: An Automated Foreign Accent Identification Program

    ERIC Educational Resources Information Center

    Frost, Wende

    2013-01-01

    The speech of non-native (L2) speakers of a language contains phonological rules that differentiate them from native speakers. These phonological rules characterize or distinguish accents in an L2. The Shibboleth program creates combinatorial rule-sets to describe the phonological pattern of these accents and classifies L2 speakers into their…

  6. The Evaluation of Second Language Fluency and Foreign Accent

    ERIC Educational Resources Information Center

    Wu, Chen-Huei

    2011-01-01

    What is second language fluency? What is a foreign accent? Is it possible for an adult second language learner to speak fluently with a heavy accent or vice versa? What factors contribute to the perception of fluency and a foreign accent? What acoustic attributes correlate with the perception of fluency and a foreign accent? To answer these…

  7. Does a Foreign Accent Sell? The Effect of Foreign Accents in Radio Commercials for Congruent and Non-Congruent Products

    ERIC Educational Resources Information Center

    Hendriks, Berna; van Meurs, Frank; van der Meij, Els

    2015-01-01

    Commercials regularly feature foreign accents. This paper aims to investigate whether the use of foreign accents in radio commercials is more effective for congruent than incongruent products, and whether foreign-accented commercials are evaluated differently than non-accented commercials. In an experiment, a group of 228 Dutch participants rated…

  8. Limitations on adaptation to foreign accents

    PubMed Central

    Trude, Alison M.; Tremblay, Annie; Brown-Schmidt, Sarah

    2013-01-01

    Although foreign accents can be highly dissimilar to native speech, existing research suggests that listeners readily adapt to foreign accents after minimal exposure. However, listeners often report difficulty understanding non-native accents, and the time-course and specificity of adaptation remain unclear. Across five experiments, we examined whether listeners could use a newly learned feature of a foreign accent to eliminate lexical competitors during online speech perception. Participants heard the speech of a native English speaker and a native speaker of Québec French who, in English, pronounces /i/ as [i] (e.g., weak as wick) before all consonants except voiced fricatives. We examined whether listeners could learn to eliminate a shifted /i/-competitor (e.g., weak) when interpreting the accented talker produce an unshifted word (e.g., wheeze). In four experiments, adaptation was strikingly limited, though improvement across the course of the experiment and with stimulus variations indicates learning was possible. In a fifth experiment, adaptation was not improved when a native English talker produced the critical vowel shift, demonstrating that the limitation is not simply due to the fact the accented talker was non-native. These findings suggest that although listeners can arrive at the correct interpretation of a foreign accent, this process can pose significant difficulty. PMID:24014935

  9. The Penefit of Salience: Salient Accented, but Not Unaccented Words Reveal Accent Adaptation Effects

    PubMed Central

    Grohe, Ann-Kathrin; Weber, Andrea

    2016-01-01

    In two eye-tracking experiments, the effects of salience in accent training and speech accentedness on spoken-word recognition were investigated. Salience was expected to increase a stimulus' prominence and therefore promote learning. A training-test paradigm was used on native German participants utilizing an artificial German accent. Salience was elicited by two different criteria: production and listening training as a subjective criterion and accented (Experiment 1) and canonical test words (Experiment 2) as an objective criterion. During training in Experiment 1, participants either read single German words out loud and deliberately devoiced initial voiced stop consonants (e.g., Balken—“beam” pronounced as *Palken), or they listened to pre-recorded words with the same accent. In a subsequent eye-tracking experiment, looks to auditorily presented target words with the accent were analyzed. Participants from both training conditions fixated accented target words more often than a control group without training. Training was identical in Experiment 2, but during test, canonical German words that overlapped in onset with the accented words from training were presented as target words (e.g., Palme—“palm tree” overlapped in onset with the training word *Palken) rather than accented words. This time, no training effect was observed; recognition of canonical word forms was not affected by having learned the accent. Therefore, accent learning was only visible when the accented test tokens in Experiment 1, which were not included in the test of Experiment 2, possessed sufficient salience based on the objective criterion “accent.” These effects were not modified by the subjective criterion of salience from the training modality. PMID:27375540

  10. How native-like can you possibly get: fMRI evidence for processing accent

    PubMed Central

    Ghazi-Saidi, Ladan; Dash, Tanya; Ansaldo, Ana I.

    2015-01-01

    Introduction: If ever attained, adopting native-like accent is achieved late in the learning process. Resemblance between L2 and mother tongue can facilitate L2 learning. In particular, cognates (phonologically and semantically similar words across languages), offer the opportunity to examine the issue of foreign accent in quite a unique manner. Methods: Twelve Spanish speaking (L1) adults learnt French (L2) cognates and practiced their native-like pronunciation by means of a computerized method. After consolidation, they were tested on L1 and L2 oral picture- naming during fMRI scanning. Results and Discussion: The results of the present study show that there is a specific impact of accent on brain activation, even if L2 words are cognates, and belong to a pair of closely related languages. Results point that the insula is a key component of accent processing, which is in line with reports from patients with foreign accent syndrome following damage to the insula (e.g., Katz et al., 2012; Moreno-Torres et al., 2013; Tomasino et al., 2013), and healthy L2 learners (Chee et al., 2004). Thus, the left insula has been consistently related to the integration of attentional and working memory abilities, together with fine-tuning of motor programming to achieve optimal articulation. PMID:26578931

  11. The Effect of Accents on Cognitive Load and Achievement: The Relationship between Students' Accent Perception and Accented Voice Instructions in Students' Achievement

    ERIC Educational Resources Information Center

    Ahn, Jeahyeon

    2010-01-01

    The purpose of this study was to investigate how an instructor's accent influences students' learning achievement. Furthermore, this study also explored how students' accent preference may affect their learning. Unlike native voices, accented voices were not natural to the native speakers; therefore, it required more cognitive resources for…

  12. Fetal Alcohol Syndrome.

    ERIC Educational Resources Information Center

    Zerrer, Peggy

    The paper reviews Fetal Alcohol Syndrome (FAS), a series of effects seen in children whose mothers drink alcohol to excess during pregnancy. The identification of FAS and its recognition as a major health problem in need of prevention are traced. Characteristics of children with FAS are described and resultant growth retardation, abnormal physical…

  13. FAS — EDRN Public Portal

    Cancer.gov

    FAS is a member of the TNF-receptor superfamily. The FAS protein is a receptor for TNFSF6/FASLG and has been shown to play a central role in the physiological regulation of programmed cell death, and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. Several alternatively spliced transcript variants have been described, some of which are candidates for nonsense-mediated mRNA decay (NMD). The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform.

  14. [What is known about the outcome as adults for children with fetal alcohol syndrome (FAS)/fetal alcohol spectrum disorders (FASD)?].

    PubMed

    Walloch, J E; Burger, P H; Kornhuber, J

    2012-06-01

    In the field of adult psychiatry in German-speaking countries, little attention is as yet paid to the psychic defects that a fetus can sustain as a result of prenatal exposure to alcohol. Although children of alcohol-dependent mothers do present to psychiatric institutions as adults with manifold symptoms, e. g., attention deficit disorders, affective disorders or intellectual disability, fetal alcohol spectrum disorders are rarely diagnosed as an underlying cause. Appropriate therapy guidelines do not exist. Current review papers within the German-speaking countries usually stem from paediatric and adolescent psychiatry or medicine. Based on a selected review of the literature, the following paper addresses and discusses the disease entity of fetal alcohol spectrum disorders and fetal alcohol syndrome and their significance for adult psychiatry and also identifies open questions and research requirements, e. g., the development of diagnostic instruments or the establishment of diagnostic categories.

  15. Attention, Awareness, and Accents in L2 French

    ERIC Educational Resources Information Center

    Sturm, Jessica L.

    2013-01-01

    The present research applies the concepts of attention, awareness, and noticing to a previously unresolved strand of inquiry: accent marks in L2 (second language) French. Previous research found that learners who typed accented words had better recall of the accent marks than those who wrote the same words by hand. Sturm suggested that it may have…

  16. An ERP Investigation of Regional and Foreign Accent Processing

    ERIC Educational Resources Information Center

    Goslin, Jeremy; Duffy, Hester; Floccia, Caroline

    2012-01-01

    This study used event-related potentials (ERPs) to examine whether we employ the same normalisation mechanisms when processing words spoken with a regional accent or foreign accent. Our results showed that the Phonological Mapping Negativity (PMN) following the onset of the final word of sentences spoken with an unfamiliar regional accent was…

  17. Infants' Discrimination of Familiar and Unfamiliar Accents in Speech

    ERIC Educational Resources Information Center

    Butler, Joseph; Floccia, Caroline; Goslin, Jeremy; Panneton, Robin

    2011-01-01

    This study investigates infants' discrimination abilities for familiar and unfamiliar regional English accents. Using a variation of the head-turn preference procedure, 5-month-old infants demonstrated that they were able to distinguish between their own South-West English accent and an unfamiliar Welsh English accent. However, this distinction…

  18. Technology Enhanced Accent Modification (TEAM) for International Teaching Assistants (ITAs).

    ERIC Educational Resources Information Center

    Schwartz, Arthur H.

    The Technology Enhanced Accent Modification (TEAM) project created multimedia software to improve the oral proficiency of international teaching assistants (ITAs). Objectives were to: (1) develop reliable accent modification software that would operate on computers found at most colleges; (2) determine how TEAM-based accent modification…

  19. Children's Selective Trust in Native-Accented Speakers

    ERIC Educational Resources Information Center

    Kinzler, Katherine D.; Corriveau, Kathleen H.; Harris, Paul L.

    2011-01-01

    Across two experiments, preschool-aged children demonstrated selective learning of non-linguistic information from native-accented rather than foreign-accented speakers. In Experiment 1, children saw videos of a native- and a foreign-accented speaker of English who each spoke for 10 seconds, and then silently demonstrated different functions with…

  20. On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in lpr Mice

    PubMed Central

    Balomenos, Dimitrios; Shokri, Rahman; Daszkiewicz, Lidia; Vázquez-Mateo, Cristina; Martínez-A, Carlos

    2017-01-01

    Fas induces massive apoptosis in T cells after repeated in vitro T cell receptor (TCR) stimulation and is critical for lymphocyte homeostasis in Fas-deficient (lpr) mice. Although the in vitro Fas apoptotic mechanism has been defined, there is a large conceptual gap between this in vitro phenomenon and the pathway that leads to in vivo development of lymphadenopathy and autoimmunity. A striking abnormality in lpr mice is the excessive proliferation of CD4+ and CD8+ T cells, and more so of the double-negative TCR+CD4−CD8−B220+ T cells. The basis of lpr T cell hyperproliferation remains elusive, as it cannot be explained by Fas-deficient apoptosis. T cell-directed p21 overexpression reduces hyperactivation/hyperproliferation of all lpr T cell subtypes and lymphadenopathy in lpr mice. p21 controls expansion of repeatedly stimulated T cells without affecting apoptosis. These results confirm a direct link between hyperactivation/hyperproliferation, autoreactivity, and lymphadenopathy in lpr mice and, with earlier studies, suggest that Fas apoptosis-independent pathways control lpr T cell hyperproliferation. lpr T cell hyperproliferation could be an indirect result of the defective apoptosis of repeatedly stimulated lpr T cells. Nonetheless, in this perspective, we argue for an alternative setting, in which lack of Fas would directly cause lpr T cell hyperactivation/hyperproliferation in vivo. We propose that Fas/Fas ligand (FasL) acts as an activation inhibitor of recurrently stimulated T cells, and that its disruption causes overexpansion of T cells in lpr mice. Research to define the underlying mechanism of this Fas/FasL effect could resolve the phenotype of lpr mice and lead to therapeutics for related human syndromes. PMID:28344578

  1. On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in lpr Mice.

    PubMed

    Balomenos, Dimitrios; Shokri, Rahman; Daszkiewicz, Lidia; Vázquez-Mateo, Cristina; Martínez-A, Carlos

    2017-01-01

    Fas induces massive apoptosis in T cells after repeated in vitro T cell receptor (TCR) stimulation and is critical for lymphocyte homeostasis in Fas-deficient (lpr) mice. Although the in vitro Fas apoptotic mechanism has been defined, there is a large conceptual gap between this in vitro phenomenon and the pathway that leads to in vivo development of lymphadenopathy and autoimmunity. A striking abnormality in lpr mice is the excessive proliferation of CD4(+) and CD8(+) T cells, and more so of the double-negative TCR(+)CD4(-)CD8(-)B220(+) T cells. The basis of lpr T cell hyperproliferation remains elusive, as it cannot be explained by Fas-deficient apoptosis. T cell-directed p21 overexpression reduces hyperactivation/hyperproliferation of all lpr T cell subtypes and lymphadenopathy in lpr mice. p21 controls expansion of repeatedly stimulated T cells without affecting apoptosis. These results confirm a direct link between hyperactivation/hyperproliferation, autoreactivity, and lymphadenopathy in lpr mice and, with earlier studies, suggest that Fas apoptosis-independent pathways control lpr T cell hyperproliferation. lpr T cell hyperproliferation could be an indirect result of the defective apoptosis of repeatedly stimulated lpr T cells. Nonetheless, in this perspective, we argue for an alternative setting, in which lack of Fas would directly cause lpr T cell hyperactivation/hyperproliferation in vivo. We propose that Fas/Fas ligand (FasL) acts as an activation inhibitor of recurrently stimulated T cells, and that its disruption causes overexpansion of T cells in lpr mice. Research to define the underlying mechanism of this Fas/FasL effect could resolve the phenotype of lpr mice and lead to therapeutics for related human syndromes.

  2. Immunohistochemical study on Fas and Fas ligand in skin wound healing.

    PubMed

    Guan, D W; Ohshima, T; Kondo, T

    2000-02-01

    An immunohistochemical study on the expression of Fas and Fas ligand (Fas L) was performed in order to examine the role of apoptosis through Fas-Fas L in mouse skin wound healing. After a 1-cm-long incision in the central dorsum skin, mice were sacrificed at intervals ranging from 0.5 to 240 h, followed by the sampling of wound margin. The expression of Fas and Fas L in the wound margins and in uninjured skin controls was studied using frozen sections. In uninjured skin controls, a very weak expression of Fas and Fas L was detected immunohistochemically in hair follicles, sebaceous glands and epidermal cells. In wounded specimens, polymorphonuclear cells and inflammatory mononuclear ones (round-shaped and spindle-shaped types) were evident. A single immunostaining showed that Fas or Fas L was detectable in inflammatory mononuclear cells involved in the skin wound healing process. Double immunostaining for Fas and Fas L revealed that inflammatory mononuclear cells co-expressed both antigens. In situ TUNEL combined with immunostaining showed that the inflammatory mononuclear cells expressing Fas or Fas L and the polymorphonuclear cells were TUNEL-stained, although neither Fas nor Fas L was detected in the polymorphonuclear cells. The number of TUNEL-positive, inflammatory mononuclear cells expressing Fas or Fas L per 0.01 x 0.01 cm2 was counted. The average number of 10 randomly selected microscope fields reached a peak at the fibro-proliferative phase of wound healing. These results indicate that apoptosis through Fas and Fas L may play an important role for reducing the cellularity during skin wound healing in mice.

  3. Les trois accents: aigu, grave et circonflexe (2e partie) (The Three Accents: Acute, Grave and Circumflex. 2nd Part).

    ERIC Educational Resources Information Center

    Csecsy, Madeleine

    1981-01-01

    Discusses the correspondence between French phonology and spelling with regard to the role of accents. Refers the reader to the first part of the essay (n162, Jul 1981), then analyzes vowel harmony, free variation, the diacritic function of the grave accent, and the etymologic function of the circumflex accent. (MES)

  4. Evaluation of Speakers with Foreign-Accented Speech in Japan: The Effect of Accent Produced by English Native Speakers

    ERIC Educational Resources Information Center

    Tsurutani, Chiharu

    2012-01-01

    Foreign-accented speakers are generally regarded as less educated, less reliable and less interesting than native speakers and tend to be associated with cultural stereotypes of their country of origin. This discrimination against foreign accents has, however, been discussed mainly using accented English in English-speaking countries. This study…

  5. Foreign Accents, Language Acquisition, and Cerebral Dominance

    ERIC Educational Resources Information Center

    Scovel, Tom

    1969-01-01

    Paper presented to the Michigan Linguistic Society, Mount Pleasant, Michigan, October 4, 1969. Theorizes that the nature of the brain, not its nurture, inhibits the ability of a person to master the sound patterns of a second language without an accent. (DS)

  6. Predicting English Word Accent on Morphological Grounds

    ERIC Educational Resources Information Center

    Salmani Nodoushan, Mohammad Ali

    2007-01-01

    Learners of English as a foreign/Second Language (EFL/ESL) can easily learn the correct pronunciation of English words, some linguists have tried to simplify English phonology in general, and English accent in particular, over the past 50 years or so; some scholars have talked about four degrees of primary, secondary, tertiary and weak stress…

  7. Predicting English Word Accent on Morphological Grounds

    ERIC Educational Resources Information Center

    Salmani-Nodoushan, Mohammad Ali

    2007-01-01

    Learners of English as a foreign/Second Language (EFL/ESL) can easily learn the correct pronunciation of English words. Linguists have tried to simplify English phonology in general, and English accent in particular, over the past 50 years or so; some scholars have talked about four degrees of primary, secondary, tertiary and weak stress (e.g.,…

  8. Effect of Accent and Dialect on Employability

    ERIC Educational Resources Information Center

    Carlson, Holly K.; McHenry, Monica A.

    2006-01-01

    This study was designed to determine how ethnicity, the amount of perceived accent or dialect, and comprehensibility affect a speaker's employability. Sixty human resource specialists judged 3 female potential applicants. The applicants represented speakers of Spanish-influenced English, Asian-influenced English, and African American Vernacular…

  9. Strength of British English Accents in Altered Listening Conditions

    PubMed Central

    Howell, Peter; Barry, William; Vinson, David

    2007-01-01

    This work is concerned with the processing or representational level at which accent forms learned early in life can change, and whether alteration to the speaker's auditory environment can elicit an original accent. In experiment one, recordings were made of an equal number of a) speakers living in the Home Counties of Britain (around the London conurbation), but who claimed to have retained the accent of the region they originally came from, b) speakers who stated they had lost their regional accent and acquired a Home Counties accent and c) native Home Counties speakers. They read two texts in a normal listening environment. Listeners rated the similarity in accent between each of these texts and all other texts. The results showed that in the normal listening conditions, speakers who had lost their accent were rated more similar to Home Counties English speakers than to those speakers from the same region who had retained their accent. In experiment two, recordings of the same speakers under frequency shifted and delayed auditory feedback, as well as the normal listening conditions used earlier, were rated in order to see whether the manipulations of listening environment elicited the speaker's original accent. Listeners rated similarity of accent in a sample of speech recorded under normal listening against a sample read by another speaker in one of the altered listening conditions. When listening condition was altered, speakers who had lost their original accent were rated as more similar to those who had retained their accent. It is concluded that accent differences can be elicited by altering listening environment because the speech systems of these speakers are more vulnerable than speakers who do not change their original accent. PMID:16617838

  10. Alteration of Fas and Fas ligand expression during human visceral leishmaniasis

    PubMed Central

    Eidsmo, L; Wolday, D; Berhe, N; Sabri, F; Satti, I; El Hassan, A M; Sundar, S; Chiodi, F; Akuffo, H

    2002-01-01

    Several studies in murine systems have suggested a role of apoptosis in the pathogenesis of leishmaniasis. However, the role of apoptosis in visceral leishmaniasis in man has not been explored. In this study, we show that patients with visceral leishmaniasis demonstrate significant dysregulation of Fas and Fas ligand. Levels of soluble Fas (sFas) and soluble Fas ligand (sFasL) were elevated in plasma of patients with active visceral leishmaniasis (VL) and individuals co-infected with VL-HIV-1 compared to healthy controls. The levels of sFas and sFasL were normalized 6 months after successful treatment. In VL patients, the expression of membrane bound Fas, and to a lower extent FasL, were up-regulated on Leishmania donovani-infected spleen cells, the site of parasite multiplication. Expression of Fas and FasL on peripheral blood mononuclear cells was within normal range, probably reflecting that the blood is not a normal site of L. donovani infection. Furthermore, this is suggested by the finding that in vitro infection of macrophages with L. donovani up-regulated Fas expression on the surface of infected cells and enhanced the levels of sFasL in supernatants from infected cultures. How this dysregulation may affect the pathogenesis of human visceral leishmaniasis is discussed. PMID:12390320

  11. Fetal Alcohol Syndrome: Developmental Characteristics and Directions for Further Research.

    ERIC Educational Resources Information Center

    Williams, Betty Fry; And Others

    1994-01-01

    This paper presents an overview of how fetal alcohol syndrome (FAS) is identified, a review of theories on how alcohol acts to produce FAS, and a summary of the impact of the early and long-term effects of FAS. Issues that are particularly pertinent to children with FAS and their caregivers are raised. (DB)

  12. Fetal Alcohol Syndrome: A Guide for Families and Communities.

    ERIC Educational Resources Information Center

    Streissguth, Ann

    The 14 chapters of this book review the research and offer guidelines for intervention with infants and children having fetal alcohol syndrome or fetal alcohol effects (FAS/FAE). Chapters are grouped into five sections on the diseases of fetal alcohol, the science of FAS, a life-span approach to FAS, preparing people with FAS for life in the…

  13. Categorization of Regional and Foreign Accent in 5- to 7-Year-Old British Children

    ERIC Educational Resources Information Center

    Floccia, Caroline; Butler, Joseph; Girard, Frederique; Goslin, Jeremy

    2009-01-01

    This study examines children's ability to detect accent-related information in connected speech. British English children aged 5 and 7 years old were asked to discriminate between their home accent from an Irish accent or a French accent in a sentence categorization task. Using a preliminary accent rating task with adult listeners, it was first…

  14. Clinicopathological significance of Fas and Fas ligand expressions in esophageal cancer

    PubMed Central

    Wu, Guang-Zhou; Pan, Chun-Xia; Jiang, Dong; Zhang, Qiang; Li, Yin; Zheng, Shi-Ying

    2015-01-01

    Esophageal carcinomas have recently been shown to express Fas ligand (FasL) and down-regulate Fas to escape from host immune surveillance. However, the prognostic importance of Fas/FasL and their correlation with clinicopathological characteristics are yet to be delineated in this highly malignant carcinoma. Specimens from 106 esophageal squamous cell carcinoma patients were used for immuno-histochemical evaluation of Fas, FasL, and CD8 expressions. Fifty-two (49%) and 34 (32%) patients were positive for FasL and Fas, respectively. There were no associations between FasL expression and clinicopathological characteristics except lymph vessel invasion. Strong FasL expression correlated with significant (P < 0.001) decrease in tumor nest CD81 cells. However, neither FasL nor CD81 had any impact on patient survival. Strong Fas expression was correlated with depth of invasion (40.3% in pT1, T2 versus 20.5% in pT3, T4; P5 0.0308), histological differentiation (45.7% in well versus 25.4% in nonwell; P < 0.05), and lymph node metastasis (22.6% in positive versus 45.5% in negative; P < 0.01). Fas expression was one of the independent favorable prognosticators for patients’ survival (risk ratio, 3.26; P < 0.01) in esophageal SCC. Fas expression was an independent prognosticator for recurrencefree survival, whereas FasL expression did not influence the survival in esophageal squamous cell carcinoma. Down-regulation of tumor Fas may be the hallmark of immune privilege for the tumor, thus causing the patients’ poorer outcome. Tumor FasL may counterattack the host immune cells to such an extent that the prognosis is not affected. PMID:26609492

  15. Effects of contrastive accents on children's discourse comprehension.

    PubMed

    Lee, Eun-Kyung; Snedeker, Jesse

    2016-10-01

    What role do contrastive accents play in children's discourse comprehension? By 6 years of age, children use contrastive accents during online comprehension to predict upcoming referents (Ito et al., 2014; Sekerina & Trueswell, 2012). But, at this age, children's performance on offline tasks of accent comprehension is poor (e.g., Wells et al., 2004). To examine whether the asymmetry could reflect a developmental stage in which the processing system uses contrastive accents to make local predictions, but fails to incorporate this information into discourse representations, we tested the effect of contrastive accents on children's memory of the content of a discourse. Five-year-olds heard 12 different stories consecutively, one after another, and the critical words were manipulated so that they were produced either with a contrastive L+H* accent or with a presentational H* accent. We found that children remembered facts about the contrast set better when the target word had an appropriate contrastive accent earlier than when it had a presentational accent. The results show that by 5 years, children are able to use contrastive accents for encoding a discourse, as well as for making local predictions during online comprehension.

  16. Fetal Alcohol Syndrome Resource Guide.

    ERIC Educational Resources Information Center

    Snyder, Lisa

    This resource guide provides information on programs, publications, organizations, and other resources related to prevention of fetal alcohol syndrome (FAS). The purpose of this guide is to assist health care providers to comply with Indian Health Service (IHS) FAS goals and objectives. It gives examples of community approaches to FAS prevention,…

  17. Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

    PubMed Central

    Rossin, A; Durivault, J; Chakhtoura-Feghali, T; Lounnas, N; Gagnoux-Palacios, L; Hueber, A-O

    2015-01-01

    The death receptor Fas undergoes a variety of post-translational modifications including S-palmitoylation. This protein acylation has been reported essential for an optimal cell death signaling by allowing both a proper Fas localization in cholesterol and sphingolipid-enriched membrane nanodomains, as well as Fas high-molecular weight complexes. In human, S-palmitoylation is controlled by 23 members of the DHHC family through their palmitoyl acyltransferase activity. In order to better understand the role of this post-translational modification in the regulation of the Fas-mediated apoptosis pathway, we performed a screen that allowed the identification of DHHC7 as a Fas-palmitoylating enzyme. Indeed, modifying DHHC7 expression by specific silencing or overexpression, respectively, reduces or enhances Fas palmitoylation and DHHC7 co-immunoprecipitates with Fas. At a functional level, DHHC7-mediated palmitoylation of Fas allows a proper Fas expression level by preventing its degradation through the lysosomes. Indeed, the decrease of Fas expression obtained upon loss of Fas palmitoylation can be restored by inhibiting the lysosomal degradation pathway. We describe the modification of Fas by palmitoylation as a novel mechanism for the regulation of Fas expression through its ability to circumvent its degradation by lysosomal proteolysis. PMID:25301068

  18. The status of Fas and Fas ligand expression can predict recurrence of hepatocellular carcinoma

    PubMed Central

    Ito, Y; Monden, M; Takeda, T; Eguchi, H; Umeshita, K; Nagano, H; Nakamori, S; Dono, K; Sakon, M; Nakamura, M; Tsujimoto, M; Nakahara, M; Nakao, K; Yokosaki, Y; Matsuura, N

    2000-01-01

    The status of Fas and Fas ligand (Fas L) expression was investigated in this study for 103 hepatocellular carcinomas (HCC). We studied the expression of the following three factors, Fas and Fas L expression in carcinoma cells and Fas L expression in stromal mononuclear cells (defined as stromal Fas L index). Fas expression in HCC cells was significantly decreased in cases with poor differentiation (P< 0.0001) and of larger size (P = 0.0058). Fas L expression in carcinoma cells was observed exclusively in moderately or poorly differentiated cases. Furthermore, each factor had prognostic significance for disease-free survival (DFS) (P< 0.0001, P = 0.0222 and 0.0027 respectively). We then scored the results of each factor and defined the total score as ‘Fas-Fas L risk score’. The P -value of the score for DFS was even lower than that of the clinical stage by multivariate analysis. These results suggest that the evaluation of Fas and Fas ligand expression potentially has a significant prognostic value for DFS of HCC patients, in addition to the clinical stage, and can be regarded as a new prognostic marker. © 2000 Cancer Research Campaign PMID:10735508

  19. Rapid adaptation to foreign-accented English

    NASA Astrophysics Data System (ADS)

    Clarke, Constance M.; Garrett, Merrill F.

    2004-12-01

    This study explored the perceptual benefits of brief exposure to non-native speech. Native English listeners were exposed to English sentences produced by non-native speakers. Perceptual processing speed was tracked by measuring reaction times to visual probe words following each sentence. Three experiments using Spanish- and Chinese-accented speech indicate that processing speed is initially slower for accented speech than for native speech but that this deficit diminishes within one minute of exposure. Control conditions rule out explanations for the adaptation effect based on practice with the task and general strategies for dealing with difficult speech. Further results suggest that adaptation can occur within as few as two to four sentence-length utterances. The findings emphasize the flexibility of human speech processing and require models of spoken word recognition that can rapidly accommodate significant acoustic-phonetic deviations from native language speech patterns. .

  20. Effects of pitch accents in attachment ambiguity resolution

    PubMed Central

    Lee, Eun-Kyung; Watson, Duane G.

    2011-01-01

    Previous work has found that listeners prefer to attach ambiguous syntactic constituents to nouns produced with a pitch accent (Schafer et al., 1996). This study examines what factors underlie previously established accent attachment effects by testing whether these effects are driven by a preference to attach syntactic constituents to new or important information (the Syntax Hypothesis) or whether there is a bias to respond to post-sentence probe questions with an accented word (the Salience Hypothesis). One of the predictions of the Salience Hypothesis is that selection of accented words should be greater when a sentence is complex and processing resources are limited. The results from the experiments presented here show that the probability of listeners’ selecting accented words when asked about the interpretation of a relative clause varies with sentence type: listeners selected accented words more frequently in long sentences than in short sentences, consistent with the predictions of the Salience Hypothesis. Furthermore, Experiment 4 demonstrates that listeners are more likely to respond to post-sentence questions with accented words than with non-accented words, even when no ambiguity is present, and even when the response results in an incorrect answer. These findings suggest that accent-driven attachment effects found in earlier studies reflect a post-sentence selection process rather than a syntactic processing mechanism. PMID:22287815

  1. Effects of contextual support on preschoolers' accented speech comprehension.

    PubMed

    Creel, Sarah C; Rojo, Dolly P; Paullada, Angelica Nicolle

    2016-06-01

    Young children often hear speech in unfamiliar accents, but relatively little research characterizes their comprehension capacity. The current study tested preschoolers' comprehension of familiar-accented versus unfamiliar-accented speech with varying levels of contextual support from sentence frames (full sentences vs. isolated words) and from visual context (four salient pictured alternatives vs. the absence of salient visual referents). The familiar accent advantage was more robust when visual context was absent, suggesting that previous findings of good accent comprehension in infants and young children may result from ceiling effects in easier tasks (e.g., picture fixation, picture selection) relative to the more difficult tasks often used with older children and adults. In contrast to prior work on mispronunciations, where most errors were novel object responses, children in the current study did not select novel object referents above chance levels. This suggests that some property of accented speech may dissuade children from inferring that an unrecognized familiar-but-accented word has a novel referent. Finally, children showed detectable accent processing difficulty despite presumed incidental community exposure. Results suggest that preschoolers' accented speech comprehension is still developing, consistent with theories of protracted development of speech processing.

  2. Soluble Fas and the −670 Polymorphism of Fas in Lupus Nephritis

    PubMed Central

    Bollain-y-Goytia, Juan José; Arellano-Rodríguez, Mariela; Torres-Del-Muro, Felipe de Jesús; Daza-Benítez, Leonel; Francisco Muñoz-Valle, José; Avalos-Díaz, Esperanza; Herrera-Esparza, Rafael

    2014-01-01

    This study was performed to clarify the role of soluble Fas (sFas) in lupus nephritis (LN) and establish a potential relationship between LN and the −670 polymorphism of Fas in 67 patients with systemic lupus erythematosus (SLE), including a subset of 24 LN patients with proteinuria. Additionally, a group of 54 healthy subjects (HS) was included. The allelic frequency of the −670 polymorphism of Fas was determined using PCR-RFLP analysis, and sFas levels were assessed by ELISA. Additionally, the WT-1 protein level in urine was measured. The Fas receptor was determined in biopsies by immunohistochemistry (IHC) and in situ hybridization (FISH) and apoptotic features by TUNEL. Results. The −670 Fas polymorphism showed that the G allele was associated with increased SLE susceptibility, with an odds ratio (OR) of 1.86. The sFas was significantly higher in LN patients with the G/G genotype, and this subgroup exhibited correlations between the sFas level and proteinuria and increased urinary WT-1 levels. LN group shows increased expression of Fas and apoptotic features. In conclusion, our results indicate that the G allele of the −670 polymorphism of Fas is associated with genetic susceptibility in SLE patients with elevated levels of sFas in LN with proteinuria. PMID:25505993

  3. Fas-FasL expression and myocardial cell apoptosis in patients with viral myocarditis.

    PubMed

    Huang, T F; Wu, X H; Wang, X; Lu, I J

    2016-06-20

    The aim of the current study was to investigate Fas and FasL expression and myocardial cell apoptosis in viral myocarditis patients. Human heart specimens were selected from patients who were autopsied between February 2012 and February 2015; of these, 25 patients were diagnosed with viral myocarditis. Another 15 cases with no diagnosis of myocarditis were selected for the control group. All tissue specimens were divided into two parts, one for reverse transcription-polymerase chain reaction analysis and the other for immunohistochemical and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses. In situ detection of apoptosis was performed by the TUNEL method, which revealed that myocardial cells from the viral myocarditis group exhibited significant apoptosis, whereas no apoptotic cells were observed in the control group. The number of cells staining positive for Fas and FasL protein in the viral myocarditis group was significantly higher than that in the control group (P < 0.05). There was also a correlation between Fas and FasL protein expression levels and scores (r = 0.92, P < 0.05). The mRNA expression of Fas and FasL was significantly higher in the viral myocarditis group than in the control group (P < 0.05). In conclusion, the Fas-FasL system may be involved in the pathogenesis of viral myocarditis. Furthermore, cytotoxic T lymphocytes may mediate cardiac muscle cells apoptosis via Fas-FasL signaling, and thus participate in the pathogenesis of viral myocarditis.

  4. Accents in the workplace: their effects during a job interview.

    PubMed

    Deprez-Sims, Anne-Sophie; Morris, Scott B

    2010-12-01

    As the workplace becomes increasingly global, organizations are more likely to employ persons from other countries whose accents clearly identify them as different from the local workforce. Understanding the impact of accents in the workplace is important because accents can be salient in the same way as ethnicity, age, gender, and skin color and may be a source of employment discrimination. The present study looked at the influence of accents on the evaluation of job applicants during an interview for a human resource manager position. Participants from the US were asked to evaluate an applicant with one of three accents (Midwestern US, French, Colombian) by listening to an audiofile. The results showed that the applicant with the Midwestern US accent was evaluated more positively than the applicant with the French accent; however, the applicant with the Colombian accent did not receive an evaluation that differed significantly from those given to the applicants with either the French or the Midwestern US accent. Analyses of process variables indicated that the bias against the French-accented applicant was mediated by perceived lower similarity. These results are consistent with the similarity-attraction hypothesis, which states that demographic variables will impact judgments to the extent to which they make the decision-maker view the applicant as similar or dissimilar. The ability of accent to trigger bias highlights the importance of considering the full array of characteristics that can lead to discrimination in employment settings. Research on employment discrimination has traditionally focused on visual cues such as gender and ethnicity, but in an interview situation, the way the applicant speaks is also important.

  5. Posttranslational regulation of Fas ligand function

    PubMed Central

    Voss, Matthias; Lettau, Marcus; Paulsen, Maren; Janssen, Ottmar

    2008-01-01

    The TNF superfamily member Fas ligand acts as a prototypic death factor. Due to its ability to induce apoptosis in Fas (APO-1, CD95) expressing cells, Fas ligand participates in essential effector functions of the immune system. It is involved in natural killer cell- and T cell-mediated cytotoxicity, the establishment of immune privilege, and in termination of immune responses by induction of activation-induced cell death. In addition, Fas ligand-positive tumours may evade immune surveillance by killing Fas-positive tumour-infiltrating cells. Given these strong cytotoxic capabilities of Fas ligand, it is obvious that its function has to be strictly regulated to avoid uncontrolled damage. In hematopoietic cells, the death factor is stored in secretory lysosomes and is mobilised to the immunological synapse only upon activation. The selective sorting to and the release from this specific lysosomal compartment requires interactions of the Fas ligand cytosolic moiety, which mediates binding to various adapter proteins involved in trafficking and cytoskeletal reorganisation. In addition, Fas ligand surface expression is further regulated by posttranslational ectodomain shedding and subsequent regulated intramembrane proteolysis, releasing a soluble ectodomain cytokine into the extracellular space and an N-terminal fragment with a potential role in intracellular signalling processes. Moreover, other posttranslational modifications of the cytosolic domain, including phosphorylation and ubiquitylation, have been described to affect various aspects of Fas ligand biology. Since FasL is regarded as a potential target for immunotherapy, the further characterisation of its biological regulation and function will be of great importance for the development and evaluation of future therapeutic strategies. PMID:19114018

  6. Processing changes when listening to foreign-accented speech

    PubMed Central

    Romero-Rivas, Carlos; Martin, Clara D.; Costa, Albert

    2015-01-01

    This study investigates the mechanisms responsible for fast changes in processing foreign-accented speech. Event Related brain Potentials (ERPs) were obtained while native speakers of Spanish listened to native and foreign-accented speakers of Spanish. We observed a less positive P200 component for foreign-accented speech relative to native speech comprehension. This suggests that the extraction of spectral information and other important acoustic features was hampered during foreign-accented speech comprehension. However, the amplitude of the N400 component for foreign-accented speech comprehension decreased across the experiment, suggesting the use of a higher level, lexical mechanism. Furthermore, during native speech comprehension, semantic violations in the critical words elicited an N400 effect followed by a late positivity. During foreign-accented speech comprehension, semantic violations only elicited an N400 effect. Overall, our results suggest that, despite a lack of improvement in phonetic discrimination, native listeners experience changes at lexical-semantic levels of processing after brief exposure to foreign-accented speech. Moreover, these results suggest that lexical access, semantic integration and linguistic re-analysis processes are permeable to external factors, such as the accent of the speaker. PMID:25859209

  7. Scandinavian Accents in Their Relation to One Another

    ERIC Educational Resources Information Center

    Liberman, A. S.

    1975-01-01

    This paper is concerned with four Scandinavian prosodemes: accent 1, accent 2, stoed, and no stoed. The aim is to establish the function of each of them, i.e., the role they play in the system of each Scandinavian language. Available from Liber Laeromedel, Box 1205, S-22105 Lund, Sweden. (Author/TL)

  8. Segmentals and Global Foreign Accent: The Japanese Flap in EFL.

    ERIC Educational Resources Information Center

    Riney, Timothy J.; Takada, Mari; Ota, Mitsuhiko

    2000-01-01

    Reports the results of research on the extent to which global foreign accent in English is related to a discrete segmental feature of pronunciation, substitution of the Japanese flap for /l/ and /r/ in two phonological environments. Results showed a strong negative correlation between a nativelike accent and flap substitution. (Author/VWL)

  9. Structural Influences on Initial Accent Placement in French

    ERIC Educational Resources Information Center

    Astesano, Corine; Bard, Ellen Gurman; Turk, Alice

    2007-01-01

    In addition to the phrase-final accent (FA), the French phonological system includes a phonetically distinct Initial Accent (IA). The present study tested two proposals: that IA marks the onset of phonological phrases, and that it has an independent rhythmic function. Eight adult native speakers of French were instructed to read syntactically…

  10. Accent, Intelligibility, and Comprehensibility. Evidence from Four L1s.

    ERIC Educational Resources Information Center

    Derwing, Tracey M.; Munro, Murray J.

    1997-01-01

    This study extends previous research on the relationships among intelligibility, perceived comprehensibility, and accentedness. The researchers obtained accent and comprehensibility ratings and transcriptions of accented speech of Cantonese, Japanese, Polish, and Spanish intermediate English-as-a-Second-Language students from native English…

  11. Measuring Implicit and Explicit Attitudes toward Foreign-Accented Speech

    ERIC Educational Resources Information Center

    Pantos, Andrew J.

    2010-01-01

    The purpose of this research was to investigate the nature of listeners' attitudes toward foreign-accented speech and the manner in which those attitudes are formed. This study measured 165 participants' implicit and explicit attitudes toward US- and foreign-accented audio stimuli. Implicit attitudes were measured with an audio Implicit…

  12. Listening between the Lines: Social Assumptions around Foreign Accents

    ERIC Educational Resources Information Center

    Fraser, Catriona; Kelly, Barbara

    2012-01-01

    This paper investigates the effect of listener attitudes on the ability to understand a foreign (non-Australian) accent. The research focuses on individual listener characteristics, such as attitude and frequency of contact with accented speakers, rather than speech production. Data was collected through a web-based survey and analysis employed…

  13. Putting Accent in Its Place: Rethinking Obstacles to Communication

    ERIC Educational Resources Information Center

    Derwing, Tracey M.; Munro, Murray J.

    2009-01-01

    One of the most salient aspects of speech is accent--either dialectal differences attributable to region or class, or phonological variations resulting from L1 influence on the L2. Our primary concern is with the latter, because of the strong social, psychological, and communicative consequences of speaking with an L2 accent. The decline of…

  14. Intonation and Accent in English: What Teachers Need to Know.

    ERIC Educational Resources Information Center

    Taylor, David S.

    1993-01-01

    Presenting an account of the general workings and functions of English intonation and accentuation, the discussion notes the prominent role of accent placement. An attempted overall framework for interpreting intonation and accent in English takes account of the discourse dimension to render the subject accessible to both teacher and learner.…

  15. The FasFADD death domain complex structure reveals the basis of DISC assembly and disease mutations

    SciTech Connect

    Wang, Liwei; Yang, Jin Kuk; Kabaleeswaran, Venkataraman; Rice, Amanda J.; Cruz, Anthony C.; Park, Ah Young; Yin, Qian; Damko, Ermelinda; Jang, Se Bok; Raunser, Stefan; Robinson, Carol V.; Siegel, Richard M.; Walz, Thomas; Wu, Hao

    2010-10-10

    The death-inducing signaling complex (DISC) formed by the death receptor Fas, the adaptor protein FADD and caspase-8 mediates the extrinsic apoptotic program. Mutations in Fas that disrupt the DISC cause autoimmune lymphoproliferative syndrome (ALPS). Here we show that the Fas-FADD death domain (DD) complex forms an asymmetric oligomeric structure composed of 5-7 Fas DD and 5 FADD DD, whose interfaces harbor ALPS-associated mutations. Structure-based mutations disrupt the Fas-FADD interaction in vitro and in living cells; the severity of a mutation correlates with the number of occurrences of a particular interaction in the structure. The highly oligomeric structure explains the requirement for hexameric or membrane-bound FasL in Fas signaling. It also predicts strong dominant negative effects from Fas mutations, which are confirmed by signaling assays. The structure optimally positions the FADD death effector domain (DED) to interact with the caspase-8 DED for caspase recruitment and higher-order aggregation.

  16. Recognition memory reveals just how CONTRASTIVE contrastive accenting really is

    PubMed Central

    Fraundorf, Scott H.; Watson, Duane G.; Benjamin, Aaron S.

    2010-01-01

    The effects of pitch accenting on memory were investigated in three experiments. Participants listened to short recorded discourses that contained contrast sets with two items (e.g. British scientists and French scientists); a continuation specified one item from the set. Pitch accenting on the critical word in the continuation was manipulated between non-contrastive (H* in the ToBI system) and contrastive (L+H*). On subsequent recognition memory tests, the L+H* accent increased hits to correct statements and correct rejections of the contrast item (Experiments 1–3), but did not impair memory for other parts of the discourse (Experiment 2). L+H* also did not facilitate correct rejections of lures not in the contrast set (Experiment 3), indicating that contrastive accents do not simply strengthen the representation of the target item. These results suggest comprehenders use pitch accenting to encode and update information about multiple elements in a contrast set. PMID:20835405

  17. Linguistic Processing of Accented Speech Across the Lifespan

    PubMed Central

    Cristia, Alejandrina; Seidl, Amanda; Vaughn, Charlotte; Schmale, Rachel; Bradlow, Ann; Floccia, Caroline

    2012-01-01

    In most of the world, people have regular exposure to multiple accents. Therefore, learning to quickly process accented speech is a prerequisite to successful communication. In this paper, we examine work on the perception of accented speech across the lifespan, from early infancy to late adulthood. Unfamiliar accents initially impair linguistic processing by infants, children, younger adults, and older adults, but listeners of all ages come to adapt to accented speech. Emergent research also goes beyond these perceptual abilities, by assessing links with production and the relative contributions of linguistic knowledge and general cognitive skills. We conclude by underlining points of convergence across ages, and the gaps left to face in future work. PMID:23162513

  18. Performance of American Indian Children with Fetal Alcohol Syndrome on the Test of Language Development.

    ERIC Educational Resources Information Center

    Carney, Laura J.; Chermak, Gail D.

    1991-01-01

    Twenty-seven American Indian children (ages 4-12), 10 with Fetal Alcohol Syndrome (FAS) and 17 normally developing control subjects, were administered the Test of Language Development. FAS children exhibited depressed performance on most subtests. The older FAS children presented syntactic deficits whereas the younger FAS subjects presented more…

  19. Malaysian University Students' Attitudes towards Six Varieties of Accented Speech in English

    ERIC Educational Resources Information Center

    Ahmed, Zainab Thamer; Abdullah, Ain Nadzimah; Heng, Chan Swee

    2014-01-01

    Previous language attitude studies indicated that in many countries all over the world, English language learners perceived native accents, either American or British, more positively than the non-native accents such as the Japanese, Korean, and Austrian accents. However, in Malaysia it is still unclear which accent Malaysian learners of English…

  20. Accent imitation positively affects language attitudes

    PubMed Central

    Adank, Patti; Stewart, Andrew J.; Connell, Louise; Wood, Jeffrey

    2013-01-01

    People in conversation tend to accommodate the way they speak. It has been assumed that this tendency to imitate each other's speech patterns serves to increase liking between partners in a conversation. Previous experiments examined the effect of perceived social attractiveness on the tendency to imitate someone else's speech and found that vocal imitation increased when perceived attractiveness was higher. The present experiment extends this research by examining the inverse relationship and examines how overt vocal imitation affects attitudes. Participants listened to sentences spoken by two speakers of a regional accent (Glaswegian) of English. They vocally repeated (speaking in their own accent without imitating) the sentences spoken by a Glaswegian speaker, and subsequently imitated sentences spoken by a second Glaswegian speaker (order counterbalanced across participants). After each repeating or imitation session, participants completed a questionnaire probing the speakers' perceived power, competence, and social attractiveness. Imitating had a positive effect on the perceived social attractiveness of the speaker compared to repeating. These results are interpreted in light of Communication Accommodation Theory. PMID:23734137

  1. Accent imitation positively affects language attitudes.

    PubMed

    Adank, Patti; Stewart, Andrew J; Connell, Louise; Wood, Jeffrey

    2013-01-01

    People in conversation tend to accommodate the way they speak. It has been assumed that this tendency to imitate each other's speech patterns serves to increase liking between partners in a conversation. Previous experiments examined the effect of perceived social attractiveness on the tendency to imitate someone else's speech and found that vocal imitation increased when perceived attractiveness was higher. The present experiment extends this research by examining the inverse relationship and examines how overt vocal imitation affects attitudes. Participants listened to sentences spoken by two speakers of a regional accent (Glaswegian) of English. They vocally repeated (speaking in their own accent without imitating) the sentences spoken by a Glaswegian speaker, and subsequently imitated sentences spoken by a second Glaswegian speaker (order counterbalanced across participants). After each repeating or imitation session, participants completed a questionnaire probing the speakers' perceived power, competence, and social attractiveness. Imitating had a positive effect on the perceived social attractiveness of the speaker compared to repeating. These results are interpreted in light of Communication Accommodation Theory.

  2. Fetal Alcohol Syndrome a Global Problem

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_163096.html Fetal Alcohol Syndrome a Global Problem: Report Countries with highest alcohol ... 000 children worldwide are born each year with fetal alcohol syndrome (FAS), a new report finds. The syndrome refers ...

  3. Listening with an accent: speech perception in a second language by late bilinguals.

    PubMed

    Leikin, Mark; Ibrahim, Raphiq; Eviatar, Zohar; Sapir, Shimon

    2009-10-01

    The goal of the present study was to examine functioning of late bilinguals in their second language. Specifically, we asked how native and non-native Hebrew speaking listeners perceive accented and native-accented Hebrew speech. To achieve this goal we used the gating paradigm to explore the ability of healthy late fluent bilinguals (Russian and Arabic native speakers) to recognize words in L2 (Hebrew) when they were spoken in an accent like their own, a native accent (Hebrew speakers), or another foreign accent (American accent). The data revealed that for Hebrew speakers, there was no effect of accent, whereas for the two bilingual groups (Russian and Arabic native speakers), stimuli with an accent like their own and the native Hebrew accent, required significantly less phonological information than the other foreign accents. The results support the hypothesis that phonological assimilation works in a similar manner in these two different groups.

  4. Fetal Alcohol Syndrome: Facts and Prevention.

    ERIC Educational Resources Information Center

    Shelton, Maria; Cook, Martha

    1993-01-01

    This article provides a brief introduction to fetal alcohol syndrome (FAS) including characteristics, incidence, current government programs, successful local programs, and implications for school administrators. (DB)

  5. Accent trumps race in guiding children’s social preferences

    PubMed Central

    Kinzler, Katherine D.; Shutts, Kristin; DeJesus, Jasmine; Spelke, Elizabeth S.

    2011-01-01

    A series of experiments investigated the effect of speakers’ language, accent, and race on children’s social preferences. When presented with photographs and voice recordings of novel children, 5-year-old children chose to be friends with native speakers of their native language rather than foreign-language or foreign-accented speakers. These preferences were not exclusively due to the intelligibility of the speech, as children found the accented speech to be comprehensible, and did not make social distinctions between foreign-accented and foreign-language speakers. Finally, children chose same-race children as friends when the target children were silent, but they chose other-race children with a native accent when accent was pitted against race. A control experiment provided evidence that children’s privileging of accent over race was not due to the relative familiarity of each dimension. The results, discussed in an evolutionary framework, suggest that children preferentially evaluate others along dimensions that distinguished social groups in prehistoric human societies. PMID:21603154

  6. Complementary hemispheric specialization for word and accent detection.

    PubMed

    Berman, Steven M; Mandelkern, Mark A; Phan, Hao; Zaidel, Eran

    2003-06-01

    When we hear a familiar word pronounced in a foreign accent, which parts of the brain identify the word and which identify the accent? Here we present converging evidence from PET blood flow, event-related scalp potentials, and behavioral responses during dichotic listening, showing homologous and complementary hemispheric specialization for word and accent detection. Accuracy of detecting target words was greater when stimuli were presented to the right ear, indicating left hemisphere specialization, with no ear advantage for detecting target accents. Detection of words also produced increased blood flow in a left frontal area associated with motor and phonetic processing, and a left temporal area associated with semantic memory. Homologous areas of the right hemisphere, together with right prefrontal and precuneus regions, showed increased blood flow during detection of accents. Separate analyses for each detection task indicated that voxels whose activity maximally correlated with accuracy were in the left hemisphere for word detection, but in the right hemisphere for accent detection. Voxels whose activity maximally correlated with inaccuracy were in the opposite hemisphere for both tasks, strengthening the interpretation that between-task differences in brain activation are related to lateralized specializations for task performance. ERP waveforms and reaction times suggested that greater left hemisphere activation during word detection preceded greater right hemisphere activation during accent detection. The results are interpreted as supporting left hemisphere specialization for extraction of the linguistic, phonetic, and semantic information contained in speech, and right hemisphere specialization for pragmatics, the social context of linguistic communication.

  7. When pitch Accents Encode Speaker Commitment: Evidence from French Intonation.

    PubMed

    Michelas, Amandine; Portes, Cristel; Champagne-Lavau, Maud

    2016-06-01

    Recent studies on a variety of languages have shown that a speaker's commitment to the propositional content of his or her utterance can be encoded, among other strategies, by pitch accent types. Since prior research mainly relied on lexical-stress languages, our understanding of how speakers of a non-lexical-stress language encode speaker commitment is limited. This paper explores the contribution of the last pitch accent of an intonation phrase to convey speaker commitment in French, a language that has stress at the phrasal level as well as a restricted set of pitch accents. In a production experiment, participants had to produce sentences in two pragmatic contexts: unbiased questions (the speaker had no particular belief with respect to the expected answer) and negatively biased questions (the speaker believed the proposition to be false). Results revealed that negatively biased questions consistently exhibited an additional unaccented F0 peak in the preaccentual syllable (an H+!H* pitch accent) while unbiased questions were often realized with a rising pattern across the accented syllable (an H* pitch accent). These results provide evidence that pitch accent types in French can signal the speaker's belief about the certainty of the proposition expressed in French. It also has implications for the phonological model of French intonation.

  8. Apoptosis of nur77/N10-transgenic thymocytes involves the Fas/Fas ligand pathway.

    PubMed Central

    Weih, F; Ryseck, R P; Chen, L; Bravo, R

    1996-01-01

    The orphan nuclear receptor Nur77/N10 has recently been demonstrated to be involved in apoptosis of T cell hybridomas. We report here that chronic expression of Nur77/N10 in thymocytes of transgenic mice results in a dramatic reduction of CD4+CD8+ double-positive as well as CD4+CD8- and CD4-CD8+ single-positive cell populations due to an early onset of apoptosis. CD4-CD8- double-negative and CD25+ precursor cells, however, are unaffected. Moreover, nur77/N10-transgenic thymocytes show increased expression of Fas ligand (FasL), while the levels of the Fas receptor (Fas) are not increased. The mouse spontaneous mutant gld (generalized lymphoproliferative disease) carries a point mutation in the extracellular domain of the FasL gene that abolishes the ability of FasL to bind to Fas. Thymuses from nur77/N10-transgenic mice on a gld/gld background have increased cellularity and an almost normal profile of thymocyte subpopulations. Our results demonstrate that one pathway of apoptosis triggered by Nur77/N10 in double-positive thymocytes occurs through the upregulation of FasL expression resulting in increased signaling through Fas. Images Fig. 1 Fig. 2 Fig. 4 PMID:8643610

  9. dFasArt: dynamic neural processing in FasArt model.

    PubMed

    Cano-Izquierdo, Jose-Manuel; Almonacid, Miguel; Pinzolas, Miguel; Ibarrola, Julio

    2009-05-01

    The temporal character of the input is, generally, not taken into account in the neural models. This paper presents an extension of the FasArt model focused on the treatment of temporal signals. FasArt model is proposed as an integration of the characteristic elements of the Fuzzy System Theory in an ART architecture. A duality between the activation concept and membership function is established. FasArt maintains the structure of the Fuzzy ARTMAP architecture, implying a static character since the dynamic response of the input is not considered. The proposed novel model, dynamic FasArt (dFasArt), uses dynamic equations for the processing stages of FasArt: activation, matching and learning. The new formulation of dFasArt includes time as another characteristic of the input. This allows the activation of the units to have a history-dependent character instead of being only a function of the last input value. Therefore, dFasArt model is robust to spurious values and noisy inputs. As experimental work, some cases have been used to check the robustness of dFasArt. A possible application has been proposed for the detection of variations in the system dynamics.

  10. Nonylphenol induces thymocyte apoptosis through Fas/FasL pathway by mimicking estrogen in vivo.

    PubMed

    Yao, Genhong; Hou, Yayi

    2004-05-01

    Nonylphenol (NP) is the final biodegradation product of nonylphenol polyethoxylates, which are widely used surfactants in domestic and industrial products. Nonylphenol has been reported to have estrogenic activity and shown to have potential reproductive toxicity. However, its influence on immune system function remains unclear. In this study, we investigated the effects of nonylphenol on apoptosis and Fas/FasL gene expression in rat thymus. Nonylphenol were given orally by gavages at 125, 250, and 375mg/kg per day. Negative and positive controls were treated with the vehicle and E(2) 10ng/kg per day, respectively. Atrophy of thymus was determined by in situ morphological examination using hematoxylin and eosin staining. Apoptotic cells were identified by terminal deoxynucleotide transferase-mediated deoxy-UTP nick end labeling (TUNEL) assay. A semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method was used to analyze Fas and FasL mRNA levels. The results showed that both nonylphenol and E(2) increased the rates of apoptotic death; reduced the expression of Fas; enhanced the expression of FasL. These findings demonstrated that nonylphenol with estrogen-like activity might affect the regulation of the immune function through thymocyte apoptosis. This apoptosis was mediated by altering the expression of Fas and FasL mRNA.

  11. Fas and FasL expression in the spinal cord following cord hemisection in the monkey.

    PubMed

    Jia, Liu; Yu, Zou; Hui, Li; Yu-Guang, Guan; Xin-Fu, Zhou; Chao, You; Yanbin, Xiyang; Xi, Zhan; Jun, Wang; Xin-Hua, Heng; Xin-Hua, Hen; Ting-Hua, Wang

    2011-03-01

    The changes of endogenous Fas/FasL in injured spinal cord, mostly in primates, are not well known. In this study, we investigated the temporal changes in the expression of Fas and FasL and explored their possible roles in the ventral horn of the spinal cord and associated precentral gyrus following T(11) spinal cord hemisection in the adult rhesus monkey. A significant functional improvement was seen with the time going on in monkeys subjected to cord hemisection. Apoptotic cells were also seen in the ventral horn of injured spinal cord with TUNEL staining, and a marked increase presents at 7 days post operation (dpo). Simultaneously, the number of Fas and FasL immunoreactive neurons in the spinal cords caudal and rostral to injury site and their intracellular optical density (OD) in the ipsilateral side of injury site at 7 dpo increased significantly more than that of control group and contralateral sides. This was followed by a decrease and returned to normal level at 60 dpo. No positive neurons were observed in precentral gyrus. The present results may provide some insights to understand the role of Fas/FasL in the spinal cord but not motor cortex with neuronal apoptosis and neuroplasticity in monkeys subjected to hemisection spinal cord injury.

  12. Relationship of Acute Lung Inflammatory Injury to Fas/FasL System

    PubMed Central

    Neff, Thomas A.; Guo, Ren-Feng; Neff, Simona B.; Sarma, J. Vidya; Speyer, Cecilia L.; Gao, Hongwei; Bernacki, Kurt D.; Huber-Lang, Markus; McGuire, Stephanie; Hoesel, L. Marco; Riedemann, Niels C.; Beck-Schimmer, Beatrice; Zetoune, Firas S.; Ward, Peter A.

    2005-01-01

    There is mounting evidence that apoptosis plays a significant role in tissue damage during acute lung injury. To evaluate the role of the apoptosis mediators Fas and FasL in acute lung injury, Fas (lpr)- or FasL (gld)-deficient and wild-type mice were challenged with intrapulmonary deposition of IgG immune complexes. Lung injury parameters (125I-albumin leak, accumulation of myeloperoxidase, and wet lung weights) were measured and found to be consistently reduced in both lpr and gld mice. In wild-type mice, lung injury was associated with a marked increase in Fas protein in lung. Inflamed lungs of wild-type mice showed striking evidence of activated caspase-3, which was much diminished in inflamed lungs from lpr mice. Intratracheal administration of a monoclonal Fas-activating antibody (Jo2) in wild-type mice induced MIP-2 and KC production in bronchoalveolar lavage fluids, and a murine alveolar macrophage cell line (MH-S) showed significantly increased MIP-2 production after incubation with this antibody. Bronchoalveolar lavage fluid content of MIP-2 and KC was substantially reduced in lpr mice after lung injury when compared to levels in wild-type mice. These data suggest that the Fas/FasL system regulates the acute lung inflammatory response by positively affecting CXC-chemokine production, ultimately leading to enhanced neutrophil influx and tissue damage. PMID:15743781

  13. Predicting foreign-accent adaptation in older adults.

    PubMed

    Janse, Esther; Adank, Patti

    2012-01-01

    We investigated comprehension of and adaptation to speech in an unfamiliar accent in older adults. Participants performed a speeded sentence verification task for accented sentences: one group upon auditory-only presentation, and the other group upon audiovisual presentation. Our questions were whether audiovisual presentation would facilitate adaptation to the novel accent, and which cognitive and linguistic measures would predict adaptation. Participants were therefore tested on a range of background tests: hearing acuity, auditory verbal short-term memory, working memory, attention-switching control, selective attention, and vocabulary knowledge. Both auditory-only and audiovisual groups showed improved accuracy and decreasing response times over the course of the experiment, effectively showing accent adaptation. Even though the total amount of improvement was similar for the auditory-only and audiovisual groups, initial rate of adaptation was faster in the audiovisual group. Hearing sensitivity and short-term and working memory measures were associated with efficient processing of the novel accent. Analysis of the relationship between accent comprehension and the background tests revealed furthermore that selective attention and vocabulary size predicted the amount of adaptation over the course of the experiment. These results suggest that vocabulary knowledge and attentional abilities facilitate the attention-shifting strategies proposed to be required for perceptual learning.

  14. Stem Cell Therapies for Intervertebral Disc Degeneration: Immune Privilege Reinforcement by Fas/FasL Regulating Machinery.

    PubMed

    Ma, Chi-Jiao; Liu, Xu; Che, Lu; Liu, Zhi-Heng; Samartzis, Dino; Wang, Hai-Qiang

    2015-01-01

    As a main contributing factor to low back pain, intervertebral disc degeneration (IDD) is the fundamental basis for various debilitating spinal diseases. The pros and cons of current treatment modalities necessitate biological treatment strategies targeting for reversing or altering the degeneration process in terms of molecules or genes. The advances in stem cell research facilitate the studies aiming for possible clinical application of stem cell therapies for IDD. Human NP cells are versatile with cell morphology full of variety, capable of synthesizing extracellular matrix components, engulfing substances by autophagy and phagocytosis, mitochondrial vacuolization indicating dysfunction, expressing Fas and FasL as significant omens of immune privileged sites. Human discs belong to immune privilege organs with functional FasL expression, which can interact with invasive immune cells by Fas-FasL regulatory machinery. IDD is characterized by decreased expression level of FasL with dysfunctional FasL, which in turn unbalances the interaction between NP cells and immune cells. Certain modulation factors might play a role in the process, such as miR-155. Accumulating evidence indicates that Fas-FasL network expresses in a variety of stem cells. Given the expression of functional FasL and insensitive Fas in stem cells (we term as FasL privilege), transplantation of stem cells into the disc may regenerate the degenerative disc by not only differentiating into NP-like cells, increasing extracellular matrix, but also reinforce immune privilege via interaction with immune cells by Fas-FasL network.

  15. Role of Fas/FasL in regulation of inflammation in vaginal tissue during HSV-2 infection.

    PubMed

    Krzyzowska, M; Shestakov, A; Eriksson, K; Chiodi, F

    2011-03-17

    To assess the role of Fas in lesion development during genital HSV-2 infection, we used a well-established HSV-2 murine model applied to MRL-Fas(lpr)/J (Fas-/-) and C3-Fasl(gld)/J (FasL-/-) C57BL6 mice. In vitro infection of murine keratinocytes and epithelial cells was used to clarify molecular details of HSV-2 infection. Despite upregulation of Fas and FasL, HSV-2-infected keratinocytes and epithelial cells showed a moderate level of apoptosis due to upregulated expression of the anti-apoptotic factors Bcl-2, Akt kinase and NF-κB. Inflammatory lesions within the HSV-2-infected epithelium of C57BL6 mice consisted of infected cells upregulating Fas, FasL and Bcl-2, uninfected cells upregulating Fas and neutrophils expressing both Fas and FasL. Apoptosis was detected in HSV-2-infected cells and to even higher extent in non-infected cells surrounding HSV-2 infection sites. HSV-2 infection of Fas- and FasL-deficient mice led to increased apoptosis and stronger recruitment of neutrophils within the infection sites. We conclude that the Fas pathway participates in regulation of inflammatory response in the vaginal epithelium at the initial stage of HSV-2 infection.

  16. The signaling pathways by which the Fas/FasL system accelerates oocyte aging.

    PubMed

    Zhu, Jiang; Lin, Fei-Hu; Zhang, Jie; Lin, Juan; Li, Hong; Li, You-Wei; Tan, Xiu-Wen; Tan, Jing-He

    2016-02-01

    In spite of great efforts, the mechanisms for postovulatory oocyte aging are not fully understood. Although our previous work showed that the FasL/Fas signaling facilitated oocyte aging, the intra-oocyte signaling pathways are unknown. Furthermore, the mechanisms by which oxidative stress facilitates oocyte aging and the causal relationship between Ca2+ rises and caspase-3 activation and between the cell cycle and apoptosis during oocyte aging need detailed investigations. Our aim was to address these issues by studying the intra-oocyte signaling pathways for Fas/FasL to accelerate oocyte aging. The results indicated that sFasL released by cumulus cells activated Fas on the oocyte by increasing reactive oxygen species via activating NADPH oxidase. The activated Fas triggered Ca2+ release from the endoplasmic reticulum by activating phospholipase C-γ pathway and cytochrome c pathway. The cytoplasmic Ca2+ rises activated calcium/calmodulin-dependent protein kinase II (CaMKII) and caspase-3. While activated CaMKII increased oocyte susceptibility to activation by inactivating maturation-promoting factor (MPF) through cyclin B degradation, the activated caspase-3 facilitated further Ca2+releasing that activates more caspase-3 leading to oocyte fragmentation. Furthermore, caspase-3 activation and fragmentation were prevented in oocytes with a high MPF activity, suggesting that an oocyte must be in interphase to undergo apoptosis.

  17. Targeting the Fas/FasL system in Rheumatoid Arthritis therapy: Promising or risky?

    PubMed

    Calmon-Hamaty, Flavia; Audo, Rachel; Combe, Bernard; Morel, Jacques; Hahne, Michael

    2015-10-01

    Rheumatoid Arthritis (RA) is a chronic inflammatory disease affecting synovial joints. Tumor necrosis factor (TNF) α is a key component of RA pathogenesis and blocking this cytokine is the most common strategy to treat the disease. Though TNFα blockers are very efficient, one third of the RA patients are unresponsive or present side effects. Therefore, the development of novel therapeutic approaches is required. RA pathogenesis is characterized by the hyperplasia of the synovium, closely associated to the pseudo-tumoral expansion of fibroblast-like synoviocytes (FLS), which invade and destroy the joint structure. Hence, depletion of RA FLS has been proposed as an alternative therapeutic strategy. The TNF family member Fas ligand (FasL) was reported to trigger apoptosis in FLS of arthritic joints by binding to its receptor Fas and therefore suggested as a promising candidate for targeting the hyperplastic synovial tissue. However, this cytokine is pleiotropic and recent data from the literature indicate that Fas activation might have a disease-promoting role in RA by promoting cell proliferation. Therefore, a FasL-based therapy for RA requires careful evaluation before being applied. In this review we aim to overview what is known about the apoptotic and non-apoptotic effects of Fas/FasL system and discuss its relevance in RA.

  18. In vivo analysis of Fas/FasL interactions in HIV-infected patients.

    PubMed Central

    Badley, A D; Dockrell, D H; Algeciras, A; Ziesmer, S; Landay, A; Lederman, M M; Connick, E; Kessler, H; Kuritzkes, D; Lynch, D H; Roche, P; Yagita, H; Paya, C V

    1998-01-01

    Recent insights into the pharmacological control of HIV replication and the molecular mechanisms of peripheral T cells homeostasis allowed us to investigate in vivo the mechanisms mediating T cell depletion in HIV-infected patients. Before the initiation of highly active antiretroviral therapy (HAART), a high degree of lymphoid tissue apoptosis is present, which is reduced upon HAART initiation (P < 0.001) and directly correlates with reduction of viral load and increases of peripheral T lymphocytes (P < 0.01). Because Fas/FasL interactions play a key role in peripheral T lymphocyte homeostasis, we investigated the susceptibility to Fas-mediated apoptosis in peripheral T lymphocytes and of FasL expression in lymphoid tissue before and during HAART. High levels of Fas-susceptibility found in peripheral CD4 T lymphocytes before HAART were significantly reduced after HAART, coinciding with decreases in viral load (P = 0.018) and increases in peripheral CD4 T lymphocyte counts (P < 0.01). However, the increased FasL expression in the lymphoid tissue of HIV-infected individuals was not reduced after HAART. These results demonstrate that lymphoid tissue apoptosis directly correlates with viral load and peripheral T lymphocyte numbers, and suggest that HIV-induced susceptibility to Fas-dependent apoptosis may play a key role in the regulation of T cell homeostasis in HIV-infected individuals. PMID:9649560

  19. Fas/Fas ligand interactions promote activation-induced cell death of NK T lymphocytes.

    PubMed

    Leite-de-Moraes, M C; Herbelin, A; Gouarin, C; Koezuka, Y; Schneider, E; Dy, M

    2000-10-15

    NKT cells are a versatile population whose immunoregulatory functions are modulated by their microenvironment. We demonstrate herein that in addition to their IFN-gamma production, NKT lymphocytes stimulated with IL-12 plus IL-18 in vitro underwent activation in terms of CD69 expression, blast transformation, and proliferation. Yet they were unable to survive in culture because, once activated, they were rapidly eliminated by apoptosis, even in the presence of their survival factor IL-7. This process was preceded by up-regulation of Fas (CD95) and Fas ligand expression in response to IL-12 plus IL-18 and was blocked by zVAD, a large spectrum caspase inhibitor, as well as by anti-Fas ligand mAb, suggesting the involvement of the Fas pathway. In accordance with this idea, NKT cells from Fas-deficient C57BL/6-lpr/lpr mice did not die in these conditions, although they shared the same features of cell activation as their wild-type counterpart. Activation-induced cell death occurred also after TCR engagement in vivo, since NKT cells became apoptotic after injection of their cognate ligand, alpha-galactosylceramide, in wild-type, but not in Fas-deficient, mice. Taken together, our data provide the first evidence for a new Fas-dependent mechanism allowing the elimination of TCR-dependent or -independent activated NKT cells, which are potentially dangerous to the organism.

  20. The Fetal Alcohol Syndrome--Recent International Statistics.

    ERIC Educational Resources Information Center

    Phillipson, Richard

    1988-01-01

    This paper explores incidence rates of Fetal Alcohol Syndrome (FAS) and describes physical and cognitive impairments exhibited by FAS children. It examines program strategies for prevention of FAS in the United States and reviews research undertaken at the Edinburgh University Medical School, Scotland, concerning alcohol effects on the ovum before…

  1. Adaptation to novel accents by toddlers.

    PubMed

    White, Katherine S; Aslin, Richard N

    2011-03-01

    Word recognition is a balancing act: listeners must be sensitive to phonetic detail to avoid confusing similar words, yet, at the same time, be flexible enough to adapt to phonetically variable pronunciations, such as those produced by speakers of different dialects or by non-native speakers. Recent work has demonstrated that young toddlers are sensitive to phonetic detail during word recognition; pronunciations that deviate from the typical phonological form lead to a disruption of processing. However, it is not known whether young word learners show the flexibility that is characteristic of adult word recognition. The present study explores whether toddlers can adapt to artificial accents in which there is a vowel category shift with respect to the native language. 18-20-month-olds heard mispronunciations of familiar words (e.g., vowels were shifted from [a] to [æ]: "dog" pronounced as "dag"). In test, toddlers were tolerant of mispronunciations if they had recently been exposed to the same vowel shift, but not if they had been exposed to standard pronunciations or other vowel shifts. The effects extended beyond particular items heard in exposure to words sharing the same vowels. These results indicate that, like adults, toddlers show flexibility in their interpretation of phonological detail. Moreover, they suggest that effects of top-down knowledge on the reinterpretation of phonological detail generalize across the phono-lexical system.

  2. A lack of Fas/FasL signalling leads to disturbances in the antiviral response during ectromelia virus infection.

    PubMed

    Bień, K; Sobańska, Z; Sokołowska, J; Bąska, P; Nowak, Z; Winnicka, A; Krzyzowska, M

    2016-04-01

    Ectromelia virus (ECTV) is an orthopoxvirus (OPV) that causes mousepox, the murine equivalent of human smallpox. Fas receptor-Fas ligand (FasL) signaling is involved in apoptosis of immune cells and virus-specific cytotoxicity. The Fas/FasL pathway also plays an important role in controlling the local inflammatory response during ECTV infection. Here, the immune response to the ECTV Moscow strain was examined in Fas (-) (lpr), FasL (-) (gld) and C57BL6 wild-type mice. During ECTV-MOS infection, Fas- and FasL mice showed increased viral titers, decreased total numbers of NK cells, CD4(+) and CD8(+) T cells followed by decreased percentages of IFN-γ expressing NK cells, CD4(+) and CD8(+) T cells in spleens and lymph nodes. At day 7 of ECTV-MOS infection, Fas- and FasL-deficient mice had the highest regulatory T cell (Treg) counts in spleen and lymph nodes in contrast to wild-type mice. Furthermore, at days 7 and 10 of the infection, we observed significantly higher numbers of PD-L1-expressing dendritic cells in Fas (-) and FasL (-) mice in comparison to wild-type mice. Experiments in co-cultures of CD4(+) T cells and bone-marrow-derived dendritic cells showed that the lack of bilateral Fas-FasL signalling led to expansion of Tregs. In conclusion, our results demonstrate that during ECTV infection, Fas/FasL can regulate development of tolerogenic DCs and Tregs, leading to an ineffective immune response.

  3. Immune privilege and FasL: two ways to inactivate effector cytotoxic T lymphocytes by FasL-expressing cells

    PubMed Central

    Li, Jie-Hui; Rosen, Dalia; Sondel, Paul; Berke, Gideon

    2002-01-01

    The theory that Fas ligand (FasL)-expressing tumours are immune-privileged and can directly counterattack Fas-expressing effector T lymphocytes has recently been questioned and several alternative mechanisms have been proposed. To address this controversial issue, we analysed the impact of FasL-expressing tumours on in vivo-primed cytotoxic T lymphocytes (CTLs) and the mechanisms involved. CTLs were obtained from the peritoneal cavity (PEL) after in vivo priming with syngeneic or allogeneic murine tumour cells. We have found that PEL populations undergo Fas-based apoptotic cell death when co-cultured with FasL-expressing tumour cells and that PEL destruction of cognate targets in a 51Cr-release assay was markedly inhibited by the pre-exposure to either cognate or non-cognate tumour cells expressing FasL. Furthermore, cytocidal function of PEL was markedly inhibited by preincubation with FasL-negative tumour cells, if and only if they were the cognate targets of the CTL; this CTL inhibition involved FasL–Fas interactions. The killing function of ‘bystander’ PELs, reactive to a third-party target cell, was inhibited by co-cultivation with PELs mixed with their cognate target. This activation-induced CTL fratricide was not influenced by the expression of FasL on the cognate target cells. These studies demonstrate the existence of two distinct pathways whereby FasL-expressing cells inhibit in vivo-primed FasL- and Fas-expressing CTLs: first, by FasL-based direct tumour counterattack, and second, by FasL-mediated activation-induced cell death of the CTLs, which is consistent with the concept that FasL expression in vivo could play a role in inducing immune privilege. PMID:11918688

  4. Two Adjacent Trimeric Fas Ligands Are Required for Fas Signaling and Formation of a Death-Inducing Signaling Complex

    PubMed Central

    Holler, Nils; Tardivel, Aubry; Kovacsovics-Bankowski, Magdalena; Hertig, Sylvie; Gaide, Olivier; Martinon, Fabio; Tinel, Antoine; Deperthes, David; Calderara, Silvio; Schulthess, Therese; Engel, Jürgen; Schneider, Pascal; Tschopp, Jürg

    2003-01-01

    The membrane-bound form of Fas ligand (FasL) signals apoptosis in target cells through engagement of the death receptor Fas, whereas the proteolytically processed, soluble form of FasL does not induce cell death. However, soluble FasL can be rendered active upon cross-linking. Since the minimal extent of oligomerization of FasL that exerts cytotoxicity is unknown, we engineered hexameric proteins containing two trimers of FasL within the same molecule. This was achieved by fusing FasL to the Fc portion of immunoglobulin G1 or to the collagen domain of ACRP30/adiponectin. Trimeric FasL and hexameric FasL both bound to Fas, but only the hexameric forms were highly cytotoxic and competent to signal apoptosis via formation of a death-inducing signaling complex. Three sequential early events in Fas-mediated apoptosis could be dissected, namely, receptor binding, receptor activation, and recruitment of intracellular signaling molecules, each of which occurred independently of the subsequent one. These results demonstrate that the limited oligomerization of FasL, and most likely of some other tumor necrosis factor family ligands such as CD40L, is required for triggering of the signaling pathways. PMID:12556501

  5. The Contribution of the Fas/FasL Apoptotic Pathway in Ulcer Formation during Leishmania major-Induced Cutaneous Leishmaniasis

    PubMed Central

    Eidsmo, Liv; Nylen, Susanne; Khamesipour, Ali; Hedblad, Mari-Anne; Chiodi, Francesca; Akuffo, Hannah

    2005-01-01

    Cutaneous leishmaniasis (CL), caused by the intracellular protozoan Leishmania major, is characterized by lesion formation and ulceration at the site of infection. The mechanism of ulcer formation during CL is not fully understood. The expression of Fas and FasL and the levels of apoptosis in skin biopsies and in restimulated blood mononuclear cells from patients with 1 to 7 months of L. major-induced CL were analyzed using immunohistochemistry and fluorescence-activated cell sorting analysis. The levels of soluble Fas and FasL were also analyzed by enzyme-linked immunosorbent assay. A substantial number of apoptotic keratinocytes were observed mainly in the superficial epidermis of morphologically active and healing CL skin samples. Fas expression was increased on epidermis in active CL, whereas Fas expression was similar in healing and healthy epidermis. FasL-expressing macrophages and T cells were found in subepidermal infiltrate, mainly in active disease. When CL peripheral blood mononuclear cells were restimulated with L. major, Fas was up-regulated on effector T cells, and high levels of sFasL were secreted. Supernatants from restimulated cultures induced apoptosis in human keratinocytes (HaCaT), possibly through Fas/FasL interactions. Our results indicate that FasL-expressing effector T cells and macrophages may act to induce apoptosis and ulcer formation in Fas-expressing keratinocytes during L. major infection. PMID:15793290

  6. Intracellular Fas ligand in normal and malignant breast epithelium does not induce apoptosis in Fas-sensitive cells

    PubMed Central

    Ragnarsson, G B; Mikaelsdottir, E K; Vidarsson, H; Jónasson, J G; Ólafsdóttir, K; Kristjánsdóttir, K; Kjartansson, J; Ögmundsdóttir, H M; Rafnar, T

    2000-01-01

    Fas ligand (FasL) is expressed on some cancers and may play a role in the immune evasion of the tumour. We used immuno-histochemistry to study the expression of Fas and FasL in tissue samples from breast cancer patients, as well as normal breast tissue. Our results show that Fas and FasL are co-expressed both in normal tissue and in breast tumours. Fas and FasL mRNA were expressed in fresh normal and malignant breast tissue, as well as cultured breast epithelium and breast cancer cell lines. Flow cytometry analysis of live cells failed to detect FasL on the surface of normal or malignant breast cells; however, both stained positive for FasL after permeabilization. Fas was detected on the surface of normal breast cells and T47D and MCF-10A cell lines but only intracellularly in other breast cell lines tested. Neither normal breast epithelium nor breast cell lines induced Fas-dependent apoptosis in Jurkat cells. Finally, 20 tumour samples were stained for apoptosis. Few apoptotic cells were detected and there was no increase in apoptotic cells on the borders between tumour cells and lymphocytes. We conclude that FasL is expressed intracellularly in both normal and malignant breast epithelium and unlikely to be important for the immune evasion of breast tumours. © 2000 Cancer Research Campaign http://www.bjcancer.com PMID:11104571

  7. Foreign accent conversion in computer assisted pronunciation training

    PubMed Central

    Felps, Daniel; Bortfeld, Heather; Gutierrez-Osuna, Ricardo

    2010-01-01

    Learners of a second language practice their pronunciation by listening to and imitating utterances from native speakers. Recent research has shown that choosing a well-matched native speaker to imitate can have a positive impact on pronunciation training. Here we propose a voice-transformation technique that can be used to generate the (arguably) ideal voice to imitate: the own voice of the learner with a native accent. Our work extends previous research, which suggests that providing learners with prosodically corrected versions of their utterances can be a suitable form of feedback in computer assisted pronunciation training. Our technique provides a conversion of both prosodic and segmental characteristics by means of a pitch-synchronous decomposition of speech into glottal excitation and spectral envelope. We apply the technique to a corpus containing parallel recordings of foreign-accented and native-accented utterances, and validate the resulting accent conversions through a series of perceptual experiments. Our results indicate that the technique can reduce foreign accentedness without significantly altering the voice quality properties of the foreign speaker. Finally, we propose a pedagogical strategy for integrating accent conversion as a form of behavioral shaping in computer assisted pronunciation training. PMID:21124807

  8. Foreign accent conversion in computer assisted pronunciation training.

    PubMed

    Felps, Daniel; Bortfeld, Heather; Gutierrez-Osuna, Ricardo

    2009-10-01

    Learners of a second language practice their pronunciation by listening to and imitating utterances from native speakers. Recent research has shown that choosing a well-matched native speaker to imitate can have a positive impact on pronunciation training. Here we propose a voice-transformation technique that can be used to generate the (arguably) ideal voice to imitate: the own voice of the learner with a native accent. Our work extends previous research, which suggests that providing learners with prosodically corrected versions of their utterances can be a suitable form of feedback in computer assisted pronunciation training. Our technique provides a conversion of both prosodic and segmental characteristics by means of a pitch-synchronous decomposition of speech into glottal excitation and spectral envelope. We apply the technique to a corpus containing parallel recordings of foreign-accented and native-accented utterances, and validate the resulting accent conversions through a series of perceptual experiments. Our results indicate that the technique can reduce foreign accentedness without significantly altering the voice quality properties of the foreign speaker. Finally, we propose a pedagogical strategy for integrating accent conversion as a form of behavioral shaping in computer assisted pronunciation training.

  9. Contending with foreign accent in early word learning.

    PubMed

    Schmale, Rachel; Hollich, George; Seidl, Amanda

    2011-11-01

    By their second birthday, children are beginning to map meaning to form with relative ease. One challenge for these developing abilities is separating information relevant to word identity (i.e. phonemic information) from irrelevant information (e.g. voice and foreign accent). Nevertheless, little is known about toddlers' abilities to ignore irrelevant phonetic detail when faced with the demanding task of word learning. In an experiment with English-learning toddlers, we examined the impact of foreign accent on word learning. Findings revealed that while toddlers aged 2 ; 6 successfully generalized newly learned words spoken by a Spanish-accented speaker and a native English speaker, success of those aged 2 ; 0 was restricted. Specifically, toddlers aged 2 ; 0 failed to generalize words when trained by the native English speaker and tested by the Spanish-accented speaker. Data suggest that exposure to foreign accent in training may promote generalization of newly learned forms. These findings are considered in the context of developmental changes in early word representations.

  10. Foreign accents: suggested competencies for improving communicative pronunciation.

    PubMed

    Sikorski, Lorna D

    2005-05-01

    In the past 20 years, many speech-language pathologists (SLPs) have joined their English as a Second Language (ESL) colleagues to address the pronunciation skills of second language speakers of English. This paper introduces SLPs to the ESL term "communicative pronunciation" as the underpinning for the commonly accepted terms "accent modification" or "accent reduction." Initially, professionals in both speech pathology and ESL felt that accent intervention was outside the scope of speech pathology practice, though that stance is softening. If an essential part of our mission as speech pathologists is to improve communicative competence for all persons, then making pronunciation more intelligible falls under that heading. This article on foreign accents limits discussion to: (1) the rationale for intervening with foreign accented adults; (2) an outline of a broader scope and definition of effective instruction for this population; (3) suggestions for trainer preparation; (4) recommendations for productive literature searches; and (5) a brief discussion of principles guiding assessment and instruction planning. The article includes relevant research and references outside the field of speech pathology that should stimulate future productive research efforts as well as more in-depth papers on specific instruction and assessment issues. While this article is intended to stand alone, readers may benefit from the content and references in another article in this issue by the same author.

  11. The influence of an Alaska Native accent and reputation on perceived therapist credibility.

    PubMed

    Swift, Joshua K; Mayra, Jenna; Justice, Chantel; Freitas-Murrell, Brittany

    2015-01-01

    In this study, we examined the influence of an Alaska Native (AN) accent and reputation on perceived therapist credibility after controlling for universal-diverse orientation. Participants listened to and rated therapist audio recordings that differed in AN accent (strong, minimal) and reputational cues (expert, recent graduate, student). While credibility ratings of the accent conditions did not differ in the expert and recent graduate scenarios, the graduate student therapist was seen as less attractive and useful when she spoke with a strong accent.

  12. A new version of the HBSC Family Affluence Scale - FAS III: Scottish Qualitative Findings from the International FAS Development Study.

    PubMed

    Hartley, Jane E K; Levin, Kate; Currie, Candace

    A critical review of the Family Affluence Scale (FAS) concluded that FAS II was no longer discriminatory within very rich or very poor countries, where a very high or a very low proportion of children were categorised as high FAS or low FAS respectively (Currie et al. 2008). The review concluded that a new version of FAS - FAS III - should be developed to take into account current trends in family consumption patterns across the European region, the US and Canada. In 2012, the FAS Development and Validation Study was conducted in eight countries - Denmark, Greenland, Italy, Norway, Poland, Romania, Slovakia and Scotland. This paper describes the Scottish qualitative findings from this study. The Scottish qualitative fieldwork comprising cognitive interviews and focus groups sampled from 11, 13 and 15 year-old participants from 18 of the most- and least- economically deprived schools. These qualitative results were used to inform the final FAS III recommendations.

  13. A Neural Marker for Social Bias Toward In-group Accents

    PubMed Central

    Bestelmeyer, Patricia E.G.; Belin, Pascal; Ladd, D. Robert

    2015-01-01

    Accents provide information about the speaker's geographical, socio-economic, and ethnic background. Research in applied psychology and sociolinguistics suggests that we generally prefer our own accent to other varieties of our native language and attribute more positive traits to it. Despite the widespread influence of accents on social interactions, educational and work settings the neural underpinnings of this social bias toward our own accent and, what may drive this bias, are unexplored. We measured brain activity while participants from two different geographical backgrounds listened passively to 3 English accent types embedded in an adaptation design. Cerebral activity in several regions, including bilateral amygdalae, revealed a significant interaction between the participants' own accent and the accent they listened to: while repetition of own accents elicited an enhanced neural response, repetition of the other group's accent resulted in reduced responses classically associated with adaptation. Our findings suggest that increased social relevance of, or greater emotional sensitivity to in-group accents, may underlie the own-accent bias. Our results provide a neural marker for the bias associated with accents, and show, for the first time, that the neural response to speech is partly shaped by the geographical background of the listener. PMID:25452578

  14. A Neural Marker for Social Bias Toward In-group Accents.

    PubMed

    Bestelmeyer, Patricia E G; Belin, Pascal; Ladd, D Robert

    2015-10-01

    Accents provide information about the speaker's geographical, socio-economic, and ethnic background. Research in applied psychology and sociolinguistics suggests that we generally prefer our own accent to other varieties of our native language and attribute more positive traits to it. Despite the widespread influence of accents on social interactions, educational and work settings the neural underpinnings of this social bias toward our own accent and, what may drive this bias, are unexplored. We measured brain activity while participants from two different geographical backgrounds listened passively to 3 English accent types embedded in an adaptation design. Cerebral activity in several regions, including bilateral amygdalae, revealed a significant interaction between the participants' own accent and the accent they listened to: while repetition of own accents elicited an enhanced neural response, repetition of the other group's accent resulted in reduced responses classically associated with adaptation. Our findings suggest that increased social relevance of, or greater emotional sensitivity to in-group accents, may underlie the own-accent bias. Our results provide a neural marker for the bias associated with accents, and show, for the first time, that the neural response to speech is partly shaped by the geographical background of the listener.

  15. Native Speakers' Perceptions of Fluency and Accent in L2 Speech

    ERIC Educational Resources Information Center

    Pinget, Anne-France; Bosker, Hans Rutger; Quené, Hugo; de Jong, Nivja H.

    2014-01-01

    Oral fluency and foreign accent distinguish L2 from L1 speech production. In language testing practices, both fluency and accent are usually assessed by raters. This study investigates what exactly native raters of fluency and accent take into account when judging L2. Our aim is to explore the relationship between objectively measured temporal,…

  16. Role of Fas/FasL in regulation of inflammation in vaginal tissue during HSV-2 infection

    PubMed Central

    Krzyzowska, M; Shestakov, A; Eriksson, K; Chiodi, F

    2011-01-01

    To assess the role of Fas in lesion development during genital HSV-2 infection, we used a well-established HSV-2 murine model applied to MRL-Faslpr/J (Fas−/−) and C3-Faslgld/J (FasL−/−) C57BL6 mice. In vitro infection of murine keratinocytes and epithelial cells was used to clarify molecular details of HSV-2 infection. Despite upregulation of Fas and FasL, HSV-2-infected keratinocytes and epithelial cells showed a moderate level of apoptosis due to upregulated expression of the anti-apoptotic factors Bcl-2, Akt kinase and NF-κB. Inflammatory lesions within the HSV-2-infected epithelium of C57BL6 mice consisted of infected cells upregulating Fas, FasL and Bcl-2, uninfected cells upregulating Fas and neutrophils expressing both Fas and FasL. Apoptosis was detected in HSV-2-infected cells and to even higher extent in non-infected cells surrounding HSV-2 infection sites. HSV-2 infection of Fas- and FasL-deficient mice led to increased apoptosis and stronger recruitment of neutrophils within the infection sites. We conclude that the Fas pathway participates in regulation of inflammatory response in the vaginal epithelium at the initial stage of HSV-2 infection. PMID:21412278

  17. Contributions of Fas-Fas Ligand Interactions to the Pathogenesis of Mouse Hepatitis Virus in the Central Nervous System

    PubMed Central

    Parra, Beatriz; Lin, Mark T.; Stohlman, Stephen A.; Bergmann, Cornelia C.; Atkinson, Roscoe; Hinton, David R.

    2000-01-01

    The pathogenesis of the neurotropic strain of mouse hepatitis virus in Fas-deficient mice suggested that Fas-mediated cytotoxicity may be required during viral clearance after the loss of perforin-mediated cytotoxicity. The absence of both Fas- and perforin-mediated cytolysis resulted in an uncontrolled infection, suggesting a redundancy of cytolytic pathways to control virus replication. PMID:10666278

  18. Improving communication through accent modification: growing the nursing workforce.

    PubMed

    Carr, Suzanne Marie; DeKemel-Ichikawa, Kathryn

    2012-01-01

    A pilot program was developed to reduce the attrition rate among nursing students, especially those in ethnic and minority groups. The presence of accents and dialects among some of these students created communication difficulties which had the potential to negatively impact both academic success and patient safety in healthcare settings. Screening processes used to identify students with reduced speech intelligibility, specific accent modification methods and other speech improvement lessons implemented to improve overall communication abilities are described. Clarity of communication improved in all pilot program students.

  19. Roles of proinflammatory cytokines and the Fas/Fas ligand interaction in the pathogenesis of inflammatory myopathies.

    PubMed

    Kondo, Masahiro; Murakawa, Yohko; Harashima, Nanae; Kobayashi, Shotai; Yamaguchi, Shuhei; Harada, Mamoru

    2009-09-01

    Within the lesions of inflammatory myopathies, muscle fibres and invading mononuclear cells express Fas and Fas ligand (FasL), respectively. However, the roles of the Fas/FasL interaction in the pathogenesis of inflammatory myopathies are not fully understood. In the present study, we investigated the roles of proinflammatory cytokines and the Fas/FasL system in the pathogenesis of inflammatory myopathies. In vitro culturing of muscle cells with the proinflammatory cytokines interferon-gamma, tumour necrosis factor-alpha, and interleukin (IL)-1beta synergistically increased Fas expression, susceptibility to Fas-mediated apoptosis, and the expression of cytoplasmic caspases 8 and 3. In addition, culturing of muscle cells with activated CD4(+) T cells induced muscle cell apoptosis, which was partially inhibited by anti-FasL antibody. We also tested the possibility that T helper (Th) 17, which is an IL-17-producing helper T-cell subset that plays crucial roles in autoimmune and inflammatory responses, participates in the pathogenesis of inflammatory myopathies. Interestingly, in vitro culturing of dendritic cells with anti-Fas immunoglobulin M (IgM) or activated CD4(+) T cells induced the expression of mRNA for IL-23p19, but not for IL-12p35, in addition to proinflammatory cytokines. Furthermore, IL-23p19 and IL-17 mRNAs were detected in the majority of biopsy samples from patients with inflammatory myopathies. Taken together, these results suggest that proinflammatory cytokines enhance Fas-mediated apoptosis of muscle cells, and that the Fas/FasL interaction between invading dendritic cells and CD4(+) T cells induces local production of IL-23 and proinflammatory cytokines, which can promote the proliferation of Th17 cells and enhance Fas-mediated apoptosis of muscle cells, respectively.

  20. A Multi-Perspective Investigation of Attitudes towards English Accents in Hong Kong: Implications for Pronunciation Teaching

    ERIC Educational Resources Information Center

    Chan, Jim Y. H.

    2016-01-01

    The study reported in this article examined Hong Kong students' attitudes towards English accents from three interrelated perspectives: (1) their awareness of accents, (2) their perception of accents in relation to the dimensions of status and solidarity, and (3) their choice of accents in various local language-using contexts. By means of the…

  1. A Fas(hi) Lymphoproliferative Phenotype Reveals Non-Apoptotic Fas Signaling in HTLV-1-Associated Neuroinflammation.

    PubMed

    Menezes, Soraya Maria; Leal, Fabio E; Dierckx, Tim; Khouri, Ricardo; Decanine, Daniele; Silva-Santos, Gilvaneia; Schnitman, Saul V; Kruschewsky, Ramon; López, Giovanni; Alvarez, Carolina; Talledo, Michael; Gotuzzo, Eduardo; Nixon, Douglas F; Vercauteren, Jurgen; Brassat, David; Liblau, Roland; Vandamme, Anne Mieke; Galvão-Castro, Bernardo; Van Weyenbergh, Johan

    2017-01-01

    Human T-cell lymphotropic virus (HTLV)-1 was the first human retrovirus to be associated to cancer, namely adult T-cell leukemia (ATL), but its pathogenesis remains enigmatic, since only a minority of infected individuals develops either ATL or the neuroinflammatory disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A functional FAS -670 polymorphism in an interferon (IFN)-regulated STAT1-binding site has been associated to both ATL and HAM/TSP susceptibility. Fas(hi) T stem cell memory (Tscm) cells have been identified as the hierarchical apex of ATL, but have not been investigated in HAM/TSP. In addition, both FAS and STAT1 have been identified in an IFN-inducible HAM/TSP gene signature, but its pathobiological significance remains unclear. We comprehensively explored Fas expression (protein/mRNA) and function in lymphocyte activation, apoptosis, proliferation, and transcriptome, in PBMC from a total of 47 HAM/TSP patients, 40 asymptomatic HTLV-1-infected individuals (AC), and 58 HTLV-1 -uninfected healthy controls. Fas surface expression followed a two-step increase from HC to AC and from AC to HAM/TSP. In HAM/TSP, Fas levels correlated positively to lymphocyte activation markers, but negatively to age of onset, linking Fas(hi) cells to earlier, more aggressive disease. Surprisingly, increased lymphocyte Fas expression in HAM/TSP was linked to decreased apoptosis and increased lymphoproliferation upon in vitro culture, but not to proviral load. This Fas(hi) phenotype is HAM/TSP-specific, since both ex vivo and in vitro Fas expression was increased as compared to multiple sclerosis (MS), another neuroinflammatory disorder. To elucidate the molecular mechanism underlying non-apoptotic Fas signaling in HAM/TSP, we combined transcriptome analysis with functional assays, i.e., blocking vs. triggering Fas receptor in vitro with antagonist and agonist-, anti-Fas mAb, respectively. Treatment with agonist anti-Fas mAb restored apoptosis

  2. The influence of talker and foreign-accent variability on spoken word identification

    PubMed Central

    Bent, Tessa; Frush Holt, Rachael

    2013-01-01

    In spoken word identification and memory tasks, stimulus variability from numerous sources impairs performance. In the current study, the influence of foreign-accent variability on spoken word identification was evaluated in two experiments. Experiment 1 used a between-subjects design to test word identification in noise in single-talker and two multiple-talker conditions: multiple talkers with the same accent and multiple talkers with different accents. Identification performance was highest in the single-talker condition, but there was no difference between the single-accent and multiple-accent conditions. Experiment 2 further explored word recognition for multiple talkers in single-accent versus multiple-accent conditions using a mixed design. A detriment to word recognition was observed in the multiple-accent condition compared to the single-accent condition, but the effect differed across the language backgrounds tested. These results demonstrate that the processing of foreign-accent variation may influence word recognition in ways similar to other sources of variability (e.g., speaking rate or style) in that the inclusion of multiple foreign accents can result in a small but significant performance decrement beyond the multiple-talker effect. PMID:23464037

  3. Automaticity and Stability of Adaptation to a Foreign-Accented Speaker.

    PubMed

    Witteman, Marijt J; Bardhan, Neil P; Weber, Andrea; McQueen, James M

    2015-06-01

    In three cross-modal priming experiments we asked whether adaptation to a foreign-accented speaker is automatic, and whether adaptation can be seen after a long delay between initial exposure and test. Dutch listeners were exposed to a Hebrew-accented Dutch speaker with two types of Dutch words: those that contained [I] (globally accented words), and those in which the Dutch [i] was shortened to [I] (specific accent marker words). Experiment 1, which served as a baseline, showed that native Dutch participants showed facilitatory priming for globally accented, but not specific accent, words. In experiment 2, participants performed a 3.5-minute phoneme monitoring task, and were tested on their comprehension of the accented speaker 24 hours later using the same cross-modal priming task as in experiment 1. During the phoneme monitoring task, listeners were asked to detect a consonant that was not strongly accented. In experiment 3, the delay between exposure and test was extended to 1 week. Listeners in experiments 2 and 3 showed facilitatory priming for both globally accented and specific accent marker words. Together, these results show that adaptation to a foreign-accented speaker can be rapid and automatic, and can be observed after a prolonged delay in testing.

  4. Less is not more: neural responses to missing and superfluous accents in context.

    PubMed

    Dimitrova, Diana V; Stowe, Laurie A; Redeker, Gisela; Hoeks, John C J

    2012-12-01

    Prosody, particularly accent, aids comprehension by drawing attention to important elements such as the information that answers a question. A study using ERP registration investigated how the brain deals with the interpretation of prosodic prominence. Sentences were embedded in short dialogues and contained accented elements that were congruous or incongruous with respect to a preceding question. In contrast to previous studies, no explicit prosodic judgment task was added. Robust effects of accentuation were evident in the form of an "accent positivity" (200-500 msec) for accented elements irrespective of their congruity. Our results show that incongruously accented elements, that is, superfluous accents, activate a specific set of neural systems that is inactive in case of incongruously unaccented elements, that is, missing accents. Superfluous accents triggered an early positivity around 100 msec poststimulus, followed by a right-lateralized negative effect (N400). This response suggests that redundant information is identified immediately and leads to the activation of a neural system that is associated with semantic processing (N400). No such effects were found when contextually expected accents were missing. In a later time window, both missing and superfluous accents triggered a late positivity on midline electrodes, presumably related to making sense of both kinds of mismatching stimuli. These results challenge previous findings of greater processing for missing accents and suggest that the natural processing of prosody involves a set of distinct, temporally organized neural systems.

  5. Involvement of Fas and FasL in Ectromelia virus-induced apoptosis in mouse brain.

    PubMed

    Krzyzowska, Małgorzata; Cymerys, Joanna; Winnicka, Anna; Niemiałtowski, Marek

    2006-02-01

    In this study we showed that the virulent Moscow strain of Ectromelia virus (ECTV-MOS) infection leads to induction of apoptosis in the BALB/c mouse central nervous system. ECTV-MOS-infected cells and inflammation sites were found in brain parenchyma between 5 and 15 days after footpad infection with ECTV-MOS. Infected cells consisted of microglia and monocytes, astrocytes and oligodendrocytes and these type of cells underwent apoptosis within 5-15 days post infection (d.p.i.). The highest number of apoptotic cells was found at 5 and 10 d.p.i. and represented mainly microglia (61.4% and 38.6% of apoptotic cells, respectively) and astrocytes (21% and 8.9%, respectively). The number of apoptotic oligodendrocytes was 5.4% and 4.5%, respectively. Fluorometric assays demonstrated involvement of caspase-1, -3 and -8 but not caspase-9 in apoptosis in ECTV-MOS-infected mouse brains. Expression of Fas/FasL was significantly increased on ECTV-MOS-infected cells between 5 and 15 d.p.i., whereas Fas was up-regulated also on the surrounding, non-infected cells. Taking together we may conclude that ECTV-MOS infection of microglia and astrocytes leads to local inflammation resulting in Fas/FasL up-regulation and apoptosis, which limits mouse central nervous system infection with ECTV-MOS.

  6. Attitudes towards Foreign Accents among Adult Multilingual Language Users

    ERIC Educational Resources Information Center

    Dewaele, Jean-Marc; McCloskey, James

    2015-01-01

    The present study investigates inter-individual variation (linked to personality traits, multilingualism and sociobiographical variables) in the attitudes that 2035 multilinguals have of their own and others' foreign accent (FA). Data were collected through an online questionnaire. We found that multilinguals who were extraverted, emotionally…

  7. Effects of context on electrophysiological response to musical accents.

    PubMed

    Palmer, Caroline; Jewett, Lisa R; Steinhauer, Karsten

    2009-07-01

    Listeners' aesthetic and emotional responses to music typically occur in the context of long musical passages that contain structures defined in terms of the events that precede them. We describe an electrophysiological study of listeners' brain responses to musical accents that coincided in longer musical sequences. Musically trained listeners performed a timbre-change detection task in which a single-tone timbre change was positioned within 4-bar melodies composed of 350-ms tones to coincide or not with melodic contour accents and temporal accents (induced with temporal gaps). Event-related potential responses to (task-relevant) attended timbre changes elicited an early negativity (MMN/N2b) around 200 ms and a late positive component around 350 ms (P300), reflecting updating of the timbre change in working memory. The amplitudes of both components changed systematically across the sequence, consistent with expectancy-based context effects. Furthermore, melodic contour changes modulated the MMN/N2b response (but not the P300) to timbre changes in later sequence positions. In contrast, task-irrelevant temporal gaps elicited an MMN that was not modulated by position within the context; absence of a P300 indicated that temporal-gap accents were not updated in working memory. Listeners' neural responses to musical structure changed systematically as sequential predictability and listeners' expectations changed across the melodic context.

  8. The Spoken Self: An Ethnographic Exploration of Accent and Identity

    ERIC Educational Resources Information Center

    Rehn, Stefanie

    2010-01-01

    This study examines the relationship between accent and identity in three Chinese graduate students attending a large research-one university in the northeastern United States. The study is based on Och's (1993) concept if identity as jointly constructed by the individual herself and the persons and conventions of her culture. It also examines the…

  9. Tracing Possible Roots of a Portuguese Accent in English.

    ERIC Educational Resources Information Center

    Salies, Tania Gastao

    Differences in the English and Brazilian Portuguese (BP) phonological systems that may lead to a slight accent in Brazilian learners of English as a Second Language (ESL) are examined. Segmental and suprasegmental features of the two systems are compared and contrasted, noting areas in which ESL learners may tend to substitute a BP segment for a…

  10. The Developmental Trajectory of Toddlers' Comprehension of Unfamiliar Regional Accents

    ERIC Educational Resources Information Center

    van Heugten, Marieke; Krieger, Dena R.; Johnson, Elizabeth K.

    2015-01-01

    Efficient language use involves the capacity to flexibly adjust to varied pronunciations of words. Although children can contend with some accent variability before their second birthday, it is currently unclear when and how this ability reaches its mature state. In a series of five experiments, we examine the developmental trajectory of toddlers'…

  11. Accuracy Trumps Accent in Children's Endorsement of Object Labels

    ERIC Educational Resources Information Center

    Corriveau, Kathleen H.; Kinzler, Katherine D.; Harris, Paul L.

    2013-01-01

    Past research provides evidence that children use at least 2 potentially competing strategies when choosing informants: they attend to informants' past accuracy and to their social identity (e.g., their status as native- vs. foreign-accented speakers). We explore how children reconcile these 2 strategies when they are put in conflict and whether…

  12. Regional and Foreign Accent Processing in English: Can Listeners Adapt?

    ERIC Educational Resources Information Center

    Floccia, Caroline; Butler, Joseph; Goslin, Jeremy; Ellis, Lucy

    2009-01-01

    Recent data suggest that the first presentation of a foreign accent triggers a delay in word identification, followed by a subsequent adaptation. This study examines under what conditions the delay resumes to baseline level. The delay will be experimentally induced by the presentation of sentences spoken to listeners in a foreign or a regional…

  13. L2-Accented Speech in L3 Production

    ERIC Educational Resources Information Center

    Wrembel, Magdalena

    2010-01-01

    The paper is aimed at investigating the sources of cross-linguistic influence in the third language (L3) phonology, and, particularly, the impact of the second language (L2) on the phonological acquisition of another foreign language. The study consisted in foreign accent judgements performed by a group of expert judges who were presented with…

  14. The Foundations of Accent and Intelligibility in Pronunciation Research

    ERIC Educational Resources Information Center

    Munro, Murray J.; Derwing, Tracey M.

    2011-01-01

    Our goal in developing this timeline was to trace the empirical bases of current approaches to L2 pronunciation teaching, with particular attention to the concepts of "accent" and "intelligibility". The process of identifying suitable works for inclusion challenged us in several ways. First, the number of empirical studies of pronunciation…

  15. Native and Nonnative Processing of Japanese Pitch Accent

    ERIC Educational Resources Information Center

    Wu, Xianghua; Tu, Jung-Yueh; Wang, Yue

    2012-01-01

    The theoretical framework of this study is based on the prevalent debate of whether prosodic processing is influenced by higher level linguistic-specific circuits or reflects lower level encoding of physical properties. Using the dichotic listening technique, the study investigates the hemispheric processing of Japanese pitch accent by native…

  16. Computer-Assisted Accent Modification: A Report on Practice Effects.

    ERIC Educational Resources Information Center

    Ferrier, Linda J.; Reid, Lawry N.; Chenausky, Karen

    1999-01-01

    This study evaluated the use of the computer-assisted accent-modification program, Speech Works, with beginning college students of English as a second language with a non-speech-language pathologist trainer. Students who had weekly one-on-one sessions with a teacher and independent practice, especially when the practice was computer monitored,…

  17. Prosodic Transfer: From Chinese Lexical Tone to English Pitch Accent

    ERIC Educational Resources Information Center

    Ploquin, Marie

    2013-01-01

    Chinese tones are associated with a syllable to convey meaning, English pitch accents are prominence markers associated with stressed syllables. As both are created by pitch modulation, their pitch contours can be quite similar. The experiment reported here examines whether native speakers of Chinese produce, when speaking English, the Chinese…

  18. "Speaking Proper": Accent, Dialect, and Identity. Occasional Papers, 22.

    ERIC Educational Resources Information Center

    Hooper, Janet

    Attitudes toward usage, accent, and dialect in spoken English are examined, drawing on literature in the field and data from a British study of year 9 students' (pupils aged 13-14) language awareness. The dilemma inherent in teaching standard spoken usage while encouraging maintenance of ethnic and regional identity is examined, with attention…

  19. The Effect of Accent on Listening Comprehension: A Singapore Study

    ERIC Educational Resources Information Center

    Wilcox, George K.

    1978-01-01

    A study was conducted at Nanyang University in Singapore with Chinese-educated students who supposedly received 12 years of instruction in English but who were still deficient in the language. Comprehension of four different English accents were tested, and two tests of measuring aural comprehension were compared. (SW)

  20. Accents and Dialects: Creating a National Professional Statement.

    ERIC Educational Resources Information Center

    Montgomery, Judy K.

    1999-01-01

    Reviews and discusses the process that the American Speech-Language-Hearing Association (ASHA) engaged in to develop their current policy on accented or dialect inflected speech to educate and assist its members and others with such speech who may be subject to discrimination in educational programs, employment, or delivery of services. (Author/DB)

  1. Accent, Identity, and a Fear of Loss? ESL Students' Perspectives

    ERIC Educational Resources Information Center

    McCrocklin, Shannon; Link, Stephanie

    2016-01-01

    Because many theorists propose a connection between accent and identity, some theorists have justifiably been concerned about the ethical ramifications of L2 pronunciation teaching. However, English-as-a-second-language (ESL) students often state a desire to sound like native speakers. With little research into ESL students' perceptions of links…

  2. Metalloproteinase-mediated release of human Fas ligand

    PubMed Central

    1995-01-01

    Fas ligand (FasL) is a type II integral membrane protein homologous with tumor necrosis factor (TNF). Recent studies indicate that TNF is processed to yield the soluble cytokine by metalloproteinases at the cell surface of activated macrophages and T cells. In the present study, we investigated whether FasL is also released by metalloproteinases. Treatment with hydroxamic acid inhibitors of matrix metalloproteinases specifically led to accumulation of membrane-type FasL (p40) on the surface of human FasL cDNA transfectants and activated human T cells, as estimated by surface immunofluorescence and immunoprecipitation with newly established anti-human FasL monoclonal antibodies. This surface accumulation of mFasL was associated with the decrease of soluble FasL (p27) in the supernatant as estimated by quantitative ELISA and immunoprecipitation with anti-human FasL monoclonal antibodies. These results indicate that human FasL is efficiently released from the cell surface by metalloproteinases like TNF. PMID:7500022

  3. Fetal Alcohol Syndrome: Understanding the Problem; Understanding the Solution; What Indian Communities Can Do.

    ERIC Educational Resources Information Center

    Streissguth, Ann P.

    1994-01-01

    Summarizes facts about fetal alcohol syndrome (FAS), including physical and mental symptoms; cause; prevalence overall and in Indian communities; and problems of infants, children, and adults with FAS. Emphasizes the importance of public awareness, professional education, and provision of community services to prevent FAS. Outlines specific…

  4. Recognizing and Managing Children with Fetal Alcohol Syndrome/Fetal Alcohol Effects: A Guidebook.

    ERIC Educational Resources Information Center

    McCreight, Brenda

    A family counselor and mother of adopted children with Fetal Alcohol Syndrome/Effects (FAS/E) offers practical advice and information on dealing with FAS/E's lifelong effects on behavior and learning. The book begins by discussing the historical, medical, and social aspects of FAS/E, and details common behavioral characteristics associated with…

  5. Pitch accents in context: how listeners process accentuation in referential communication.

    PubMed

    Bögels, Sara; Schriefers, Herbert; Vonk, Wietske; Chwilla, Dorothee J

    2011-06-01

    We investigated whether listeners are sensitive to (mis)matching accentuation patterns with respect to contrasts in the linguistic and visual context, using Event-Related Potentials. We presented participants with displays of two pictures followed by a spoken reference to one of these pictures (e.g., "the red ball"). The referent was contrastive with respect to the linguistic context (utterance in the previous trial: e.g., "the blue ball") or with respect to the visual context (other picture in the display; e.g., a display with a red ball and a blue ball). The spoken reference carried a pitch accent on the noun ("the red BALL") or on the adjective ("the RED ball"), or an intermediate ('neutral') accentuation. For the linguistic context, we found evidence for the Missing Accent Hypothesis: Listeners showed processing difficulties, in the form of increased negativities in the ERPs, for missing accents, but not for superfluous accents. 'Neutral' or intermediate accents were interpreted as 'missing' accents when they occurred late in the referential utterance, but not when they occurred early. For the visual context, we found evidence for the Missing Accent Hypothesis for a missing accent on the adjective (an increase in negativity in the ERPs) and a superfluous accent on the noun (no effect). However, a redundant color adjective (e.g., in the case of a display with a red ball and a red hat) led to less processing problems when the adjective carried a pitch accent.

  6. Fas transduces dual apoptotic and trophic signals in hematopoietic progenitors.

    PubMed

    Pearl-Yafe, Michal; Stein, Jerry; Yolcu, Esma S; Farkas, Daniel L; Shirwan, Haval; Yaniv, Isaac; Askenasy, Nadir

    2007-12-01

    Stem cells and progenitors are often required to realize their differentiation potential in hostile microenvironments. The Fas/Fas ligand (FasL) interaction is a major effector pathway of apoptosis, which negatively regulates the expansion of differentiated hematopoietic cells. The involvement of this molecular interaction in the function of hematopoietic stem and progenitor cells is not well understood. In the murine syngeneic transplant setting, both Fas and FasL are acutely upregulated in bone marrow-homed donor cells; however, the Fas(+) cells are largely insensitive to FasL-induced apoptosis. In heterogeneous populations of lineage-negative (lin(-)) bone marrow cells and progenitors isolated by counterflow centrifugal elutriation, trimerization of the Fas receptor enhanced the clonogenic activity. Inhibition of caspases 3 and 8 did not affect the trophic signals mediated by Fas, yet it efficiently blocked the apoptotic pathways. Fas-mediated tropism appears to be of physiological significance, as pre-exposure of donor cells to FasL improved the radioprotective qualities of hematopoietic progenitors, resulting in superior survival of myeloablated hosts. Under these conditions, the activity of long-term reconstituting cells was not affected, as determined in sequential secondary and tertiary transplants. Dual caspase-independent tropic and caspase-dependent apoptotic signaling place the Fas receptor at an important junction of activation and death. This regulatory mechanism of hematopoietic homeostasis activates progenitors to promote the recovery from aplasia and converts into a negative regulator in distal stages of cell differentiation. Disclosure of potential conflicts of interest is found at the end of this article.

  7. RGD-FasL Induces Apoptosis in Hepatocellular Carcinoma

    PubMed Central

    Liu, Zhongchen; Wang, Juan; Yin, Ping; Qiu, Jinhua; Liu, Ruizhen; Li, Wenzhu; Fan, Xin; Cheng, Xiaofeng; Chen, Caixia; Zhang, Jiakai; Zhuang, Guohong

    2009-01-01

    Despite impressive results obtained in animal models, the clinical use of Fas ligand (FasL) as an anticancer drug is limited by severe toxicity. Systemic toxicity of death ligands may be prevented by using genes encoding membrane-bound death ligands and by targeted transgene expression through either targeted transduction or targeted transcription. Selective induction of tumor cell death is a promising anticancer strategy. A fusion protein is created by fusing the extracellular domain of Fas ligand (FasL) to the peptide arginine-glycine-aspartic acid (RGD) that selectively targets avβ3-integrins on tumor endothelial cells. The purpose of this study is to evaluate the effects of RGD-FasL on tumor growth and survival in a murine hepatocellular carcinoma (HCC) tumor model. Treatment with RGD-FasL displaying an obvious suppressive effect on the HCC tumor model as compared to that with FasL (p < 0.05) and resulted in a more additive effect on tumor growth delay in this model. RGD-FasL treatment significantly enhanced mouse survival and caused no toxic effect, such as weight loss, organ failure, or other treatment-related toxicities. Apoptosis was detected by flow cytometric analysis and TUNEL assays; those results also showed that RGD-FasL is a more potent inducer of cell apoptosis for H22 and H9101 cell lines than FasL (p < 0.05). In conclusion, RGD-FasL appears to be a low-toxicity selective inducer of tumor cell death, which merits further investigation in preclinical and clinical studies. Furthermore, this approach offers a versatile technology for complexing target ligands with therapeutic recombinant proteins. To distinguish the anti-tumor effects of FasL in vivo, tumor and liver tissues were harvested to examine for evidence of necrotic cells, tumor cells, or apoptotic cells by Hematoxylin and eosin (H&E) staining. PMID:19728930

  8. The induction of Bim expression in human T-cell blasts is dependent on nonapoptotic Fas/CD95 signaling.

    PubMed

    Bosque, Alberto; Aguiló, Juan Ignacio; Alava, M Angeles; Paz-Artal, Estela; Naval, Javier; Allende, Luis M; Anel, Alberto

    2007-02-15

    The BH3-only protein Bim is required for maintaining the homeostasis of the immune system, since Bim regulates the down-modulation of T-cell responses, mainly through cytokine deprivation. Using T-cell blasts from healthy donors and also from patients with autoimmune lymphoproliferative syndromes (ALPSs) due to homozygous loss-of-function mutation of FasL (ALPS-Ic) or heterozygous mutation in the Fas/CD95 death domain (ALPS-Ia), it is shown that the induction of Bim expression during the process of human T-cell blast generation is strictly dependent on FasL/Fas-mediated signaling. The main pathway by which Fas signaling regulates the levels of Bim expression in human T-cell blasts is the death-domain- and caspase-independent generation of discrete levels of H2O2, which results in the net increase of Foxo3a levels. The present results connect the 2 main pathways described until the moment for the control of T-cell responses: death receptor-mediated activation-induced cell death and apoptosis by cytokine deprivation.

  9. FAS Inactivation Releases Unconventional Germinal Center B Cells that Escape Antigen Control and Drive IgE and Autoantibody Production.

    PubMed

    Butt, Danyal; Chan, Tyani D; Bourne, Katherine; Hermes, Jana R; Nguyen, Akira; Statham, Aaron; O'Reilly, Lorraine A; Strasser, Andreas; Price, Susan; Schofield, Peter; Christ, Daniel; Basten, Antony; Ma, Cindy S; Tangye, Stuart G; Phan, Tri Giang; Rao, V Koneti; Brink, Robert

    2015-05-19

    The mechanistic links between genetic variation and autoantibody production in autoimmune disease remain obscure. Autoimmune lymphoproliferative syndrome (ALPS) is caused by inactivating mutations in FAS or FASL, with autoantibodies thought to arise through failure of FAS-mediated removal of self-reactive germinal center (GC) B cells. Here we show that FAS is in fact not required for this process. Instead, FAS inactivation led to accumulation of a population of unconventional GC B cells that underwent somatic hypermutation, survived despite losing antigen reactivity, and differentiated into a large population of plasma cells that included autoantibody-secreting clones. IgE(+) plasma cell numbers, in particular, increased after FAS inactivation and a major cohort of ALPS-affected patients were found to have hyper-IgE. We propose that these previously unidentified cells, designated "rogue GC B cells," are a major driver of autoantibody production and provide a mechanistic explanation for the linked production of IgE and autoantibodies in autoimmune disease.

  10. Spontaneous and Fas-induced apoptosis of low-grade MDS erythroid precursors involves the endoplasmic reticulum.

    PubMed

    Gyan, E; Frisan, E; Beyne-Rauzy, O; Deschemin, J-C; Pierre-Eugene, C; Randriamampita, C; Dubart-Kupperschmitt, A; Garrido, C; Dreyfus, F; Mayeux, P; Lacombe, C; Solary, E; Fontenay, M

    2008-10-01

    Spontaneous apoptosis of bone marrow erythroid precursors accounts for the anemia that characterizes most low-grade myelodysplastic syndromes (MDS). We have shown that death of these precursors involved the Fas-dependent activation of caspase-8. To explore the pathway leading from caspase-8 activation to apoptosis, we transduced MDS bone marrow CD34(+) cells with a lentivirus encoding wild-type (WT) or endoplasmic reticulum (ER)-targeted Bcl-2 protein before inducing their erythroid differentiation. Both WT-Bcl-2 and ER-targeted Bcl-2 prevented spontaneous and Fas-dependent apoptosis in MDS erythroid precursors. ER-targeted Bcl-2 inhibited mitochondrial membrane depolarization and cytochrome c release in MDS erythroid precursors undergoing apoptosis, indicating a role for the ER in the death pathway, upstream of the mitochondria. MDS erythroid precursors demonstrated elevated ER Ca(2+) stores and these stores remained unaffected by ER-targeted Bcl-2. The ER-associated protein Bcl-2-associated protein (BAP) 31 was cleaved by caspase-8 in MDS erythroid precursors undergoing apoptosis. The protective effect of ER-targeted Bcl-2 toward spontaneous and Fas-induced apoptosis correlated with inhibition of BAP31 cleavage. A protective effect of erythropoietin against Fas-induced BAP31 cleavage and apoptosis was observed. We propose that apoptosis of MDS erythroid precursors involves the ER, downstream of Fas and upstream of the mitochondria, through the cleavage of the ER-associated BAP31 protein.

  11. Evaluating causes of foreign accent in English sentences spoken by native speakers of Italian differing in age of arrival (AOA) in Canada

    NASA Astrophysics Data System (ADS)

    Flege, James; Mackay, Ian; Imai, Satomi

    2003-04-01

    This study evaluated potential causes of foreign accent (FA) by including native Italian (NI) speakers with a later age of arrival (AOA) in Canada than in previous studies. Three NI groups (n=18 each) differing in AOA (means=10, 18, and 26 years) participated. Listeners used a 9-point scale to rate sentences produced by the three NI groups and native English controls. The ratings obtained for all four groups differed significantly. The stronger foreign accents of the AOA-18 than AOA-10 group might be attributed to the passing of a critical period, or to stronger cross-language interference by more robust Italian phonetic categories. The difference might also be attributed to differences in language use. This is because the AOA-10 and AOA-18 groups (but not the AOA-18 and AOA-26 groups) differed significantly in percentage of English and Italian use, length of residence in Canada, and years of education in Canada. None of these explanations will apparently explain the stronger FAs of the AOA-26 than AOA-18 group. The difference between these groups might be attributed to cognitive aging [Hakuta et al., Appl. Psycholinguistics (in press)], which results in gradually less successful second-language acquisition across the adult life span. [Work supported by NIH.

  12. Lymphocytes with Aberrant Expression of Fas or Fas-ligand Attenuate Immune Bone Marrow Failure in a Mouse Model

    PubMed Central

    Omokaro, Stephanie O.; Desierto, Marie J.; Eckhaus, Michael A.; Ellison, Felicia M.; Chen, Jichun; Young, Neal S.

    2012-01-01

    Bone marrow (BM) and lymphocyte samples from aplastic anemia patients show up-regulated Fas and Fas-ligand (FasL) expression respectively, supporting a relationship between immune-mediated BM destruction and the Fas apoptotic pathway. Mice with spontaneous lymphoproliferation (lpr) and generalized lymphoproliferative disease (gld) mutations exhibit abnormal expression of Fas and FasL; serving as potential models to elucidate underlying mechanisms of BM failure. We examined cellular and functional characteristics of lpr and gld mutants on the C57BL/6 (B6) background. Lymph node (LN) cells from lpr and gld mice produced less apoptosis when co-incubated with C.B10-H2b/LilMcd (C.B10) BM cells in vitro. This functional difference was confirmed by infusing lpr, gld, and B6 LN cells into sub-lethally irradiated CB10 mice; all donor LN cells showed significant T cell expansion and activation but only B6 LN cells caused severe BM destruction. Mice infused with gld LN cells developed mild to moderate BM failure, despite receiving FasL-deficient effectors, thus suggesting the existence of alternative pathways or incomplete penetrance of the mutation. Paradoxically, mice that received Fas-deficient lpr LN cells also had reduced BM failure, likely due to down-regulation of pro-apoptotic genes, an effect that can be overcome by higher doses of lpr LN cells. Our model demonstrates that abnormal Fas or FasL expression interferes with the development of pancytopenia and marrow hypoplasia, validating a major role for the Fas/FasL cytotoxic pathway in immune-mediated BM failure, although disruption of this pathway does not completely abolish marrow destruction. PMID:19265119

  13. Lymphocytes with aberrant expression of Fas or Fas ligand attenuate immune bone marrow failure in a mouse model.

    PubMed

    Omokaro, Stephanie O; Desierto, Marie J; Eckhaus, Michael A; Ellison, Felicia M; Chen, Jichun; Young, Neal S

    2009-03-15

    Bone marrow (BM) and lymphocyte samples from aplastic anemia patients show up-regulated Fas and Fas-ligand (FasL) expression, respectively, supporting a relationship between immune-mediated BM destruction and the Fas apoptotic pathway. Mice with spontaneous lymphoproliferation (lpr) and generalized lymphoproliferative disease (gld) mutations exhibit abnormal expression of Fas and FasL, serving as potential models to elucidate underlying mechanisms of BM failure. We examined cellular and functional characteristics of lpr and gld mutants on the C57BL/6 (B6) background. Lymph node (LN) cells from lpr and gld mice produced less apoptosis when coincubated with C.B10-H2(b)/LilMcd (C.B10) BM cells in vitro. This functional difference was confirmed by infusing lpr, gld, and B6 LN cells into sublethally irradiated CB10 mice. All donor LN cells showed significant T cell expansion and activation, but only B6 LN cells caused severe BM destruction. Mice infused with gld LN cells developed mild to moderate BM failure despite receiving FasL-deficient effectors, thus suggesting the existence of alternative pathways or incomplete penetrance of the mutation. Paradoxically, mice that received Fas-deficient lpr LN cells also had reduced BM failure, likely due to down-regulation of proapoptotic genes, an effect that can be overcome by higher doses of lpr LN cells. Our model demonstrates that abnormal Fas or FasL expression interferes with the development of pancytopenia and marrow hypoplasia, validating a major role for the Fas/FasL cytotoxic pathway in immune-mediated BM failure, although disruption of this pathway does not completely abolish marrow destruction.

  14. Cysteine proteinases Fas1 and Fas2 are diagnostic markers for Fasciola hepatica infection in alpacas (Lama pacos).

    PubMed

    Neyra, Victor; Chavarry, Elizabeth; Espinoza, Jose R

    2002-04-19

    Circulating antibody against Fasciola hepatica antigens was determined by enzyme-linked immunosorbent assay (ELISA) and immunoelectrophoresis in alpacas naturally exposed to F. hepatica. Serological assay parameters were established by using sera from eight infected animals and seven controls with no record of this parasitic infection. Excretory--secretory (ES-) products, Fas1- and Fas2-ELISA were used to survey 307 alpacas from a F. hepatica endemic area in the Peruvian Andes. Seroprevalence of F. hepatica infection varied from 56.7, 64.8 and 66.8% measured by Fas1-, Fas2- and ES-ELISA, respectively. The sensitivity for ES-ELISA was 95%, corresponding Fas1- and Fas2-ELISA sensitivity values were 90 and 95%. In this population, 7% of animals were positive for F. hepatica eggs in faeces, other parasites detected were Trichuris sp. (40%), Nematodirus sp. (34.6%), Lamanema sp. (12.8%) and Eimeria sp. (11.8%). The results show that F. hepatica infected animals elicit circulating antibodies against ES, Fas1 and Fas2. Fas2-ELISA may be proposed as a sensitive assay for the immunodiagnosis of fasciolosis in alpacas.

  15. Fetal Alcohol Syndrome: Implications for Educators.

    ERIC Educational Resources Information Center

    Ackerman, Margaret E.

    This paper provides a discussion of definitions, historical precursors, and prevalence figures for children with fetal alcohol syndrome (FAS) and highlights relevant medical and behavioral characteristics. It also addresses the educational implications of working with children with FAS in terms of instruction and curriculum. Educators are urged…

  16. Fetal Alcohol Syndrome: A Description of Oral Motor, Articulatory, Short-Term Memory, Grammatical, and Semantic Abilities.

    ERIC Educational Resources Information Center

    Becker, Marianne; And Others

    1990-01-01

    The communication skills of 8 children (ages 4 to 9) with Fetal Alcohol Syndrome FAS) were assessed and compared with non-FAS children matched for ethnic background, living situation, and nonverbal cognitive ability. FAS children showed abnormalities of the speech mechanism and inconsistent articulation, comprehension, and grammatical abilities.…

  17. Palmitoylation of human FasL modulates its cell death-inducing function

    PubMed Central

    Guardiola-Serrano, F; Rossin, A; Cahuzac, N; Lückerath, K; Melzer, I; Mailfert, S; Marguet, D; Zörnig, M; Hueber, A-O

    2010-01-01

    Fas ligand (FasL) is a transmembrane protein that regulates cell death in Fas-bearing cells. FasL-mediated cell death is essential for immune system homeostasis and the elimination of viral or transformed cells. Because of its potent cytotoxic activity, FasL expression at the cell surface is tightly regulated, for example, via processing by ADAM10 and SPPL2a generating soluble FasL and the intracellular fragments APL (ADAM10-processed FasL form) and SPA (SPPL2a-processed APL). In this study, we report that FasL processing by ADAM10 counteracts Fas-mediated cell death and is strictly regulated by membrane localization, interactions and modifications of FasL. According to our observations, FasL processing occurs preferentially within cholesterol and sphingolipid-rich nanodomains (rafts) where efficient Fas–FasL contact occurs, Fas receptor and FasL interaction is also required for efficient FasL processing, and FasL palmitoylation, which occurs within its transmembrane domain, is critical for efficient FasL-mediated killing and FasL processing. PMID:21368861

  18. Expression of ADAM10, Fas, FasL and Soluble FasL in Patients with Oral Squamous Cell Carcinoma (OSCC) and their Association with Clinical-Pathological Parameters.

    PubMed

    Zepeda-Nuño, José Sergio; Guerrero-Velázquez, Celia; Del Toro-Arreola, Susana; Vega-Magaña, Natali; Ángeles-Sánchez, Julián; Haramati, Jesse; Pereira-Suárez, Ana L; Bueno-Topete, Miriam R

    2017-04-01

    ADAM10 has been implicated in the progression of various solid tumors. ADAM10 regulates the cleavage of the FasL ectodomain from the plasma membrane of different cell types, generating the soluble FasL fragment (sFasL). Currently, there are few studies in oral squamous cell carcinoma (OSCC) that correlate levels of ADAM10 and FasL in the tumor microenvironment with clinical parameters of the disease. To determine the expression of ADAM10, Fas, FasL and sFasL in patients with OSCC and its association with TNM stage. Twenty-five patients with OSCC and 25 healthy controls were included. Biopsies of tumor tissue from patients with OSCC and buccal mucosa in controls were obtained. ADAM10, Fas, and FasL were analyzed by Western blotting. sFasL was quantified by ELISA. ADAM10 and Fas decreased significantly in OSCC compared with controls. Relatedly, within the OSCC group, Fas and ADAM10 decreased in accordance with tumor disease stage; in stages I/II, as well as in tumors of smaller diameter (T1-T2), ADAM10 showed higher levels when compared to patients with T3-T4 tumors and in stage III-IV. FasL in the tumor microenvironment and serum FasL showed no significant differences between both groups. Levels of complete FasL and cleaved FasL were positively correlated in controls; this correlation is preserved in patients with tumors in early stages (I-II), but is lost in later stage (III-IV). The dysregulation of ADAM10, Fas and FasL could be useful indicators of the progression and severity of OSCC.

  19. Pitch Accent Alignment in Romance: Primary and Secondary Associations with Metrical Structure

    ERIC Educational Resources Information Center

    Prieto, Pilar; D'Imperio, Mariapaola; Fivela, Barbara Gili

    2005-01-01

    The article describes the contrastive possibilities of alignment of high accents in three Romance varieties, namely, Central Catalan, Neapolitan Italian, and Pisa Italian. The Romance languages analyzed in this article provide crucial evidence that small differences in alignment in rising accents should be encoded phonologically. To account for…

  20. Cross-Linguistic Expression of Contrastive Accent: Clinical Assessment in Spanish and English

    ERIC Educational Resources Information Center

    Martinez-Castilla, Pastora; Peppe, Sue

    2010-01-01

    Well-documented Romance-Germanic differences in the use of accent in speech to convey information-structure and focus cause problems for the assessment of prosodic skills in populations with clinical disorders. The strategies for assessing the ability to use lexical and contrastive accent in English and Spanish are reviewed, and studies in the…

  1. Effects of Speaker Variability on Learning Foreign-Accented English for EFL Learners

    ERIC Educational Resources Information Center

    Gao, Yuan; Low, Renae; Jin, Putai; Sweller, John

    2013-01-01

    Using a cognitive load theory approach, we investigated the effects of speaker variability when individuals are learning to understand English as a foreign language (EFL) spoken by foreign-accented speakers. The use of multiple, Indian-accented speakers was compared to that of a single speaker for Chinese EFL learners with a higher or lower…

  2. Utterance-Final Lengthening Is Predictive of Infants' Discrimination of English Accents

    ERIC Educational Resources Information Center

    White, Laurence; Floccia, Caroline; Goslin, Jeremy; Butler, Joseph

    2014-01-01

    Infants in their first year manifest selective patterns of discrimination between languages and between accents of the same language. Prosodic differences are held to be important in whether languages can be discriminated, together with the infant's familiarity with one or both of the accents heard. However, the nature of the prosodic cues that…

  3. Children's Use of Semantic Context in Perception of Foreign-Accented Speech

    ERIC Educational Resources Information Center

    Holt, Rachael Frush; Bent, Tessa

    2017-01-01

    Purpose: The purpose of this study is to evaluate children's use of semantic context to facilitate foreign-accented word recognition in noise. Method: Monolingual American English speaking 5- to 7-year-olds (n = 168) repeated either Mandarin- or American English-accented sentences in babble, half of which contained final words that were highly…

  4. Novel Accent Perception in Typically-Developing School-Aged Children

    ERIC Educational Resources Information Center

    Newton, Caroline; Ridgway, Samuel

    2016-01-01

    Many schools in Western countries like the United Kingdom have become increasingly diverse communities in recent years, and children are likely to be exposed to a variety of accents that are different from their own. While there is a wide body of research exploring accent comprehension in the adult population and in infancy, little has been done…

  5. Degree of Perceived Accent in Finnish as a Second Language for Turkish Children Born in Finland

    ERIC Educational Resources Information Center

    Uzal, Melike; Peltonen, Teemu; Huotilainen, Minna; Aaltonen, Olli

    2015-01-01

    This study investigated whether children born in a second language (L2) environment pronounce their L2 with foreign accents and, if so, when foreign accents first emerge. This study also examined the latest age of onset (AO) of extensive L2 experience at which native L2 pronunciation is possible and explored several factors that affect the degree…

  6. Using Visual Accents to Enhance Attending to Communication Symbols for Students with Severe Multiple Disabilities.

    ERIC Educational Resources Information Center

    Bailey, Brent R.; Downing, June

    1994-01-01

    Visual accents can create unique communication graphics to increase attending behavior necessary for learning symbol/referent relationships by students with severe vision loss. Accenting procedures use size, color, contrast, shape, and graphic pattern to enhance the probability that the learner will self-initiate attending to the visual symbol.…

  7. "THE BACON" Not "the Bacon": How Children and Adults Understand Accented and Unaccented Noun Phrases

    ERIC Educational Resources Information Center

    Arnold, Jennifer E.

    2008-01-01

    Two eye-tracking experiments examine whether adults and 4- and 5-year-old children use the presence or absence of accenting to guide their interpretation of noun phrases (e.g., "the bacon") with respect to the discourse context. Unaccented nouns tend to refer to contextually accessible referents, while accented variants tend to be used for less…

  8. Contextual Evidence for the Representation of Pitch Accents in Standard Serbian

    ERIC Educational Resources Information Center

    Zsiga, Elizabeth; Zec, Draga

    2013-01-01

    This paper reports the results of an experiment that elicits contextual effects on Rising and Falling accents in Standard Serbian, with the goal of determining their acoustic correlates and their phonological representation. Materials systematically vary the distance between pitch accents, inducing "tone crowding," in order to identify the…

  9. The role of planum temporale in processing accent variation in spoken language comprehension.

    PubMed

    Adank, Patti; Noordzij, Matthijs L; Hagoort, Peter

    2012-02-01

    A repetition-suppression functional magnetic resonance imaging paradigm was used to explore the neuroanatomical substrates of processing two types of acoustic variation-speaker and accent-during spoken sentence comprehension. Recordings were made for two speakers and two accents: Standard Dutch and a novel accent of Dutch. Each speaker produced sentences in both accents. Participants listened to two sentences presented in quick succession while their haemodynamic responses were recorded in an MR scanner. The first sentence was spoken in Standard Dutch; the second was spoken by the same or a different speaker and produced in Standard Dutch or in the artificial accent. This design made it possible to identify neural responses to a switch in speaker and accent independently. A switch in accent was associated with activations in predominantly left-lateralized areas including posterior temporal regions, including superior temporal gyrus, planum temporale (PT), and supramarginal gyrus, as well as in frontal regions, including left pars opercularis of the inferior frontal gyrus (IFG). A switch in speaker recruited a predominantly right-lateralized network, including middle frontal gyrus and prenuneus. It is concluded that posterior temporal areas, including PT, and frontal areas, including IFG, are involved in processing accent variation in spoken sentence comprehension.

  10. Business and Technology Students' Preferences for English-Language Accents: Implications for Business Communication.

    ERIC Educational Resources Information Center

    Scott, James Calvert; Green, Diana J.; Rosewarne, David

    1997-01-01

    Multiple recordings of a message in various accents were heard by 218 college students, including 26 nonnative English speakers. Ranked English accents in descending order were General American, British, Australian, Indian, Estuary, and Japanese. Perceptual differences were related to gender, ethnicity, nationality, and region. Implications for…

  11. Shades of Cosmopolitanism: EFL Teachers' Perspectives on English Accents and Pronunciation Teaching in the Gulf

    ERIC Educational Resources Information Center

    Buckingham, Louisa

    2015-01-01

    Research suggests that passing for a native English speaker (NES) is often perceived as desirable by teachers of English as a Foreign Language (EFL) and employers, and students may claim to prefer certain NES accents as learning models. While this may be partly motivated by the prevalence of a particular regional accent in ESL contexts or…

  12. Phonetic Parameters and Perceptual Judgments of Accent in English by American and Japanese Listeners

    ERIC Educational Resources Information Center

    Riney, Timothy J.; Takagi, Naoyuki; Inutsuka, Kumiko

    2005-01-01

    In this study we identify some of the phonetic parameters that correlate with nonnative speakers' (NNSs) perceptual judgments of accent in English and investigate NNS listener perceptions of English from a World Englishes point of view. Our main experiment involved 3,200 assessments of the perceived degree of accent in English of two speaker…

  13. Evaluating the Effects of Chronological Age and Sentence Duration on Degree of Perceived Foreign Accent

    ERIC Educational Resources Information Center

    Mackay, Ian R. A.; Flege, James E.; Imai, Satomi

    2006-01-01

    Immigrants' age of arrival (AOA) in a country where a second language (L2) must be learned has consistently been shown to affect the degree of perceived L2 foreign accent. Although the effect of AOA appears strong, AOA is typically correlated with other variables that might influence degree of foreign accent. This study examined the pronunciation…

  14. Attitudes of Native and Nonnative Speakers toward Selected Regional Accents of U.S. English.

    ERIC Educational Resources Information Center

    Alford, Randall L.; Strother, Judith B.

    1990-01-01

    Provides data from a study that sought to determine and compare the attitudes of both native and nonnative speakers of English who listened to the specific regional accents of the English spoken in the United States. The groups judgments differed, and nonnative speakers were better able to perceive differences in regional accents of U.S. English.…

  15. Foreign Accent, Comprehensibility, and Intelligibility in the Speech of Second Language Learners.

    ERIC Educational Resources Information Center

    Munro, Murray J.; Derwing, Tracey M.

    1995-01-01

    Examines the interrelationships among accentedness, perceived comprehensibility, and intelligibility in the speech of second-language (L2) learners. The findings suggest that although strength of foreign accent is correlated with perceived comprehensibility and intelligibility, a strong foreign accent does not necessarily reduce the…

  16. The Effect of Foreign Accent and Speaking Rate on Native Speaker Comprehension.

    ERIC Educational Resources Information Center

    Anderson-Hsieh, Janet; Koehler, Kenneth

    1988-01-01

    A study investigated the effect of foreign accent and speaking rate on native English speaker comprehension. Three native Chinese speakers and one native speaker of American English read passages at different speaking rates. Comprehension scores showed that an increase in speaking rate and heavily accented English decreased listener comprehension.…

  17. Factors Affecting Accent Acquisition: The Case of Russian Immigrants in Israel

    ERIC Educational Resources Information Center

    Abu-Rabia, Salim; Iliyan, Salman

    2011-01-01

    A debate centers on whether the native accent is acquired early in life or whether it can be acquired at any time. This study investigated factors that may affect native accent acquisition in a second language. Participants in this study were 50 Russians who immigrated to Israel, 17 males and 33 females. Their age on arrival was 5 to 25 years.…

  18. Comparing Foreign Accent in L1 Attrition and L2 Acquisition: Range and Rater Effects

    ERIC Educational Resources Information Center

    Schmid, Monika S.; Hopp, Holger

    2014-01-01

    This study examines the methodology of global foreign accent ratings in studies on L2 speech production. In three experiments, we test how variation in raters, range within speech samples, as well as instructions and procedures affects ratings of accent in predominantly monolingual speakers of German, non-native speakers of German, as well as…

  19. Investigating Attitudes towards an Emerging Standard of English: Evaluations of Newscasters' Accents in Trinidad

    ERIC Educational Resources Information Center

    Deuber, Dagmar; Leung, Glenda-Alicia

    2013-01-01

    This paper addresses the issue of the emergence of new standards of English in the postcolonial world by means of a language attitude study conducted in the Caribbean island of Trinidad that involved rating the accents of newscasters. Accents represented in the clips played to respondents comprised various local as well as non-local ones. The…

  20. From One to Multiple Accents on a Test of L2 Listening Comprehension

    ERIC Educational Resources Information Center

    Ockey, Gary J.; French, Robert

    2016-01-01

    Concerns about the need for assessing multidialectal listening skills for global contexts are becoming increasingly prevalent. However, the inclusion of multiple accents on listening assessments may threaten test fairness because it is not practical to include every accent that may be encountered in the language use domain on these tests. Given…

  1. Perceptions about Representative English-Language Accents from Prospective and Practicing Providers of Business-Related Language Services in Argentina

    ERIC Educational Resources Information Center

    Scott, James Calvert; Green, Diana J.; Rosewarne, David D.

    2004-01-01

    The purposes of the study were (a) to identify perceptions about representative English-language accents from prospective and practicing providers of business-related language services residing in Argentina and (b) to examine the differences in their perceptions of these English-language accents. The respondents ranked the accents in this order:…

  2. Fas/FasL, Bcl2 and Caspase-8 gene polymorphisms in Chinese patients with rheumatoid arthritis.

    PubMed

    Zhu, Aiping; Wang, Mingjie; Zhou, Guoxin; Zhang, Hui; Liu, Ruiping; Wang, Yong

    2016-06-01

    Apoptosis signals are necessary for maintaining homeostasis and an adequate immune response. Dysregulation of apoptosis-related genes in the immune system has an important impact on autoimmune diseases such as rheumatoid arthritis (RA). Thus, we investigated the association between Fas rs2234767 G/A, FasL rs763110 C/T, Bcl2 rs12454712 T/C, Bcl2 rs17757541 C/G, and Caspase-8 rs1035142 G/T polymorphisms and RA susceptibility in a Chinese population. These five single-nucleotide polymorphisms (SNPs) were studied in a Chinese population consisting of 615 patients with RA and 839 controls. Genotyping was performed using a custom-by-design 48-Plex SNP scan TM kit. Furthermore, we undertook a meta-analysis between FasL rs763110 C/T and RA. This study indicated that Fas rs2234767 and Bcl2 rs17757541 polymorphisms were risk factors for RA. No association was observed between FasL rs763110 C/T, Bcl2 rs12454712 T/C, and Caspase-8 rs1035142 G/T polymorphisms and RA in this study. The results of this meta-analysis suggested no significant association between FasL rs763110 C/T and RA. However, stratification analysis of this meta-analysis indicated that FasL rs763110 C/T increased the risk of Caucasian RA patients. In conclusion, this study demonstrated that Fas rs2234767 G/A and Bcl2 rs17757541 T/C polymorphisms might be associated with an increased risk of RA. This meta-analysis revealed that FasL rs763110 C/T was associated with an increased risk of Caucasian RA patients.

  3. Enhanced expression of Fas and FasL modulates apoptosis in the lungs of severe P. falciparum malaria patients with pulmonary edema

    PubMed Central

    Punsawad, Chuchard; Viriyavejakul, Parnpen; Setthapramote, Chayanee; Palipoch, Sarawoot

    2015-01-01

    Apoptosis mediated by Fas/FasL has been implicated in pulmonary disorders. However, little is known about the relationship between Fas and FasL in the process of lung injury during malaria infection. Paraffin-embedded lung tissues from malaria patients were divided into two groups: those with pulmonary edema (PE) and those without pulmonary edema (non-PE). Normal lung tissues were used as the control group. Cellular expression of Fas, FasL, and the markers of apoptotic caspases, including cleaved caspase-3 and cleaved caspase-8 in the lung tissues were investigated by the immunohistochemistry (IHC) method. Semi-quantitative analysis of IHC staining revealed that cellular expression of Fas, FasL, cleaved caspase-8, and cleaved caspase-3 were significantly increased in the lungs of patients with PE compared with the lungs of patients with non-PE and control groups (all P < 0.05). In addition, significant positive correlations were obtained between Fas and apoptosis (rs = 0.937, P < 0.001) and FasL and apoptosis (rs = 0.808, P < 0.001). Significant positive correlations were found between Fas and FasL expression (rs = 0.827, P < 0.001) and between cleaved caspase-8 and cleaved caspase-3 expression (rs = 0.823, P < 0.001), which suggests that Fas-dependent initiator and effector caspases, including cleaved caspase-8 and caspase-3, are necessary for inducing apoptosis in the lungs of patients with severe P. falciparum malaria. The Fas/FasL system and downstream activation of caspases are important mediators of apoptosis and may be involved in the pathogenesis of pulmonary edema in severe P. falciparum malaria patients. The proper regulation of the Fas/FasL pathway can be a potential treatment for pulmonary complications in falciparum malaria patients. PMID:26617708

  4. Fas Protects Breast Cancer Stem Cells from Death

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-13-1-0301 TITLE: Fas Protects Breast Cancer Stem Cells from Death PRINCIPAL INVESTIGATOR: Paolo Ceppi CONTRACTING...sensitive to Fas-mediated apoptosis, while the BCSCs part is more sensitive to the death induced by the elimination of CD95 (a phenomenon we have recently...identification of novel molecular targets for the treatment of breast cancer. I have in fact observed a significant enhancement of cancer cell death by

  5. Pigment epithelial-derived factor (PEDF)-triggered lung cancer cell apoptosis relies on p53 protein-driven Fas ligand (Fas-L) up-regulation and Fas protein cell surface translocation.

    PubMed

    Li, Lei; Yao, Ya-Chao; Fang, Shu-Huan; Ma, Cai-Qi; Cen, Yi; Xu, Zu-Min; Dai, Zhi-Yu; Li, Cen; Li, Shuai; Zhang, Ting; Hong, Hong-Hai; Qi, Wei-Wei; Zhou, Ti; Li, Chao-Yang; Yang, Xia; Gao, Guo-Quan

    2014-10-31

    Pigment epithelium-derived factor (PEDF), a potent antiangiogenesis agent, has recently attracted attention for targeting tumor cells in several types of tumors. However, less is known about the apoptosis-inducing effect of PEDF on human lung cancer cells and the underlying molecular events. Here we report that PEDF has a growth-suppressive and proapoptotic effect on lung cancer xenografts. Accordingly, in vitro, PEDF apparently induced apoptosis in A549 and Calu-3 cells, predominantly via the Fas-L/Fas death signaling pathway. Interestingly, A549 and Calu-3 cells are insensitive to the Fas-L/Fas apoptosis pathway because of the low level of cell surface Fas. Our results revealed that, in addition to the enhancement of Fas-L expression, PEDF increased the sensitivity of A549 and Calu-3 cells to Fas-L-mediated apoptosis by triggering the translocation of Fas protein to the plasma membrane in a p53- and FAP-1-dependent manner. Similarly, the up-regulation of Fas-L by PEDF was also mediated by p53. Furthermore, peroxisome proliferator-activated receptor γ was determined to be the upstream regulator of p53. Together, these findings uncover a novel mechanism of tumor cell apoptosis induced by PEDF and provide a potential therapeutic strategy for tumors that are insensitive to Fas-L/Fas-dependent apoptosis because of a low level of cell surface Fas.

  6. Pigment Epithelial-derived Factor (PEDF)-triggered Lung Cancer Cell Apoptosis Relies on p53 Protein-driven Fas Ligand (Fas-L) Up-regulation and Fas Protein Cell Surface Translocation*

    PubMed Central

    Li, Lei; Yao, Ya-Chao; Fang, Shu-Huan; Ma, Cai-Qi; Cen, Yi; Xu, Zu-Min; Dai, Zhi-Yu; Li, Cen; Li, Shuai; Zhang, Ting; Hong, Hong-Hai; Qi, Wei-Wei; Zhou, Ti; Li, Chao-Yang; Yang, Xia; Gao, Guo-Quan

    2014-01-01

    Pigment epithelium-derived factor (PEDF), a potent antiangiogenesis agent, has recently attracted attention for targeting tumor cells in several types of tumors. However, less is known about the apoptosis-inducing effect of PEDF on human lung cancer cells and the underlying molecular events. Here we report that PEDF has a growth-suppressive and proapoptotic effect on lung cancer xenografts. Accordingly, in vitro, PEDF apparently induced apoptosis in A549 and Calu-3 cells, predominantly via the Fas-L/Fas death signaling pathway. Interestingly, A549 and Calu-3 cells are insensitive to the Fas-L/Fas apoptosis pathway because of the low level of cell surface Fas. Our results revealed that, in addition to the enhancement of Fas-L expression, PEDF increased the sensitivity of A549 and Calu-3 cells to Fas-L-mediated apoptosis by triggering the translocation of Fas protein to the plasma membrane in a p53- and FAP-1-dependent manner. Similarly, the up-regulation of Fas-L by PEDF was also mediated by p53. Furthermore, peroxisome proliferator-activated receptor γ was determined to be the upstream regulator of p53. Together, these findings uncover a novel mechanism of tumor cell apoptosis induced by PEDF and provide a potential therapeutic strategy for tumors that are insensitive to Fas-L/Fas-dependent apoptosis because of a low level of cell surface Fas. PMID:25225287

  7. Investigations of Rocket Engine Combustion Emissions During ACCENT

    NASA Astrophysics Data System (ADS)

    Ross, M. N.; Friedl, R. R.

    2001-12-01

    The composition of rocket combustion emissions and the atmospheric processes that determine their stratospheric impacts are poorly understood. While present day rocket emissions do not significantly affect stratospheric chemistry, the potential for vigorous growth of the space transportation industry in coming decades suggests that rocket emissions and their stratospheric impacts should be better understood. A variety of in-situ measurements and modeling results were obtained during the Atmospheric Chemistry of Combustion Emissions Near the Tropopause (ACCENT) effort that will be used to evaluate the role of rocket exhaust in perturbing ozone chemistry in plume wakes and in the global stratosphere. We present a review of the ACCENT rocket emissions science objectives, summarize data obtained during the WB-57F plume wake sorties, and briefly discuss how the data will help resolve several outstanding questions regarding the impact of rocket emissions on the stratosphere. These include measurement of the emission indices for several important rocket engine combustion products and validation of plume wake chemistry models.

  8. Auditory perceptual simulation: Simulating speech rates or accents?

    PubMed

    Zhou, Peiyun; Christianson, Kiel

    2016-07-01

    When readers engage in Auditory Perceptual Simulation (APS) during silent reading, they mentally simulate characteristics of voices attributed to a particular speaker or a character depicted in the text. Previous research found that auditory perceptual simulation of a faster native English speaker during silent reading led to shorter reading times that auditory perceptual simulation of a slower non-native English speaker. Yet, it was uncertain whether this difference was triggered by the different speech rates of the speakers, or by the difficulty of simulating an unfamiliar accent. The current study investigates this question by comparing faster Indian-English speech and slower American-English speech in the auditory perceptual simulation paradigm. Analyses of reading times of individual words and the full sentence reveal that the auditory perceptual simulation effect again modulated reading rate, and auditory perceptual simulation of the faster Indian-English speech led to faster reading rates compared to auditory perceptual simulation of the slower American-English speech. The comparison between this experiment and the data from Zhou and Christianson (2016) demonstrate further that the "speakers'" speech rates, rather than the difficulty of simulating a non-native accent, is the primary mechanism underlying auditory perceptual simulation effects.

  9. Perceiving unstressed vowels in foreign-accented English.

    PubMed

    Braun, Bettina; Lemhöfer, Kristin; Mani, Nivedita

    2011-01-01

    This paper investigated how foreign-accented stress cues affect on-line speech comprehension in British speakers of English. While unstressed English vowels are usually reduced to /ə/, Dutch speakers of English only slightly centralize them. Speakers of both languages differentiate stress by suprasegmentals (duration and intensity). In a cross-modal priming experiment, English listeners heard sentences ending in monosyllabic prime fragments--produced by either an English or a Dutch speaker of English--and performed lexical decisions on visual targets. Primes were either stress-matching ("ab" excised from absurd), stress-mismatching ("ab" from absence), or unrelated ("pro" from profound) with respect to the target (e.g., ABSURD). Results showed a priming effect for stress-matching primes only when produced by the English speaker, suggesting that vowel quality is a more important cue to word stress than suprasegmental information. Furthermore, for visual targets with word-initial secondary stress that do not require vowel reduction (e.g., CAMPAIGN), resembling the Dutch way of realizing stress, there was a priming effect for both speakers. Hence, our data suggest that Dutch-accented English is not harder to understand in general, but it is in instances where the language-specific implementation of lexical stress differs across languages.

  10. The Relationship of Serum Soluble Fas Ligand (sFasL) Level with the Extent of Coronary Artery Disease.

    PubMed

    Sahinarslan, Asife; Boyaci, Bulent; Kocaman, Sinan Altan; Topal, Salih; Ercin, Ugur; Okyay, Kaan; Bukan, Neslihan; Yalçin, Ridvan; Cengel, Atiye

    2012-03-01

    Fas/Fas ligand system contributes to the programmed cell death induced by myocardial ischemia. We investigated whether serum soluble Fas ligand (sFasL) level is independently related with the severity and extent of angiographically assessed coronary artery disease (CAD). We included 169 patients in this study. Two groups were formed based on the existence of a lesion on coronary angiography. First group included patients with normal coronary arteries (NCA; n = 53). Patients with atherosclerotic lesions were included in the second group (n = 116). We used the coronary vessel score (the number of the coronary arteries with a lesion leading to ≥ 50% luminal obstruction) and the Azar score to determine the extent and the severity of CAD. Standard enzyme-linked immunosorbent assay kits were used to measure serum sFasL levels. The serum sFasL level was higher in patients with CAD than in patients with NCA (0.52 ± 0.23 mU/mL vs. 0.45 ± 0.18 mU/mL, p = 0.023). The sFasL level correlated with Azar score (r = 0.231, p = 0.003) and with coronary vessel score (r = 0.269, p < 0.001). In the multivariate analysis, we found that age (beta: 0.188, p = 0.008), gender (beta: 0.317, p < 0.001), diabetes mellitus (DM; beta: 0.195, p = 0.008), and sFasL level (beta: 0.209, p = 0.003) were independently related with Azar score. When we used coronary vessel score as the dependent variable, we found that age (p = 0.020), gender (p < 0.001), DM (p = 0.006), and sFasL level (p = 0.001) were independent predictors. Serum sFasL level is associated with angiographically more severe CAD. Our findings suggest that sFasL level may be a biochemical surrogate of severe coronary atherosclerosis.

  11. The Relationship of Serum Soluble Fas Ligand (sFasL) Level with the Extent of Coronary Artery Disease

    PubMed Central

    Sahinarslan, Asife; Boyaci, Bulent; Kocaman, Sinan Altan; Topal, Salih; Ercin, Ugur; Okyay, Kaan; Bukan, Neslihan; Yalçin, Ridvan; Cengel, Atiye

    2012-01-01

    Fas/Fas ligand system contributes to the programmed cell death induced by myocardial ischemia. We investigated whether serum soluble Fas ligand (sFasL) level is independently related with the severity and extent of angiographically assessed coronary artery disease (CAD). We included 169 patients in this study. Two groups were formed based on the existence of a lesion on coronary angiography. First group included patients with normal coronary arteries (NCA; n = 53). Patients with atherosclerotic lesions were included in the second group (n = 116). We used the coronary vessel score (the number of the coronary arteries with a lesion leading to ≥ 50% luminal obstruction) and the Azar score to determine the extent and the severity of CAD. Standard enzyme-linked immunosorbent assay kits were used to measure serum sFasL levels. The serum sFasL level was higher in patients with CAD than in patients with NCA (0.52 ± 0.23 mU/mL vs. 0.45 ± 0.18 mU/mL, p = 0.023). The sFasL level correlated with Azar score (r = 0.231, p = 0.003) and with coronary vessel score (r = 0.269, p < 0.001). In the multivariate analysis, we found that age (beta: 0.188, p = 0.008), gender (beta: 0.317, p < 0.001), diabetes mellitus (DM; beta: 0.195, p = 0.008), and sFasL level (beta: 0.209, p = 0.003) were independently related with Azar score. When we used coronary vessel score as the dependent variable, we found that age (p = 0.020), gender (p < 0.001), DM (p = 0.006), and sFasL level (p = 0.001) were independent predictors. Serum sFasL level is associated with angiographically more severe CAD. Our findings suggest that sFasL level may be a biochemical surrogate of severe coronary atherosclerosis. PMID:23450131

  12. The neural processing of foreign-accented speech and its relationship to listener bias

    PubMed Central

    Yi, Han-Gyol; Smiljanic, Rajka; Chandrasekaran, Bharath

    2014-01-01

    Foreign-accented speech often presents a challenging listening condition. In addition to deviations from the target speech norms related to the inexperience of the nonnative speaker, listener characteristics may play a role in determining intelligibility levels. We have previously shown that an implicit visual bias for associating East Asian faces and foreignness predicts the listeners' perceptual ability to process Korean-accented English audiovisual speech (Yi et al., 2013). Here, we examine the neural mechanism underlying the influence of listener bias to foreign faces on speech perception. In a functional magnetic resonance imaging (fMRI) study, native English speakers listened to native- and Korean-accented English sentences, with or without faces. The participants' Asian-foreign association was measured using an implicit association test (IAT), conducted outside the scanner. We found that foreign-accented speech evoked greater activity in the bilateral primary auditory cortices and the inferior frontal gyri, potentially reflecting greater computational demand. Higher IAT scores, indicating greater bias, were associated with increased BOLD response to foreign-accented speech with faces in the primary auditory cortex, the early node for spectrotemporal analysis. We conclude the following: (1) foreign-accented speech perception places greater demand on the neural systems underlying speech perception; (2) face of the talker can exaggerate the perceived foreignness of foreign-accented speech; (3) implicit Asian-foreign association is associated with decreased neural efficiency in early spectrotemporal processing. PMID:25339883

  13. Evaluating the effects of bilingual dominance and language mode on overall degree of foreign accent

    NASA Astrophysics Data System (ADS)

    Imai, Satomi; Flege, James E.; Mackay, Ian R. A.

    2004-05-01

    This study evaluated the influence of bilingual dominance and language mode on overall degree of perceived foreign accent. Three groups of Italian-English bilinguals (n=12 each) were selected according to their ratio of self-rated English/Italian proficiency: English-dominant, balanced, or Italian-dominant. Language mode was manipulated by having participants repeat English phrases before and after similar Italian phrases (E1, E2) and then intermixed with Italian phrases (E3). Native English (NE) listeners rated four English phrases spoken by the bilinguals and 12 age-matched NE controls using a scale that ranged from 1 (strong foreign accent) to 9 (no foreign accent). We hypothesized that if switching into the native language (here, Italian) adversely affects pronunciation of the second language (English), the third repetitions of the English phrases (E3) should be more strongly foreign-accented than the first repetitions (E1). The foreign accent ratings decreased significantly in the following order: NE > English-dominant > balanced > Italian-dominant. That is, all three bilingual groups had detectable foreign accents, and strength of accent depended on bilingual dominance. The language mode effect was significant only for one of the four phrases examined, perhaps because it (mozzarella cheese) has distinctly different phonetic renditions in English and Italian. [Work supported by NIH.

  14. Pitch structure, but not selective attention, affects accent weightings in metrical grouping.

    PubMed

    Prince, Jon B

    2014-10-01

    Among other cues, pitch and temporal accents contribute to grouping in musical sequences. However, exactly how they combine remains unclear, possibly because of the role of structural organization. In 3 experiments, participants rated the perceived metrical grouping of sequences that either adhered to the rules of tonal Western musical pitch structure (musical key) or did not (atonal). The tonal status of sequences did not provide any grouping cues and was irrelevant to the task. Experiment 1 established equally strong levels of pitch leap accents and duration accents in baseline conditions, which were then recombined in subsequent experiments. Neither accent type was stronger or weaker for tonal and atonal contexts. In Experiment 2, pitch leap accents dominated over duration accents, but the extent of this advantage was greater when sequences were tonal. Experiment 3 ruled out an attentional origin of this effect by replicating this finding while explicitly manipulating attention to pitch or duration accents between participant groups. Overall, the presence of tonal pitch structure made the dimension of pitch more salient at the expense of time. These findings support a dimensional salience framework in which the presence of organizational structure prioritizes the processing of the more structured dimension regardless of task relevance, independent from psychophysical difficulty, and impervious to attentional allocation.

  15. Programmed Cell Death of Embryonic Motoneurons Triggered through the FAS Death Receptor

    PubMed Central

    Raoul, Cédric; Henderson, Christopher E.; Pettmann, Brigitte

    1999-01-01

    About 50% of spinal motoneurons undergo programmed cell death (PCD) after target contact, but little is known about how this process is initiated. Embryonic motoneurons coexpress the death receptor Fas and its ligand FasL at the stage at which PCD is about to begin. In the absence of trophic factors, many motoneurons die in culture within 2 d. Most (75%) of these were saved by Fas-Fc receptor body, which blocks interactions between Fas and FasL, or by the caspase-8 inhibitor tetrapeptide IETD. Therefore, activation of Fas by endogenous FasL underlies cell death induced by trophic deprivation. In the presence of neurotrophic factors, exogenous Fas activators such as soluble FasL or anti-Fas antibodies triggered PCD of 40–50% of purified motoneurons over the following 3–5 d; this treatment led to activation of caspase-3, and was blocked by IETD. Sensitivity to Fas activation is regulated: motoneurons cultured for 3 d with neurotrophic factors became completely resistant. Levels of Fas expressed by motoneurons varied little, but FasL was upregulated in the absence of neurotrophic factors. Motoneurons resistant to Fas activation expressed high levels of FLICE-inhibitory protein (FLIP), an endogenous inhibitor of caspase-8 activation. Our results suggest that Fas can act as a driving force for motoneuron PCD, and raise the possibility that active triggering of PCD may contribute to motoneuron loss during normal development and/or in pathological situations. PMID:10579724

  16. Mutation of FAS, XIAP, and UNC13D genes in a patient with a complex lymphoproliferative phenotype.

    PubMed

    Boggio, Elena; Aricò, Maurizio; Melensi, Matteo; Dianzani, Irma; Ramenghi, Ugo; Dianzani, Umberto; Chiocchetti, Annalisa

    2013-10-01

    This article presents a case report for a child presenting with mixed clinical features of autoimmune lymphoproliferative syndrome (ALPS), familial hemophagocytic lymphohistiocytosis (FHL), and X-linked lymphoproliferative (XLP) disease. From 6 months, he exhibited splenomegaly and lymphoadenopathy and from 4 years, he showed recurrent severe autoimmune hemocytopenia and sepsislike bouts of fever, from which he eventually died at the age of 12. Intriguingly, the patient carried mutations in FAS, XIAP, and UNC13D genes, which are involved in ALPS, XLP disease, and FHL, respectively. These mutations were inherited from the mother, who had rheumatoid arthritis but no signs of ALPS. A role for other modifying genes was suggested by the finding that the healthy father exhibited defective Fas function, without mutation of the FAS gene, and had transmitted to the patient an osteopontin (OPN) gene variant previously associated with ALPS. Therefore, several genes might influence the disease outcome in this family. In vitro analyses revealed that the FAS and the XIAP mutations decreased expression of the corresponding proteins, and the UNC13D mutation decreased granule secretion and Munc interaction with Rab-27a. These findings suggest that overlap may exist between ALPS, FHL, and XLP disease, in accordance with the notion that FHL and XLP disease are due to defective natural killer (NK)/NK T-cell function, which involves Fas. Therefore, we propose that NK cell defects should be evaluated in patients with ALPS-like characteristics, and hematopoietic stem cell transplantation should be considered in individuals with severe refractory cytopenia and FHL-like manifestations.

  17. Fetal Alcohol Syndrome and Fetal Alcohol Effects: Principles for Educators.

    ERIC Educational Resources Information Center

    Burgess,Donna M.; Streissguth, Ann P.

    1992-01-01

    Fetal alcohol syndrome (FAS), the leading cause of mental retardation, often goes unrecognized because of social and emotional taboos about alcohol and alcoholism. This article describes medical and behavioral characteristics of FAS children and describes guiding principles for educators, based on early intervention, teaching communication and…

  18. Fetal Alcohol Syndrome and Fetal Alcohol Effects in Child Development.

    ERIC Educational Resources Information Center

    Pancratz, Diane R.

    This literature review defines Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Effects (FAE) and considers their causes, diagnoses, prevalence, and educational ramifications. Effects of alcohol during each of the trimesters of pregnancy are summarized. Specific diagnostic characteristics of FAS are listed: (1) growth deficiency, (2) a…

  19. American Indians' Knowledge about Fetal Alcohol Syndrome: An Exploratory Study.

    ERIC Educational Resources Information Center

    Shostak, Myra; Brown, Lester B.

    1995-01-01

    A survey examined knowledge about fetal alcohol syndrome (FAS) and about the effects of prenatal maternal drinking on the fetus among 76 American Indians in Los Angeles, including undergraduate and graduate students and participants in a residential alcohol treatment program. Also reviews the literature on FAS symptoms, outcomes, and incidence,…

  20. Fetal Alcohol Syndrome and the Developing Socio-Emotional Brain

    ERIC Educational Resources Information Center

    Niccols, Alison

    2007-01-01

    Fetal alcohol syndrome (FAS) is currently recognized as the most common known cause of mental retardation, affecting from 1 to 7 per 1000 live-born infants. Individuals with FAS suffer from changes in brain structure, cognitive impairments, and behavior problems. Researchers investigating neuropsychological functioning have identified deficits in…

  1. Behavioral Aspects of Fetal Alcohol Syndrome. Mountain Plains Information Bulletin.

    ERIC Educational Resources Information Center

    Rice, Karen Stuut

    This paper discusses the symptoms, causes, and diagnosis of fetal alcohol syndrome (FAS) and fetal alcohol effects (FAE). It then presents information from biological and adopted parents of 14 individuals (ages 4-23 years) diagnosed with FAS or FAE, based on a parent survey concerning behavioral and educational histories of their children.…

  2. Polymorphisms in FAS and CASP8 genes may contribute to the development of ALPS phenotype: a study in 25 patients with probable ALPS.

    PubMed

    Tan, Çağman; Özgül, Rıza Köksal; Çağdaş Ayvaz, Deniz; Tezcan, İlhan; Sanal, Özden

    2015-01-01

    Defects in genes that have role in apoptotic pathways result in development of Autoimmune Lymphoproliferative Syndrome (ALPS) and ALPS related disorders. Germline and somatic FAS mutations, FASL and CASP10 mutations constitute other genetic defects in ALPS. Patients who fulfill ALPS diagnostic criteria and do not have any identified known disease causing mutations are classified as ALPS-unknown or ALPS phenotype and comprise about one third of all patients. CASP8, NRAS and KRAS gene mutations were reported for ALPS related diseases. We performed DNA sequence analysis in 25 unrelated patients with probable ALPS for FAS, FASL and CASP8 gene defects. Pathogenic mutations could not be found in the FAS, FASL and CASP8 genes. However, we found that the frequencies of SNPs rs2234978 and rs1045487 of FAS and CASP8 genes were significantly higher in the patients. Our results suggest that CASP8 and FAS gene polymorphisms in particular, may contribute to the susceptibility to development of ALPS phenotype.

  3. Dysregulation of autoimmunity caused by silica exposure and alteration of Fas-mediated apoptosis in T lymphocytes derived from silicosis patients.

    PubMed

    Otsuki, T; Hayashi, H; Nishimura, Y; Hyodo, F; Maeda, M; Kumagai, N; Miura, Y; Kusaka, M; Uragami, K

    2011-01-01

    Silicosis patients suffer from pulmonary fibrosis caused by silica inhalation, as well as autoimmune diseases known as the adjuvant effects of silica. Caplan syndrome complicated with rheumatoid arthritis (RA) is well known epidemiologically, and the incidence of complicated systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and antineutrophilic cytoplasmic antibody (ANCA)-related nephritis have been reported frequently in silicosis patients. To explore the detailed mechanisms of silica-induced dysregulation of autoimmunity, we had focused on Fas/CD95 and Fas-mediated apoptosis because Fas is one of the most important molecules regarding apoptosis of lymphocytes and its alteration makes some T cells survive longer. Additionally, if the long-survived T cells include the self-recognizing T-cell clones, it is easily thought that autoimmune diseases will appear in this situation. Furthermore, regulatory T cells (Treg) showing CD4+25+ and forkhead box P3 (FoxP3)-positive have been a central player in regulating activation of self- and foreign-antigen recognizing T cells, and it has been reported that activation of Treg causes its higher expression of Fas/CD95. Thus, in this review, we introduce the alteration of Fas and related molecules as found in silicosis and also present the Treg function of the CD4+25+ fraction in peripheral blood mononuclear cells derived from silicosis patients.

  4. Induction of Fas receptor and Fas ligand by nodularin is mediated by NF-{kappa}B in HepG2 cells

    SciTech Connect

    Feng Gong; Li Ying; Bai Yansheng

    2011-03-15

    Nodularin is a natural toxin with multiple features, including inhibitor of protein phosphatases 1 and 2A as well as tumor initiator and promoter. One unique feature of nodularin is that this chemical is a hepatotoxin. It can accumulate into the liver after contact and lead to severe damage to hepatocyte, such as apoptosis. Fas receptor (Fas) and Fas ligand (FasL) system is a critical signaling network triggering apoptosis. In current study, we investigated whether nodularin can induce Fas and FasL expression in HepG2 cell, a well used in vitro model for the study of human hepatocytes. Our data showed nodularin induced Fas and FasL expression, at both mRNA and protein level, in a time- and dose-dependent manner. We also found nodularin induced apoptosis at the concentration and incubation time that Fas and FasL were significantly induced. Neutralizing antibody to FasL reduced nodularin-induced apoptosis. Further studies demonstrated that nodularin promoted nuclear translocation and activation of p65 subunit of NF-{kappa}B. By applying siRNA targeting p65, which knocked down p65 in HepG2 cells, we successfully impaired the activation of NF-{kappa}B by nodularin. In these p65 knockdown cells, we observed that Fas and FasL expression and apoptosis induced by nodularin were significantly reduced. These findings suggest the induction of Fas and FasL expression and thus cell apoptosis in HepG2 cells by nodularin is mediated through NF-{kappa}B pathway.

  5. Fast neutrons-induced apoptosis is Fas-independent in lymphoblastoid cells

    SciTech Connect

    Fischer, Barbara; Benzina, Sami; Jeannequin, Pierre; Dufour, Patrick; Bergerat, Jean-Pierre; Denis, Jean-Marc; Gueulette, John; Bischoff, Pierre L. . E-mail: Pierre.Bischoff@ircad.u-strasbg.fr

    2005-08-26

    We have previously shown that ionizing radiation-induced apoptosis in human lymphoblastoid cells differs according to their p53 status, and that caspase 8-mediated cleavage of BID is involved in the p53-dependent pathway. In the present study, we investigated the role of Fas signaling in caspase 8 activation induced by fast neutrons irradiation in these cells. Fas and FasL expression was assessed by flow cytometry and by immunoblot. We also measured Fas aggregation after irradiation by fluorescence microscopy. We found a decrease of Fas expression after irradiation, but no change in Fas ligand expression. We also showed that, in contrast to the stimulation of Fas by an agonistic antibody, Fas aggregation did not occur after irradiation. Altogether, our data strongly suggest that fast neutrons induced-apoptosis is Fas-independent, even in p53-dependent apoptosis.

  6. Fas-activated serine/threonine kinase (FAST K) synergizes with TIA-1/TIAR proteins to regulate Fas alternative splicing.

    PubMed

    Izquierdo, José M; Valcárcel, Juan

    2007-01-19

    The factors and mechanisms that mediate the effects of intracellular signaling cascades on alternative pre-mRNA splicing are poorly understood. TIA-1 (T-cell intracellular antigen 1) and TIAR (TIA-1-related) proteins regulate alternative pre-mRNA splicing by promoting the use of suboptimal 5' splice sites followed by uridine-rich intronic enhancer sequences. These proteins promote, for example, inclusion of Fas receptor exon 6, which leads to an mRNA encoding a pro-apoptotic form of the receptor at the expense of the form that skips exon 6, which encodes an anti-apoptotic form. Fas-activated serine/threonine kinase (FAST K) is known to interact with and phosphorylate TIA-1. Here we have tested the possibility that FAST K influences alternative pre-mRNA splicing by affecting the activity of TIA-1/TIAR. Depletion of FAST K form Jurkat cells leads to skipping of exon 6 from endogenous Fas transcripts. Conversely, FAST K overexpression enhances exon 6 inclusion of Fas reporters transfected in HeLa cells. Consistent with the possibility that the effects of FAST K are mediated by changes in the function of TIA-1/TIAR, the effects of FAST K overexpression (i) are largely suppressed by depletion of TIA-1 and TIAR and (ii) are significantly compromised by mutation of a TIA-1/TIAR-responsive enhancer present downstream of exon 6 5' splice site. Furthermore, in vitro phosphorylation of TIA-1 by FAST K results in enhanced U1 snRNP recruitment. Interestingly, this enhancement is not due to increased binding of TIA-1 to the pre-mRNA. Taken together, the results connect Fas signaling with the activity of splicing factors that modulate Fas alternative splicing, suggesting the existence of an autoregulatory loop that could serve to amplify Fas responses.

  7. Fas ligand enhances hematopoietic cell engraftment through abrogation of alloimmune responses and nonimmunogenic interactions.

    PubMed

    Pearl-Yafe, Michal; Yolcu, Esma S; Stein, Jerry; Kaplan, Ofer; Yaniv, Isaac; Shirwan, Haval; Askenasy, Nadir

    2007-06-01

    Early after transplantation, donor lineage-negative bone marrow cells (lin(-) BMC) constitutively upregulated their expression of Fas ligand (FasL), suggesting an involvement of the Fas/FasL axis in engraftment. Following the observation of impaired engraftment in the presence of a dysfunctional Fas/FasL axis in FasL-defective (gld) donors or Fas-defective (lpr) recipients, we expressed a noncleavable FasL chimeric protein on the surface of donor lin(-) BMC. Despite a short life span of the protein in vivo, expression of FasL on the surface of all the donor lin(-) BMC improved the efficiency of engraftment twofold. The FasL-coated donor cells efficiently blunted the host alloimmune responses in primary recipients and retained their hematopoietic reconstituting potential in secondary transplants. Surprisingly, FasL protein improved the efficiency of engraftment in syngeneic transplants. The deficient engraftment in lpr recipients was not reversed in chimeric mice with Fas(-) stroma and Fas(+) BMC, demonstrating that the host marrow stroma was also a target of donor cell FasL. Hematopoietic stem and progenitor cells are insensitive to Fas-mediated apoptosis and thus can exploit the constitutive expression of FasL to exert potent veto activities in the early stages of engraftment. Manipulation of the donor cells using ectopic FasL protein accentuated the immunogenic and nonimmunogenic interactions between the donor cells and the host, alleviating the requirement for a megadose of transplanted cells to achieve a potent veto effect. Disclosure of potential conflicts of interest is found at the end of this article.

  8. Does Imitation Facilitate Word Recognition in a Non-Native Regional Accent?

    PubMed Central

    Nguyen, Noël; Dufour, Sophie; Brunellière, Angèle

    2012-01-01

    We asked to what extent phonetic convergence across speakers may facilitate later word recognition. Northern-French participants showed both a clear phonetic convergence effect toward Southern French in a word repetition task, and a bias toward the phonemic system of their own variety in the recognition of single words. Perceptual adaptation to a non-native accent may be difficult when the native accent has a phonemic contrast that is associated with a single phonemic category in the non-native accent. Convergence toward a speaker of a non-native accent in production may not prevent each speaker’s native variety to prevail in word identification. Imitation has been found in previous studies to contribute to predicting upcoming words in sentences in adverse listening conditions, but may play a more limited role in the recognition of single words. PMID:23162514

  9. FasParser: a package for manipulating sequence data.

    PubMed

    Sun, Yan-Bo

    2017-03-18

    A computer software package called 'FasParser' was developed for manipulating sequence data. It can be used on personal computers to perform series of analyses, including counting and viewing differences between two sequences at both DNA and codon levels, identifying overlapping regions between two alignments, sorting of sequences according to their IDs or lengths, concatenating sequences of multiple loci for a particular set of samples, translating nucleotide sequences to amino acids, and constructing alignments in several different formats, as well as some extracting and filtrating of data for a particular FASTA file. Majority of these functions can be run in a batch mode, which is very useful for analyzing large data sets. This package can be used by a broad audience, and is designed for researchers that do not have programming experience in sequence analyses. The GUI version of FasParser can be downloaded from https://github.com/Sun-Yanbo/FasParser, free of charge.

  10. Fluoride reduced the immune privileged function of mouse Sertoli cells via the regulation of Fas/FasL system.

    PubMed

    Sun, Zilong; Nie, Qingli; Zhang, Lianjie; Niu, Ruiyan; Wang, Jundong; Wang, Shaolin

    2017-02-01

    Previous investigations have demonstrated the adverse impacts of fluoride on Sertoli cells (SCs), such as oxidative stress and apoptosis. SCs are the crucial cellular components that can create the immune privileged environment in testis. However, the effect of fluoride on SCs immune privilege is unknown. In this study, mouse SCs were exposed to sodium fluoride with varying concentrations of 10(-5), 10(-4), and 10(-3) mol/L to establish the model of fluoride-treated SCs (F-SCs) in vitro. After 48 h of incubation, F-SCs were transplanted underneath the kidney capsule of mice for 21 days, or cocultured with spleen lymphocytes for another 48 h. Immunohistochemical analysis of GATA4 in SCs grafts underneath kidney capsule presented less SCs distribution and obvious immune cell infiltration in F-SCs groups. In addition, the levels of FasL protein and mRNA in non-cocultured F-SCs decreased with the increase of fluoride concentration. When cocultured with F-SCs, lymphocytes presented significantly high cell viability and low apoptosis in F-SCs groups. Protein and mRNA expressions of FasL in cocultured F-SCs and Fas in lymphocytes were reduced, and the caspase 8 and caspase 3 mRNA levels were also decreased in fluoride groups in a dose-dependent manner. These findings indicated that fluoride influenced the testicular immune privilege through disturbing the Fas/FasL system.

  11. Sialylation of the Fas Death Receptor by ST6Gal-I Provides Protection against Fas-mediated Apoptosis in Colon Carcinoma Cells*

    PubMed Central

    Swindall, Amanda F.; Bellis, Susan L.

    2011-01-01

    The glycosyltransferase, ST6Gal-I, adds sialic acid in an α2–6 linkage to the N-glycans of membrane and secreted glycoproteins. Up-regulation of ST6Gal-I occurs in many cancers, including colon carcinoma, and correlates with metastasis and poor prognosis. However, mechanisms by which ST6Gal-I facilitates tumor progression remain poorly understood due to limited knowledge of enzyme substrates. Herein we identify the death receptor, Fas (CD95), as an ST6Gal-I substrate, and show that α2–6 sialylation of Fas confers protection against Fas-mediated apoptosis. Intriguingly, differences in ST6Gal-I activity do not affect the function of DR4 or DR5 death receptors upon treatment with TRAIL, implicating a selective effect of ST6Gal-I on the Fas receptor. Using ST6Gal-I knockdown and forced overexpression colon carcinoma cell models, we find that α2–6 sialylation of Fas prevents apoptosis stimulated by FasL as well as the Fas-activating antibody, CH11, as evidenced by decreased activation of caspases 8 and 3. We also show that α2–6 sialylation of Fas does not alter the binding of CH11, but rather inhibits the capacity of Fas to induce apoptosis by blocking the association of FADD with Fas cytoplasmic tails, an event that initiates death-inducing signaling complex formation. Furthermore, α2–6 sialylation of Fas inhibits Fas internalization, which is required for apoptotic signaling. Although dysregulated Fas activity is a well known mechanism through which tumors evade apoptosis, the current study is the first to link Fas insensitivity to the actions of a specific sialyltransferase. This finding establishes a new paradigm by which death receptor function is impaired for the self-protection of tumors against apoptosis. PMID:21550977

  12. Effects and modeling of phonetic and acoustic confusions in accented speech

    NASA Astrophysics Data System (ADS)

    Fung, Pascale; Liu, Yi

    2005-11-01

    Accented speech recognition is more challenging than standard speech recognition due to the effects of phonetic and acoustic confusions. Phonetic confusion in accented speech occurs when an expected phone is pronounced as a different one, which leads to erroneous recognition. Acoustic confusion occurs when the pronounced phone is found to lie acoustically between two baseform models and can be equally recognized as either one. We propose that it is necessary to analyze and model these confusions separately in order to improve accented speech recognition without degrading standard speech recognition. Since low phonetic confusion units in accented speech do not give rise to automatic speech recognition errors, we focus on analyzing and reducing phonetic and acoustic confusability under high phonetic confusion conditions. We propose using likelihood ratio test to measure phonetic confusion, and asymmetric acoustic distance to measure acoustic confusion. Only accent-specific phonetic units with low acoustic confusion are used in an augmented pronunciation dictionary, while phonetic units with high acoustic confusion are reconstructed using decision tree merging. Experimental results show that our approach is effective and superior to methods modeling phonetic confusion or acoustic confusion alone in accented speech, with a significant 5.7% absolute WER reduction, without degrading standard speech recognition.

  13. Recognition of accented English in quiet and noise by younger and older listeners

    PubMed Central

    Gordon-Salant, Sandra; Yeni-Komshian, Grace H.; Fitzgibbons, Peter J.

    2010-01-01

    This study investigated the effects of age and hearing loss on perception of accented speech presented in quiet and noise. The relative importance of alterations in phonetic segments vs. temporal patterns in a carrier phrase with accented speech also was examined. English sentences recorded by a native English speaker and a native Spanish speaker, together with hybrid sentences that varied the native language of the speaker of the carrier phrase and the final target word of the sentence were presented to younger and older listeners with normal hearing and older listeners with hearing loss in quiet and noise. Effects of age and hearing loss were observed in both listening environments, but varied with speaker accent. All groups exhibited lower recognition performance for the final target word spoken by the accented speaker compared to that spoken by the native speaker, indicating that alterations in segmental cues due to accent play a prominent role in intelligibility. Effects of the carrier phrase were minimal. The findings indicate that recognition of accented speech, especially in noise, is a particularly challenging communication task for older people. PMID:21110610

  14. The way you say it, the way I feel it: emotional word processing in accented speech

    PubMed Central

    Hatzidaki, Anna; Baus, Cristina; Costa, Albert

    2015-01-01

    The present study examined whether processing words with affective connotations in a listener's native language may be modulated by accented speech. To address this question, we used the Event Related Potential (ERP) technique and recorded the cerebral activity of Spanish native listeners, who performed a semantic categorization task, while listening to positive, negative and neutral words produced in standard Spanish or in four foreign accents. The behavioral results yielded longer latencies for emotional than for neutral words in both native and foreign-accented speech, with no difference between positive and negative words. The electrophysiological results replicated previous findings from the emotional language literature, with the amplitude of the Late Positive Complex (LPC), associated with emotional language processing, being larger (more positive) for emotional than for neutral words at posterior scalp sites. Interestingly, foreign-accented speech was found to interfere with the processing of positive valence and go along with a negativity bias, possibly suggesting heightened attention to negative words. The manipulation employed in the present study provides an interesting perspective on the effects of accented speech on processing affective-laden information. It shows that higher order semantic processes that involve emotion-related aspects are sensitive to a speaker's accent. PMID:25870577

  15. Prosodic evaluation of accent distributions in spoken news bulletins of Flemish newsreaders.

    PubMed

    Swerts, Marc; Marsi, Erwin

    2012-10-01

    The current article describes research on whether the goodness of a particular speaking style correlates with the way speakers distribute pitch accents in their speech. Study 1 analyzed two Flemish newsreaders, who, according to poll ratings, had previously been judged to represent a good vs bad speaker. A perception study in which participants had to assess the quality of spoken paragraphs produced by either of the two speakers confirmed that one speaker was rated as significantly and consistently better than the other one. An exploration of the accent distributions in those paragraphs showed that the accent distributions of the better speaker were more similar to the ones of a gold standard, i.e., the accent distributions as predicted by two independent intonation experts. Study 2 compared synthetic versions of a selection of the paragraphs of study 1, generated by a Dutch text-to-speech system. It compared three basically identical versions of the texts, except that they had different accent distributions according to the gold standard, or to distributions as observed in the productions of the two newsreaders. A perception study revealed that the versions of the bad speaker were rated as being significantly worse than the other versions. The two studies thus show that variation in accent distribution can indeed affect the way spoken texts are assessed in terms of their perceived quality.

  16. Fas Protects Breast Cancer Stem Cells from Death

    DTIC Science & Technology

    2014-10-01

    apoptosis and DICE in breast cancer cells, with many potential therapeutical applications. I could also demonstrate the involvement of miRNA in the...process. Moreover, I have developed a novel plasmid-based tool to isolate BCSCS by the activity of miRNAs , and I am going to optimize and test the...relevance of its use in the next reporting period. 15. SUBJECT TERMS Fas, FasL, Cancer, Cancer Stem cells, Apoptosis, miRNA , EMT, cell death. 16

  17. FAS 33: accurately recording effects of changing prices.

    PubMed

    Sage, L G

    1987-02-01

    FAS 33 addresses the problem of distortion in conventional historical cost financial statements because of changing prices. It requires 1300 business enterprises to report selected changing price data on a supplementary basis. It has been demonstrated that it is also feasible and beneficial for hospitals to present price disclosures as supplementary information to their financial statements. The possible application of FAS 33 is supported on the basis that the accounting and reporting methods of healthcare institutions are similar to the accounting and reporting practices of profit-seeking entities.

  18. Structural and biophysical characterization of the interactions between the death domain of Fas receptor and calmodulin.

    PubMed

    Fernandez, Timothy F; Samal, Alexandra B; Bedwell, Gregory J; Chen, Yabing; Saad, Jamil S

    2013-07-26

    The extrinsic apoptotic pathway is initiated by cell surface death receptors such as Fas. Engagement of Fas by Fas ligand triggers a conformational change that allows Fas to interact with adaptor protein Fas-associated death domain (FADD) via the death domain, which recruits downstream signaling proteins to form the death-inducing signaling complex (DISC). Previous studies have shown that calmodulin (CaM) is recruited into the DISC in cholangiocarcinoma cells, suggesting a novel role of CaM in Fas-mediated signaling. CaM antagonists induce apoptosis through a Fas-related mechanism in cholangiocarcinoma and other cancer cell lines possibly by inhibiting Fas-CaM interactions. The structural determinants of Fas-CaM interaction and the underlying molecular mechanisms of inhibition, however, are unknown. Here we employed NMR and biophysical techniques to elucidate these mechanisms. Our data show that CaM binds to the death domain of Fas (FasDD) with an apparent dissociation constant (Kd) of ~2 μM and 2:1 CaM:FasDD stoichiometry. The interactions between FasDD and CaM are endothermic and entropically driven, suggesting that hydrophobic contacts are critical for binding. We also show that both the N- and C-terminal lobes of CaM are important for binding. NMR and surface plasmon resonance data show that three CaM antagonists (N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide, tamoxifen, and trifluoperazine) greatly inhibit Fas-CaM interactions by blocking the Fas-binding site on CaM. Our findings provide the first structural evidence for Fas-CaM interactions and mechanism of inhibition and provide new insight into the molecular basis for a novel role of CaM in regulating Fas-mediated apoptosis.

  19. Up-regulation of Fas (CD95) expression in tumour cells in vivo

    PubMed Central

    Peshes-Yaloz, Naama; Rosen, Dalia; Sondel, Paul M; Krammer, Peter H; Berke, Gideon

    2007-01-01

    Both the function and regulation of Fas expression in tumours is poorly understood. Our laboratory has reported that cultured, low Fas-expressing tumours undergo massive, yet reversible, up-regulation of cell surface Fas expression when injected into mice. The present study was aimed at determining what causes this enhanced Fas expression and whether the newly expressed Fas functions as a death receptor. Newly expressed Fas is indeed capable of inducing apoptosis. Based on our observation that Fas induction is reduced when tumour cells are injected into immune-deficient mice, we propose that Fas up-regulation in vivo involves the host's immune system. Accordingly, Fas up-regulation occurs in vitro when low Fas-expressing tumour cells are cocultured with lymphoid cells. Furthermore ascitic fluid extracted from tumour-bearing mice trigger Fas up-regulation in low Fas expressing tumours. This last finding suggests that a soluble factor(s) mediates induction of Fas expression. The best candidate for this soluble factor is nitric oxide (NO) based on the following observations: the factor in the ascites is unstable; Fas expression is induced to a lesser degree after injection into inducible NO synthase (NOS)-deficient (iNOS–/–) mice when compared to control mice; similarly, coculture with iNOS–/– splenocytes induces Fas less effectively than coculture with control splenocytes; and finally, the NO donor SNAP induces considerable Fas up-regulation in tumours in vitro. Our model is that host lymphoid cells in response to a tumour increase NO synthesis, which in turn causes enhanced Fas expression in the tumour. PMID:17343612

  20. Mitochondria-independent induction of Fas-mediated apoptosis by MSSP.

    PubMed

    Nomura, Jun; Matsumoto, Ken-Ichi; Iguchi-Ariga, Sanae M M; Ariga, Hiroyoshi

    2005-11-01

    Fas-mediated apoptosis has been proposed to play an important role in homeostasis. Fas triggers apoptosis after stimulation by its ligand FasL or the Fas ligand agonist anti-Fas antibody through a mitochondria-dependent or -independent pathway, and MSSP has been identified as a transcription factor that regulates the c-myc gene and was later found to positively or negatively regulate a variety of genes, including alpha-smooth actin, MHC class I, MHC class 2 and the thyrotropin receptor. We further found that expression of the Fas gene was repressed, resulting in abrogation of the Fas-mediated induction of apoptosis both in Mssp-knockout mice and primary thymocytes. MSSP was then found to stimulate promoter activity of the Fas gene by binding to a specific region. In this study, to identify the MSSP-dependent Fas-induced apoptosis pathway, primary fibroblasts from MSSP (+/+) and MSSP (-/-) cells were treated with the combination of interleukin 1-beta and interferon-gamma and expression of the Fas gene was examined. The results showed that the Fas gene was expressed at the same levels in the two cell types. Furthermore, when these cells were treated with the anti-Fas antibody, it was found that cytochrome C was not released in the cytosol and that activations of caspase 8 and caspase 3 occurred in primary fibroblasts from MSSP (+/+) cells but not from MSSP (-/-) cells. These results indicate that Fas-mediated apoptosis induced by MSSP occurs independently of mitochondria.

  1. Fetal Alcohol Syndrome: Characteristics, Prevention, Treatment and Long Term Outlook.

    ERIC Educational Resources Information Center

    Seward, Cynthia A.; Barber, William H.

    1991-01-01

    This article discusses fetal alcohol syndrome (FAS) including causes, common characteristics, secondary characteristics, prevention, and treatment. Economic implications are noted which suggest that treatment costs are 100 times the cost of prevention programs. (DB)

  2. Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction

    PubMed Central

    Cruz, Anthony C.; Ramaswamy, Madhu; Ouyang, Claudia; Klebanoff, Christopher A.; Sengupta, Prabuddha; Yamamoto, Tori N.; Meylan, Françoise; Thomas, Stacy K.; Richoz, Nathan; Eil, Robert; Price, Susan; Casellas, Rafael; Rao, V. Koneti; Lippincott-Schwartz, Jennifer; Restifo, Nicholas P.; Siegel, Richard M.

    2016-01-01

    Mutations affecting the apoptosis-inducing function of the Fas/CD95 TNF-family receptor result in autoimmune and lymphoproliferative disease. However, Fas can also costimulate T-cell activation and promote tumour cell growth and metastasis. Palmitoylation at a membrane proximal cysteine residue enables Fas to localize to lipid raft microdomains and induce apoptosis in cell lines. Here, we show that a palmitoylation-defective Fas C194V mutant is defective in inducing apoptosis in primary mouse T cells, B cells and dendritic cells, while retaining the ability to enhance naive T-cell differentiation. Despite inability to efficiently induce cell death, the Fas C194V receptor prevents the lymphoaccumulation and autoimmunity that develops in Fas-deficient mice. These findings indicate that induction of apoptosis through Fas is dependent on receptor palmitoylation in primary immune cells, and Fas may prevent autoimmunity by mechanisms other than inducing apoptosis. PMID:28008916

  3. Superoxide anion is a natural inhibitor of FAS-mediated cell death.

    PubMed Central

    Clément, M V; Stamenkovic, I

    1996-01-01

    The cell surface receptor Fas is a major trigger of apoptosis. However, expression of the Fas receptor in many tumor cell types does not correlate with sensitivity to Fas-mediated cell death. Because a prooxidant state is a common feature of tumor cells, we examined the role of intracellular reactive oxygen intermediates in the regulation of Fas-mediated cytotoxicity. Our results show that an oxidative stress induced by increasing the intracellular superoxide anion (O2-) concentration can abrogate Fas-mediated apoptosis in cells which are constitutively sensitive to Fas. Conversely, an O2- concentration decrease is observed to sensitize cells which are naturally resistant to Fas signals. These observations suggest that intracellular O2- may play a key role in regulating cell sensitivity to a potentially lethal signal and provide tumor cells with a natural, inducible mechanism of resistance to Fas-mediated apoptosis. Images PMID:8617197

  4. Ceramide mediates FasL-induced caspase 8 activation in colon carcinoma cells to enhance FasL-induced cytotoxicity by tumor-specific cytotoxic T lymphocytes

    PubMed Central

    Coe, Genevieve L.; Redd, Priscilla S.; Paschall, Amy V.; Lu, Chunwan; Gu, Lilly; Cai, Houjian; Albers, Thomas; Lebedyeva, Iryna O.; Liu, Kebin

    2016-01-01

    FasL-mediated cytotoxicity is one of the mechanisms that CTLs use to kill tumor cells. However, human colon carcinoma often deregulates the Fas signaling pathway to evade host cancer immune surveillance. We aimed at testing the hypothesis that novel ceramide analogs effectively modulate Fas function to sensitize colon carcinoma cells to FasL-induced apoptosis. We used rational design and synthesized twenty ceramide analogs as Fas function modulators. Five ceramide analogs, IG4, IG7, IG14, IG17, and IG19, exhibit low toxicity and potent activity in sensitization of human colon carcinoma cells to FasL-induced apoptosis. Functional deficiency of Fas limits both FasL and ceramide analogs in the induction of apoptosis. Ceramide enhances FasL-induced activation of the MAPK, NF-κB, and caspase 8 despite induction of potent tumor cell death. Finally, a sublethal dose of several ceramide analogs significantly increased CTL-mediated and FasL-induced apoptosis of colon carcinoma cells. We have therefore developed five novel ceramide analogs that act at a sublethal dose to enhance the efficacy of tumor-specific CTLs, and these ceramide analogs hold great promise for further development as adjunct agents in CTL-based colon cancer immunotherapy. PMID:27487939

  5. The invisible minority: revisiting the debate on foreign-accented speakers and upward mobility in the workplace.

    PubMed

    Akomolafe, Soji

    2013-01-01

    Of some of the major types of discrimination, the one that gets the least attention is national origin discrimination and in particular, accent discrimination, especially when it comes to upward mobility in the workplace. Yet, unlike other forms of discrimination, accent discrimination is rarely a subject of any robust public debate. This paper is a modest attempt to help establish a framework for understanding the relative neglect to which the discourse on accent discrimination has been subjected vis-a-vis the overall national debate on diversity. Hopefully, in the process, it will stimulate a more robust conversation on the plight of foreign-accented speakers.

  6. The Effects of Language Experience and Speech Context on the Phonetic Accommodation of English-accented Spanish Voicing.

    PubMed

    Llanos, Fernando; Francis, Alexander L

    2017-03-01

    Native speakers of Spanish with different amounts of experience with English classified stop-consonant voicing (/b/ versus /p/) across different speech accents: English-accented Spanish, native Spanish, and native English. While listeners with little experience with English classified target voicing with an English- or Spanish-like voice onset time (VOT) boundary, predicted by contextual VOT, listeners familiar with English relied on an English-like VOT boundary in an English-accented Spanish context even in the absence of clear contextual cues to English VOT. This indicates that Spanish listeners accommodated English-accented Spanish voicing differently depending on their degree of familiarization with the English norm.

  7. Amelioration of collagen-induced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer.

    PubMed Central

    Zhang, H; Yang, Y; Horton, J L; Samoilova, E B; Judge, T A; Turka, L A; Wilson, J M; Chen, Y

    1997-01-01

    Both rheumatoid arthritis and animal models of autoimmune arthritis are characterized by hyperactivation of synovial cells and hyperplasia of the synovial membrane. The activated synovial cells produce inflammatory cytokines and degradative enzymes that lead to destruction of cartilage and bones. Effective treatment of arthritis may require elimination of most or all activated synovial cells. The death factor Fas/Apo-1 and its ligand (FasL) play pivotal roles in maintaining self-tolerance and immune privilege. Fas is expressed constitutively in most tissues, and is dramatically upregulated at the site of inflammation. In both rheumatoid arthritis and animal models of autoimmune arthritis, high levels of Fas are expressed on activated synovial cells and infiltrating leukocytes in the inflamed joints. Unlike Fas, however, the levels of FasL expressed in the arthritic joints are extremely low, and most activated synovial cells survive despite high levels of Fas expression. To upregulate FasL expression in the arthritic joints, we have generated a recombinant replication-defective adenovirus carrying FasL gene; injection of the FasL virus into inflamed joints conferred high levels of FasL expression, induced apoptosis of synovial cells, and ameliorated collagen-induced arthritis in DBA/1 mice. The Fas-ligand virus also inhibited production of interferon-gamma by collagen-specific T cells. Coadministration of Fas-immunoglobulin fusion protein with the Fas-ligand virus prevented these effects, demonstrating the specificity of the Fas-ligand virus. Thus, FasL gene transfer at the site of inflammation effectively ameliorates autoimmune disease. PMID:9329958

  8. Involvement of soluble Fas Ligand in germ cell apoptosis in testis of rats undergoing autoimmune orchitis.

    PubMed

    Jacobo, Patricia Verónica; Fass, Mónica; Pérez, Cecilia Valeria; Jarazo-Dietrich, Sabrina; Lustig, Livia; Theas, María Susana

    2012-11-01

    Experimental autoimmune orchitis (EAO) is a model of chronic inflammation and infertility useful for studying immune and germ cell (GC) interactions. EAO is characterized by severe damage of seminiferous tubules (STs) with GCs that undergo apoptosis and sloughing. Based on previous results showing that Fas-Fas Ligand (L) system is one of the main mediators of apoptosis in EAO, in the present work we studied the involvement of Fas and the soluble form of FasL (sFasL) in GC death induction. EAO was induced in rats by immunization with testis homogenate and adjuvants; control (C) rats were injected with adjuvants; a group of non-immunized normal (N) rats was also studied. Activation of Fas employing an anti-Fas antibody decreased viability (trypan blue exclusion test) and induced apoptosis (TUNEL) of GCs from STs of N and EAO rats, an effect more pronounced on GCs from EAO STs. By Western blot we detected an increase in sFasL content in the testicular fluid of rats with severe EAO compared to N and C rats. By intratesticular injection of FasL conjugated to Strep-Tag molecule (FasL-Strep, BioTAGnology) and its immunofluorescent localization, we demonstrated that sFasL is able to enter the adluminal compartment of the STs. Moreover, FasL-Strep induced GC apoptosis in testicular fragments of N rats. By flow cytometry, we detected an increase in the number of membrane FasL-expressing CD4+ and CD8+ T cells in testis during EAO development but no expression of FasL by macrophages. Our results demonstrate that sFasL is locally produced in the chronically inflamed testis and that this molecule is able to enter the adluminal compartment of STs and induce apoptosis of Fas-bearing GCs.

  9. 7 CFR 1484.70 - Must Cooperators report to FAS?

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... after completion of travel (other than local travel), a Cooperator shall submit a trip report. The report must include the name(s) of the traveler(s), purpose of travel, itinerary, names and affiliations... 7 Agriculture 10 2014-01-01 2014-01-01 false Must Cooperators report to FAS? 1484.70 Section...

  10. 7 CFR 1484.70 - Must Cooperators report to FAS?

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 10 2013-01-01 2013-01-01 false Must Cooperators report to FAS? 1484.70 Section 1484.70 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT CORPORATION, DEPARTMENT OF AGRICULTURE EXPORT PROGRAMS PROGRAMS TO HELP DEVELOP FOREIGN MARKETS FOR...

  11. 7 CFR 1484.70 - Must Cooperators report to FAS?

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 10 2011-01-01 2011-01-01 false Must Cooperators report to FAS? 1484.70 Section 1484.70 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT CORPORATION, DEPARTMENT OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS PROGRAMS TO HELP DEVELOP FOREIGN MARKETS...

  12. 7 CFR 1484.30 - How does FAS formalize its working relationship with approved Cooperators?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false How does FAS formalize its working relationship with... FAS formalize its working relationship with approved Cooperators? FAS will notify each applicant in... sign the program agreement and submit the signed agreement to the Director, Marketing Operations...

  13. Trophoblasts express Fas ligand: a proposed mechanism for immune privilege in placenta and maternal invasion.

    PubMed

    Uckan, D; Steele, A; Cherry; Wang, B Y; Chamizo, W; Koutsonikolis, A; Gilbert-Barness, E; Good, R A

    1997-08-01

    Cross-linking of Fas (CD95, APO-1) and Fas ligand (FasL; CD95L) induces apoptosis of Fas-bearing cells. Recent evidence suggests that FasL. expression plays an important role in maintenance of immune privilege in murine testis and eye and in tumour escape from immune rejection in colon cancer, melanoma and hepatocellular carcinoma. Bcl-2 is a membrane protein that suppresses apoptosis in response to a variety of stimuli. In this paper we describe abundant expression of FasL protein and mRNA transcripts within the immune privileged environment of the placenta by immunohistochemistry and reverse transcription in-situ polymerase chain reaction methods. The syncytiotrophoblast layer, the main site of feto-maternal interface, and extravillous trophoblasts, demonstrated consistent immunoreactivity for FasL in term placentae. Co-occurrence of Fas and Bcl-2 were detected with a similar pattern of distribution with FasL. The TUNEL method revealed evidence of apoptosis in the placental tissues. We speculate that abundant presence of FasL in the trophoblast contributes to immune privilege in this unique environment, perhaps by fostering apoptosis of activated Fas-expressing lymphocytes of maternal origin. An apoptotic process mediated by FasL may also play a role in placental invasion during implantation and underscores similarities between the trophoblast and neoplastic cells.

  14. 7 CFR 1484.57 - Will FAS make advance payments to a Cooperator?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... an advance, FAS may require the participant to submit security in a form and amount acceptable to FAS... where a special advance is outstanding from a prior marketing plan year. Cooperators shall deposit and... reimbursement claim. All checks shall be mailed to the Director, Marketing Operations Staff, FAS, USDA....

  15. 7 CFR 1484.57 - Will FAS make advance payments to a Cooperator?

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... an advance, FAS may require the participant to submit security in a form and amount acceptable to FAS... where a special advance is outstanding from a prior marketing plan year. Cooperators shall deposit and... reimbursement claim. All checks shall be mailed to the Director, Marketing Operations Staff, FAS, USDA....

  16. 7 CFR 1484.57 - Will FAS make advance payments to a Cooperator?

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... advance, FAS may require the participant to submit security in a form and amount acceptable to FAS to... special advance is outstanding from a prior marketing plan year. Cooperators shall deposit and maintain... reimbursement claim. All checks shall be mailed to the Director, Marketing Operations Staff, FAS, USDA....

  17. Speaker and Accent Variation Are Handled Differently: Evidence in Native and Non-Native Listeners

    PubMed Central

    Kriengwatana, Buddhamas; Terry, Josephine; Chládková, Kateřina; Escudero, Paola

    2016-01-01

    Listeners are able to cope with between-speaker variability in speech that stems from anatomical sources (i.e. individual and sex differences in vocal tract size) and sociolinguistic sources (i.e. accents). We hypothesized that listeners adapt to these two types of variation differently because prior work indicates that adapting to speaker/sex variability may occur pre-lexically while adapting to accent variability may require learning from attention to explicit cues (i.e. feedback). In Experiment 1, we tested our hypothesis by training native Dutch listeners and Australian-English (AusE) listeners without any experience with Dutch or Flemish to discriminate between the Dutch vowels /I/ and /ε/ from a single speaker. We then tested their ability to classify /I/ and /ε/ vowels of a novel Dutch speaker (i.e. speaker or sex change only), or vowels of a novel Flemish speaker (i.e. speaker or sex change plus accent change). We found that both Dutch and AusE listeners could successfully categorize vowels if the change involved a speaker/sex change, but not if the change involved an accent change. When AusE listeners were given feedback on their categorization responses to the novel speaker in Experiment 2, they were able to successfully categorize vowels involving an accent change. These results suggest that adapting to accents may be a two-step process, whereby the first step involves adapting to speaker differences at a pre-lexical level, and the second step involves adapting to accent differences at a contextual level, where listeners have access to word meaning or are given feedback that allows them to appropriately adjust their perceptual category boundaries. PMID:27309889

  18. Disturbed B-lymphocyte selection in autoimmune lymphoproliferative syndrome.

    PubMed

    Janda, Ales; Schwarz, Klaus; van der Burg, Mirjam; Vach, Werner; Ijspeert, Hanna; Lorenz, Myriam Ricarda; Elgizouli, Magdeldin; Pieper, Kathrin; Fisch, Paul; Hagel, Joachim; Lorenzetti, Raquel; Seidl, Maximilian; Roesler, Joachim; Hauck, Fabian; Traggiai, Elisabetta; Speckmann, Carsten; Rensing-Ehl, Anne; Ehl, Stephan; Eibel, Hermann; Rizzi, Marta

    2016-05-05

    Fas is a transmembrane receptor involved in the maintenance of tolerance and immune homeostasis. In murine models, it has been shown to be essential for deletion of autoreactive B cells in the germinal center. The role of Fas in human B-cell selection and in development of autoimmunity in patients carrying FAS mutations is unclear. We analyzed patients with either a somatic FAS mutation or a germline FAS mutation and somatic loss-of-heterozygosity, which allows comparing the fate of B cells with impaired vs normal Fas signaling within the same individual. Class-switched memory B cells showed: accumulation of FAS-mutated B cells; failure to enrich single V, D, J genes and single V-D, D-J gene combinations of the B-cell receptor variable region; increased frequency of variable regions with higher content of positively charged amino acids; and longer CDR3 and maintenance of polyreactive specificities. Importantly, Fas-deficient switched memory B cells showed increased rates of somatic hypermutation. Our data uncover a defect in B-cell selection in patients with FAS mutations, which has implications for the understanding of the pathogenesis of autoimmunity and lymphomagenesis of autoimmune lymphoproliferative syndrome.

  19. Blockade of Fas signaling in breast cancer cells suppresses tumor growth and metastasis via disruption of Fas signaling-initiated cancer-related inflammation.

    PubMed

    Liu, Qiuyan; Tan, Qinchun; Zheng, Yuanyuan; Chen, Kun; Qian, Cheng; Li, Nan; Wang, Qingqing; Cao, Xuetao

    2014-04-18

    Mechanisms for cancer-related inflammation remain to be fully elucidated. Non-apoptotic functions of Fas signaling have been proposed to play an important role in promoting tumor progression. It has yet to be determined if targeting Fas signaling can control tumor progression through suppression of cancer-related inflammation. In the current study we found that breast cancer cells with constitutive Fas expression were resistant to apoptosis induction by agonistic anti-Fas antibody (Jo2) ligation or Fas ligand cross-linking. Higher expression of Fas in human breast cancer tissue has been significantly correlated with poorer prognosis in breast cancer patients. To determine whether blockade of Fas signaling in breast cancer could suppress tumor progression, we prepared an orthotopic xenograft mouse model with mammary cancer cells 4T1 and found that blockade of Fas signaling in 4T1 cancer cells markedly reduced tumor growth, inhibited tumor metastasis in vivo, and prolonged survival of tumor-bearing mice. Mechanistically, blockade of Fas signaling in cancer cells significantly decreased systemic or local recruitment of myeloid derived suppressor cells (MDSCs) in vivo. Furthermore, blockade of Fas signaling markedly reduced IL-6, prostaglandin E2 production from breast cancer cells by impairing p-p38, and activity of the NFκB pathway. In addition, administration of a COX-2 inhibitor and anti-IL-6 antibody significantly reduced MDSC accumulation in vivo. Therefore, blockade of Fas signaling can suppress breast cancer progression by inhibiting proinflammatory cytokine production and MDSC accumulation, indicating that Fas signaling-initiated cancer-related inflammation in breast cancer cells may be a potential target for treatment of breast cancer.

  20. Fas ligand is not only expressed in immune privileged human organs but is also coexpressed with Fas in various epithelial tissues.

    PubMed Central

    Xerri, L; Devilard, E; Hassoun, J; Mawas, C; Birg, F

    1997-01-01

    AIMS: To confirm the recent data obtained in mice, showing that the Fas ligand (FasL) is involved in the phenomenon of "immune privilege" (the apparent defect of the immune system in specific anatomical sites) and to extend this finding to humans. METHODS: The expression of FasL was analysed in a panel of histologically normal human tissues by reverse transcriptase polymerase chain reaction and Western blotting. The tissues sampled were brain, breast, bone marrow, oesophagus, kidney, liver, lung, lymph node, ovary, pancreas, pituitary gland, prostate, spleen, stomach (antrum and fundus), striated muscle, testis, thyroid, and uterus. These were obtained from patients with various neoplastic and non-neoplastic disorders; placental tissue was obtained after normal obstetric delivery, and spontaneous or voluntary abortion. RESULTS: Strong FasL expression was detected in testis and placenta. FasL expression was also detectable, although it was seen to a lesser extent, in oesophagus, prostate, lung, and uterus, which also coexpressed variable amounts of Fas mRNA or protein or both. The other organs tested for FasL expression were all negative. CONCLUSIONS: FasL in humans is expressed predominantly in immune "sanctuaries" such as testis and placenta, suggesting that, similar to mice, this expression may contribute to the immune privileged status of these organs, by preventing dangerous inflammatory responses. The coexpression of FasL and Fas in particular epithelia suggests that the physiological cell turnover of some tissues may be regulated by the Fas-FasL apoptotic pathway. Images PMID:9231156

  1. CD80 (B7.1) and CD86 (B7.2) induce EBV-transformed B cell apoptosis through the Fas/FasL pathway.

    PubMed

    Park, Ga Bin; Kim, Yeong Seok; Lee, Hyun-Kyung; Cho, Dae-Ho; Kim, Daejin; Hur, Dae Young

    2013-11-01

    CD80 and CD86 expression is strongly regulated in B cells and is induced by various stimuli (e.g., cytokines, ligation of MHC class II and CD40 ligand). Epstein-Barr virus (EBV) infection activates B lymphocytes and transforms them into lymphoblastoid cells. However, the role of CD80 and CD86 in EBV infection of B cells remains unclear. Here, we observed that cross-linking of CD80 and CD86 in EBV-transformed B cells induced apoptosis through caspase-dependent release of apoptosis-related molecules, cytochrome c and apoptosis-inducing factor (AIF) from mitochondria, because Z-VAD-fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone) and N-acetylcysteine (NAC) blocked apoptosis and disruption of mitochondria. Stimulation of CD80 and CD86 induced expression of Fas ligand (FasL) on EBV-transformed B cells and upregulated Fas and FasL expression in IM-9 cells. Apoptosis through Fas-FasL interactions was blocked by treatment of cells with ZB4, an antagonistic anti-Fas antibody. These results suggest that the co-stimulatory molecules CD80 and CD86 induced by EBV infection stimulate apoptosis of EBV-transformed lymphoblastoid B cells via the Fas/FasL pathway.

  2. When it matters how you pronounce it: the influence of regional accents on job interview outcome.

    PubMed

    Rakić, Tamara; Steffens, Melanie C; Mummendey, Amélie

    2011-11-01

    The visual dimension has featured prominently in person perception in the last 25 years. Alone, this dimension cannot give the complete 'picture' of others because language and speech (i.e., the auditory dimension) are also highly informative. Social-cognition research investigates the role of auditory information for impression formation. In a series of experiments, we tested perceived competence, hirability, and socio-intellectual status of different targets based on their regional accents. Given identical content of statements in different conditions of an alleged job interview, regional German accents (Saxon, Bavarian, and Berlin) resulted in lower perceived competence and hirability than standard German, even though the Bavarian accent at the same time resulted in higher ratings of socio-intellectual status compared to other regional accents (Experiment 1). These findings were confirmed when using a broader population sample and a 'matched guise' technique (Experiment 2). Our findings indicate that regional accents, similar to faces, can be very powerful in creating differentiated pictures of individuals.

  3. The role of accent imitation in sensorimotor integration during processing of intelligible speech

    PubMed Central

    Adank, Patti; Rueschemeyer, Shirley-Ann; Bekkering, Harold

    2013-01-01

    Recent theories on how listeners maintain perceptual invariance despite variation in the speech signal allocate a prominent role to imitation mechanisms. Notably, these simulation accounts propose that motor mechanisms support perception of ambiguous or noisy signals. Indeed, imitation of ambiguous signals, e.g., accented speech, has been found to aid effective speech comprehension. Here, we explored the possibility that imitation in speech benefits perception by increasing activation in speech perception and production areas. Participants rated the intelligibility of sentences spoken in an unfamiliar accent of Dutch in a functional Magnetic Resonance Imaging experiment. Next, participants in one group repeated the sentences in their own accent, while a second group vocally imitated the accent. Finally, both groups rated the intelligibility of accented sentences in a post-test. The neuroimaging results showed an interaction between type of training and pre- and post-test sessions in left Inferior Frontal Gyrus, Supplementary Motor Area, and left Superior Temporal Sulcus. Although alternative explanations such as task engagement and fatigue need to be considered as well, the results suggest that imitation may aid effective speech comprehension by supporting sensorimotor integration. PMID:24109447

  4. Lexically Guided Phonetic Retuning of Foreign-Accented Speech and Its Generalization

    PubMed Central

    Reinisch, Eva; Holt, Lori L.

    2014-01-01

    Listeners use lexical knowledge to retune phoneme categories. When hearing an ambiguous sound between /s/ and /f/ in lexically unambiguous contexts such as gira[s/f], listeners learn to interpret the sound as /f/ because gira[f] is a real word and gira[s] is not. Later, they apply this learning even in lexically ambiguous contexts (perceiving knife rather than nice). Although such retuning could help listeners adapt to foreign-accented speech, research has focused on single phonetic contrasts artificially manipulated to create ambiguous sounds; however, accented speech varies along many dimensions. It is therefore unclear whether analogies to adaptation to accented speech are warranted. In the present studies, the to-be-adapted ambiguous sound was embedded in a global foreign accent. In addition, conditions of cross-speaker generalization were tested with focus on the extent to which perceptual similarity between 2 speakers’ fricatives is a condition for generalization to occur. Results showed that listeners retune phoneme categories manipulated within the context of a global foreign accent, and that they generalize this short-term learning to the perception of phonemes from previously unheard speakers. However, generalization was observed only when exposure and test speakers’ fricatives were sampled across a similar perceptual space. PMID:24059846

  5. Preschool Teacher Attitude and Knowledge Regarding Fetal Alcohol Syndrome and Fetal Alcohol Effects.

    ERIC Educational Resources Information Center

    Mack, Faite R-P.

    The Centers for Disease Control estimate that each year more than 8,000 Fetal Alcohol Syndrome (FAS) babies are born, and that many more babies go undiagnosed with Fetal Alcohol Effects (FAE), a less severe condition. FAS and FAE have been identified as major contributors to poor memory, shorter attention spans, lower IQs, diminished achievement…

  6. Teaching Students with Fetal Alcohol Syndrome and Possible Prenatal Alcohol-Related Effects.

    ERIC Educational Resources Information Center

    Alberta Dept. of Education, Edmonton. Special Education Branch.

    This guide provides a review of the characteristics of children with fetal alcohol syndrome (FAS) or possible prenatal alcohol-related effects (PPAE) and describes specific intervention strategies. Section 1 offers a general review of the diagnostic procedures, the prevalence of FAS and the physical, educational, and behavioral characteristics of…

  7. Is There Evidence To Show That Fetal Alcohol Syndrome Can Be Prevented?

    ERIC Educational Resources Information Center

    Murphy-Brennan, Majella G.; Oei, Tian P. S.

    1999-01-01

    Reviews the effectiveness of prevention programs in reducing Fetal Alcohol Syndrome (FAS). Results reveal that prevention programs, to date, have been successful in raising awareness of FAS; however this awareness has not been translated into behavioral changes in high-risk drinkers as consumption levels in this group have increased. (Author/MKA)

  8. Evaluation of an Educational Program on the Fetal Alcohol Syndrome for Health Professionals.

    ERIC Educational Resources Information Center

    Russell, Marcia; And Others

    1983-01-01

    Describes knowledge, attitudes and intervention policies regarding fetal alcohol syndrome (FAS) and fetal alcohol effects among obstetricians and gynecologists (N=1,128) in New York State. Survey results showed that subjects were well-informed about FAS, and almost all advised their obstetric patients to abstain or limit their alcohol intake. (LLL)

  9. Spatial but Not Object Memory Impairments in Children with Fetal Alcohol Syndrome.

    ERIC Educational Resources Information Center

    Nadel, Lynn; Uecker, Anne

    1998-01-01

    Thirty Native American children (mean age=10.3 years), 15 identified with fetal alcohol syndrome (FAS) and 15 controls, were asked to recall places and objects in a task previously shown to be sensitive to memory skills in individuals with and without mental retardation. Children with FAS demonstrated a spatial but not an object memory impairment.…

  10. Up Front, in Hope: The Value of Early Intervention for Children with Fetal Alcohol Syndrome.

    ERIC Educational Resources Information Center

    Harwood, Maureen; Kleinfeld, Judith Smilg

    2002-01-01

    Differentiates fetal alcohol syndrome (FAS) from fetal alcohol effects (FAE) and discusses difficulties in diagnosing these conditions. Describes the effects of FAS/FAE on young children, detailing impact on sensory processing, focusing attention, and cognitive development in infants, toddlers, and preschoolers. Presents suggestions for caregivers…

  11. The Fas-FADD Death Domain Complex Structure Unravels Signalling by Receptor Clustering

    SciTech Connect

    Scott, F.; Stec, B; Pop, C; Dobaczewska, M; Lee, J; Monosov, E; Robinson, H; Salvesen, G; Schwarzenbacher, R; Riedl, S

    2009-01-01

    The death inducing signalling complex (DISC) formed by Fas receptor, FADD (Fas-associated death domain protein) and caspase 8 is a pivotal trigger of apoptosis1, 2, 3. The Fas-FADD DISC represents a receptor platform, which once assembled initiates the induction of programmed cell death. A highly oligomeric network of homotypic protein interactions comprised of the death domains of Fas and FADD is at the centre of DISC formation4, 5. Thus, characterizing the mechanistic basis for the Fas-FADD interaction is crucial for understanding DISC signalling but has remained unclear largely because of a lack of structural data. We have successfully formed and isolated the human Fas-FADD death domain complex and report the 2.7 A crystal structure. The complex shows a tetrameric arrangement of four FADD death domains bound to four Fas death domains. We show that an opening of the Fas death domain exposes the FADD binding site and simultaneously generates a Fas-Fas bridge. The result is a regulatory Fas-FADD complex bridge governed by weak protein-protein interactions revealing a model where the complex itself functions as a mechanistic switch. This switch prevents accidental DISC assembly, yet allows for highly processive DISC formation and clustering upon a sufficient stimulus. In addition to depicting a previously unknown mode of death domain interactions, these results further uncover a mechanism for receptor signalling solely by oligomerization and clustering events.

  12. Fas-induced programmed cell death is mediated by a Ras-regulated O2- synthesis.

    PubMed Central

    Gulbins, E; Brenner, B; Schlottmann, K; Welsch, J; Heinle, H; Koppenhoefer, U; Linderkamp, O; Coggeshall, K M; Lang, F

    1996-01-01

    Fas induces apoptosis in lymphocytes via a poorly defined intracellular signalling cascade. Previously, we have demonstrated the involvement and significance of a signalling cascade from the Fas receptor via sphingomyelinases and ceramide to Ras in Fas-induced apoptosis. Here we demonstrate rapid and transient synthesis of reactive oxygen intermediates (ROI) via activation of Ras after Fas. Genetic inhibition of Ras by transfection of transdominant inhibitory N17Ras blocked Fas-mediated ROI synthesis and programmed cell death. Likewise, the antioxidants N-acetyl-cysteine and N-t-butyl-phenylnitrone abolished Fas-induced cell death, pointing to an important role for Ras-triggered ROI synthesis in Fas-mediated programmed cell death. Images Figure 1 Figure 3 PMID:8943716

  13. A Comparative Analysis of the English-Language Accent Preferences of Prospective and Practicing Businesspersons from around the World

    ERIC Educational Resources Information Center

    Scott, James C.; Green, Diana J.; Blaszczynski, Carol; Rosewarne, David D.

    2007-01-01

    Problem: The studies of the English-language accent preferences of prospective and practicing businesspersons from around the world have not been integrated. Research Questions: What are the English-language accent preferences of prospective and practicing businesspersons from around the world, and how are those preferences influenced by the…

  14. Efficient Personalized Mispronunciation Detection of Taiwanese-Accented English Speech Based on Unsupervised Model Adaptation and Dynamic Sentence Selection

    ERIC Educational Resources Information Center

    Wu, Chung-Hsien; Su, Hung-Yu; Liu, Chao-Hong

    2013-01-01

    This study presents an efficient approach to personalized mispronunciation detection of Taiwanese-accented English. The main goal of this study was to detect frequently occurring mispronunciation patterns of Taiwanese-accented English instead of scoring English pronunciations directly. The proposed approach quickly identifies personalized…

  15. Accent detection is a slippery slope: Direction and rate of F0 change drives listeners’ comprehension

    PubMed Central

    Isaacs, Angela M.; Watson, Duane G.

    2011-01-01

    The present study tests whether listeners use F0, duration, or some combination of the two to identify the presence of an accented word in a short discourse. Participants’ eye movements to previously mentioned and new objects were monitored as participants listened to instructions to move objects in a display. The name of the target object on critical trials was resynthesized from naturally-produced utterances so that it had either high or low F0 and either long or short duration. Fixations to the new object were highest when there was a steep rise in F0. Fixations to the previously mentioned object were highest when there was a steep drop in F0. These results suggest that listeners use F0 slope to make decisions about the presence of an accent, and that F0 and duration by themselves do not solely determine accent interpretation. PMID:22096265

  16. Fas death receptor signalling: roles of Bid and XIAP

    PubMed Central

    Kaufmann, T; Strasser, A; Jost, P J

    2012-01-01

    Fas (also called CD95 or APO-1), a member of a subgroup of the tumour necrosis factor receptor superfamily that contain an intracellular death domain, can initiate apoptosis signalling and has a critical role in the regulation of the immune system. Fas-induced apoptosis requires recruitment and activation of the initiator caspase, caspase-8 (in humans also caspase-10), within the death-inducing signalling complex. In so-called type 1 cells, proteolytic activation of effector caspases (-3 and -7) by caspase-8 suffices for efficient apoptosis induction. In so-called type 2 cells, however, killing requires amplification of the caspase cascade. This can be achieved through caspase-8-mediated proteolytic activation of the pro-apoptotic Bcl-2 homology domain (BH)3-only protein BH3-interacting domain death agonist (Bid), which then causes mitochondrial outer membrane permeabilisation. This in turn leads to mitochondrial release of apoptogenic proteins, such as cytochrome c and, pertinent for Fas death receptor (DR)-induced apoptosis, Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP binding protein with low Pi), an antagonist of X-linked inhibitor of apoptosis (XIAP), which imposes a brake on effector caspases. In this review, written in honour of Juerg Tschopp who contributed so much to research on cell death and immunology, we discuss the functions of Bid and XIAP in the control of Fas DR-induced apoptosis signalling, and we speculate on how this knowledge could be exploited to develop novel regimes for treatment of cancer. PMID:21959933

  17. Fetal Alcohol Syndrome "Chemical Genocide."

    ERIC Educational Resources Information Center

    Asetoyer, Charon

    In the Northern Plains of the United States, 100% of Indian reservations are affected by alcohol related problems. Approximately 90% of Native American adults are currently alcohol users or abusers or are recovering from alcohol abuse. Alcohol consumption has a devastating effect on the unborn. Fetal Alcohol Syndrome (FAS) is an irreversible birth…

  18. We Care for Clean Air! The Contribution of ACCENT to Education and Communication

    NASA Astrophysics Data System (ADS)

    Schuepbach, Eva; Brimblecombe, Peter; Gross, Krisjanis; Jacobs, Mark J.; Ladstätter-Weißenmayer, Annette; Moussiopoulos, Nicolas; Slini, Theodora; Übelis, Arnolds; Uherek, Elmar

    2010-05-01

    A new booklet on: "We Care for Clean Air! Motivating the Next Generation of Atmospheric Scientists" (ISBN 978-88-95665-01-6) as recently published by the education community in ACCENT (www.accent-network.org/portal/education) is presented. Promoting creative and innovative researchers and teachers and encouraging the next generation to move into the field were among the key issues in ACCENT "Training and Education" (T&E). During the 5-year programme, a wealth of educational events (e.g., workshops) and programmes (e.g., "ACCENT FAR EAST") were organized and tools developed for teachers and learners at Universities and Schools around the globe. Activities such as National ACCENT Days or Cafés Scientifiques also targeted stakeholders, policy makers and the general public to increase the expertise in atmospheric composition change to a common level across Europe. The volume introduces the integrated learning environment, high-quality tools and methods for air quality and climate change science education created by ACCENT T&E, and provides an overview on the unbiased scientific information that has been didactically translated based on knowledge available from ongoing research projects.The core messages are that (i) the translation of complex issues in atmospheric composition and climate change science to non-scientists should be scientifically acceptable and that (ii) scientists should stay in control of the translation process. After the publication of the 4th Assessment Report of the Intergovernmental Panel for Climate Change (IPCC) in 2007, ACCENT intensified its efforts to reach greater visibility and distribute the body of know-how, skills and competencies within the networked community of atmospheric scientists in the World Wide Web. For example, a Special Issue of the "Global Change Magazine for Schools" on IPCC 2007 contains a compact introduction to the basics of global warming for direct application in the classroom, also focusing on uncertainties and

  19. The effectiveness of a multimedia program to prevent fetal alcohol syndrome.

    PubMed

    Lachausse, Robert G

    2008-07-01

    Fetal alcohol syndrome (FAS) continues to be the leading preventable cause of mental retardation in the United States. Because abstaining from alcohol prior to and throughout pregnancy is the only way to prevent FAS, some prevention programs try to target women before they become pregnant. The Fetal Alcohol Spectrum Teaching and Research Awareness Campaign (FASTRAC) is a multimedia, peer-delivered educational presentation designed to reduce the incidence of FAS. Results from an ethnically diverse sample of high school students indicate that the program increased participants' knowledge regarding FAS but had no significant effect on participants' attitudes, beliefs about the dangers of FAS or intention to use alcohol during pregnancy. The FASTRAC program failed partly because of its didactic approach and the lack of health education principles that have been shown to be effective in changing other substance use behaviors. Suggestions for improving FAS prevention education programs are offered.

  20. Theileria parva-transformed T cells show enhanced resistance to Fas/Fas ligand-induced apoptosis.

    PubMed

    Küenzi, Peter; Schneider, Pascal; Dobbelaere, Dirk A E

    2003-08-01

    Lymphocyte homeostasis is regulated by mechanisms that control lymphocyte proliferation and apoptosis. Activation-induced cell death is mediated by the expression of death ligands and receptors, which, when triggered, activate an apoptotic cascade. Bovine T cells transformed by the intracellular parasite Theileria parva proliferate in an uncontrolled manner and undergo clonal expansion. They constitutively express the death receptor Fas and its ligand, FasL but do not undergo apoptosis. Upon elimination of the parasite from the host cell by treatment with a theilericidal drug, cells become increasingly sensitive to Fas/FasL-induced apoptosis. In normal T cells, the sensitivity to death receptor killing is regulated by specific inhibitor proteins. We found that anti-apoptotic proteins such as cellular (c)-FLIP, which functions as a catalytically inactive form of caspase-8, and X-chromosome-linked inhibitor of apoptosis protein (IAP) as well as c-IAP, which can block downstream executioner caspases, are constitutively expressed in T. parva-transformed T cells. Expression of these proteins is rapidly down-regulated upon parasite elimination. Antiapoptotic proteins of the Bcl-2 family such as Bcl-2 and Bcl-x(L) are also expressed but, in contrast to c-FLIP, c-IAP, and X-chromosome-linked IAP, do not appear to be tightly regulated by the presence of the parasite. Finally, we show that, in contrast to the situation in tumor cells, the phosphoinositide 3-kinase/Akt pathway is not essential for c-FLIP expression. Our findings indicate that by inducing the expression of antiapoptotic proteins, T. parva allows the host cell to escape destruction by homeostatic mechanisms that would normally be activated to limit the continuous expansion of a T cell population.

  1. Endothelial Fas-Ligand in Inflammatory Bowel Diseases and in Acute Appendicitis

    PubMed Central

    Kokkonen, Tuomo S.; Karttunen, Tuomo J.

    2015-01-01

    Fas-mediated induction of apoptosis is a major factor in the selection of lymphocytes and downregulation of immunological processes. In the present study, we have assessed endothelial Fas-ligand (FasL) expression in normal human ileum, appendix, and colon, and compared the expression levels with that in inflammatory bowel disease and in acute appendicitis. In a normal appendix, endothelial FasL levels were constant in almost half of the mucosal vessels; but, in the normal ileum and colon, endothelial FasL was practically restricted to areas in close proximity to lymphatic follicles, and was expressed mainly in the submucosal aspect of the follicles in the vessels with high endothelium. In samples from subjects with either Crohn’s disease or ulcerative colitis, the extent of endothelial FasL expression was elevated in the submucosa and associated with an elevated number of lymphoid follicles. In inflammatory bowel disease, ulcers and areas with a high density of mononuclear cells expressing FasL also showed an elevated density of blood vessels with endothelial FasL expression. Although the function of endothelial FasL remains unclear, such a specific expression pattern suggests that endothelial FasL expression has a role in the regulation of lymphocyte access to the peripheral lymphoid tissues, including the intestinal mucosa. PMID:26374830

  2. Induction of tolerance using Fas ligand: a double-edged immunomodulator.

    PubMed

    Askenasy, Nadir; Yolcu, Esma S; Yaniv, Isaac; Shirwan, Haval

    2005-02-15

    Apoptosis mediated by Fas ligand (FasL) interaction with Fas receptor plays a pivotal regulatory role in immune homeostasis, immune privilege, and self-tolerance. FasL, therefore, has been extensively exploited as an immunomodulatory agent to induce tolerance to both autoimmune and foreign antigens with conflicting results. Difficulties associated with the use of FasL as a tolerogenic factor may arise from (1) its complex posttranslational regulation, (2) the opposing functions of different forms of FasL, (3) different modes of expression, systemic versus localized and transient versus continuous, (4) the level and duration of expression, (5) the sensitivity of target tissues to Fas/FasL-mediated apoptosis and the efficiency of antigen presentation in these tissues, and (6) the types and levels of cytokines, chemokines, and metalloproteinases in the extracellular milieu of the target tissues. Thus, the effective use of FasL as an immunomodulator to achieve durable antigen-specific immune tolerance requires careful consideration of all of these parameters and the design of treatment regimens that maximize tolerogenic efficacy, while minimizing the non-tolerogenic and toxic functions of this molecule. This review summarizes the current status of FasL as a tolerogenic agent, problems associated with its use as an immunomodulator, and new strategies to improve its therapeutic potential.

  3. D-cyclins Repress Apoptosis in Hematopoietic Cells by Controlling Death Receptor Fas and its Ligand FasL

    PubMed Central

    Choi, Yoon Jong; Saez, Borja; Anders, Lars; Hydbring, Per; Stefano, Joanna; Bacon, Nickolas A.; Cook, Colleen; Kalaszczynska, Ilona; Signoretti, Sabina; Young, Richard A.; Scadden, David T.; Sicinski, Piotr

    2014-01-01

    SUMMARY D-type cyclins (D1, D2 and D3) are components of the mammalian core cell cycle machinery and function to drive cell proliferation. Here we report that D-cyclins perform a rate-limiting anti-apoptotic function in vivo. We found that acute shutdown of all three D-cyclins in bone marrow of adult mice resulted in massive apoptosis of all hematopoietic cell types. We demonstrate that adult hematopoietic stem cells are particularly dependent on D-cyclins for survival, and they are especially sensitive to cyclin D loss. Surprisingly, we found that the anti-apoptotic function of D-cyclins also operates in quiescent hematopoietic stem and progenitor cells. Our analyses revealed that D-cyclins repress the expression of the death receptor Fas and its ligand, FasL. Acute ablation of D-cyclins upregulated these pro-apoptotic genes, and led to Fas- and caspase 8-dependent apoptosis. These results reveal an unexpected function of cell cycle proteins in controlling apoptosis in normal cell homeostasis. PMID:25087893

  4. CD8+CD122+CD49dlow regulatory T cells maintain T-cell homeostasis by killing activated T cells via Fas/FasL-mediated cytotoxicity.

    PubMed

    Akane, Kazuyuki; Kojima, Seiji; Mak, Tak W; Shiku, Hiroshi; Suzuki, Haruhiko

    2016-03-01

    The Fas/FasL (CD95/CD178) system is required for immune regulation; however, it is unclear in which cells, when, and where Fas/FasL molecules act in the immune system. We found that CD8(+)CD122(+) cells, which are mostly composed of memory T cells in comparison with naïve cells in the CD8(+)CD122(-) population, were previously shown to include cells with regulatory activity and could be separated into CD49d(low) cells and CD49d(high) cells. We established in vitro and in vivo experimental systems to evaluate the regulatory activity of CD122(+) cells. Regulatory activity was observed in CD8(+)CD122(+)CD49d(low) but not in CD8(+)CD122(+)CD49d(high) cells, indicating that the regulatory cells in the CD8(+)CD122(+) population could be narrowed down to CD49d(low) cells. CD8(+)CD122(-) cells taken from lymphoproliferation (lpr) mice were resistant to regulation by normal CD122(+) Tregs. CD122(+) Tregs taken from generalized lymphoproliferative disease (gld) mice did not regulate wild-type CD8(+)CD122(-) cells, indicating that the regulation by CD122(+) Tregs is Fas/FasL-dependent. CD122(+) Tregs taken from IL-10-deficient mice could regulate CD8(+)CD122(-) cells as equally as wild-type CD122(+) Tregs both in vitro and in vivo. MHC class I-missing T cells were not regulated by CD122(+) Tregs in vitro. CD122(+) Tregs also regulated CD4(+) cells in a Fas/FasL-dependent manner in vitro. These results suggest an essential role of Fas/FasL as a terminal effector of the CD122(+) Tregs that kill activated T cells to maintain immune homeostasis.

  5. Fetal Alcohol Syndrome Surveillance: Age of Syndrome Manifestation in Case Ascertainment

    PubMed Central

    Moberg, D. Paul; Bowser, John; Burd, Larry; Elliott, Amy J.; Punyko, Judy; Wilton, Georgiana

    2014-01-01

    Background Fetal alcohol syndrome (FAS) is a leading cause of developmental disability. Active public health surveillance through medical record abstraction has been employed to estimate FAS prevalence rates, typically based on birth cohorts. There is an extended time for FAS characteristics to become apparent in infants and young children, and there are often delays in syndrome recognition and documentation. This methodological paper analyzes the age at case ascertainment in a large surveillance program. Methods The Fetal Alcohol Syndrome Surveillance (FASSLink) Project, funded by the Centers for Disease Control and Prevention (CDC), sought to estimate FAS prevalence rates in eight U.S. states. FASSLink used linked abstractions from multiple health care records of suspected cases of FAS. The present paper analyzed data from this effort to determine the child’s age in months at confirming abstraction. Results The average age at abstraction for confirmed/probable FAS cases (n=422) was 48.3 (±19.5) months with a range of 0 to 94 months. Age of ascertainment varied by state and decreased with each birth year; the number of cases ascertained also decreased in a steep stepwise gradient over the six birth years in the study. Discussion FAS surveillance efforts should screen records of children who are much older than is typical in birth defects surveillance. To best establish rates of FAS using medical records abstraction, surveillance efforts should focus on one-year birth cohorts followed for a fixed number of years or, if using multi-year cohorts, should implement staggered end dates allowing all births to be followed for up to eight years of age. PMID:24737611

  6. Fetal Alcohol Syndrome: A Training Manual To Aid in Vocational Rehabilitation and Other Non-Medical Services.

    ERIC Educational Resources Information Center

    LaDue, Robin A.; Schacht, Robert M.; Tanner-Halverson, Patricia; McGowan, Mark

    This training manual provides vocational rehabilitation and school counselors with background information and practical tools related to fetal alcohol syndrome (FAS), with particular reference to the needs of Native Americans. The most recent reliable data (1990) for American Indians and Alaska Natives show a rate of FAS over 10 times the national…

  7. Perception of contrastive bi-syllabic lexical stress in unaccented and accented words by younger and older listeners

    PubMed Central

    Gordon-Salant, Sandra; Yeni-Komshian, Grace H.; Pickett, Erin J.; Fitzgibbons, Peter J.

    2016-01-01

    This study examined the ability of older and younger listeners to perceive contrastive syllable stress in unaccented and Spanish-accented cognate bi-syllabic English words. Younger listeners with normal hearing, older listeners with normal hearing, and older listeners with hearing impairment judged recordings of words that contrasted in stress that conveyed a noun or verb form (e.g., CONduct/conDUCT), using two paradigms differing in the amount of semantic support. The stimuli were spoken by four speakers: one native English speaker and three Spanish-accented speakers (one moderately and two mildly accented). The results indicate that all listeners showed the lowest accuracy scores in responding to the most heavily accented speaker and the highest accuracy in judging the productions of the native English speaker. The two older groups showed lower accuracy in judging contrastive lexical stress than the younger group, especially for verbs produced by the most accented speaker. This general pattern of performance was observed in the two experimental paradigms, although performance was generally lower in the paradigm without semantic support. The findings suggest that age-related difficulty in adjusting to deviations in contrastive bi-syllabic lexical stress produced with a Spanish accent may be an important factor limiting perception of accented English by older people. PMID:27036250

  8. Perception of contrastive bi-syllabic lexical stress in unaccented and accented words by younger and older listeners.

    PubMed

    Gordon-Salant, Sandra; Yeni-Komshian, Grace H; Pickett, Erin J; Fitzgibbons, Peter J

    2016-03-01

    This study examined the ability of older and younger listeners to perceive contrastive syllable stress in unaccented and Spanish-accented cognate bi-syllabic English words. Younger listeners with normal hearing, older listeners with normal hearing, and older listeners with hearing impairment judged recordings of words that contrasted in stress that conveyed a noun or verb form (e.g., CONduct/conDUCT), using two paradigms differing in the amount of semantic support. The stimuli were spoken by four speakers: one native English speaker and three Spanish-accented speakers (one moderately and two mildly accented). The results indicate that all listeners showed the lowest accuracy scores in responding to the most heavily accented speaker and the highest accuracy in judging the productions of the native English speaker. The two older groups showed lower accuracy in judging contrastive lexical stress than the younger group, especially for verbs produced by the most accented speaker. This general pattern of performance was observed in the two experimental paradigms, although performance was generally lower in the paradigm without semantic support. The findings suggest that age-related difficulty in adjusting to deviations in contrastive bi-syllabic lexical stress produced with a Spanish accent may be an important factor limiting perception of accented English by older people.

  9. Perceptual Judgments of Accented Speech by Listeners from Different First Language Backgrounds

    ERIC Educational Resources Information Center

    Kang, Okim; Vo, Son Ca Thanh; Moran, Meghan Kerry

    2016-01-01

    Research in second language speech has often focused on listeners' accent judgment and factors that affect their perception. However, the topic of listeners' application of specific sound categories in their own perceptual judgments has not been widely investigated. The current study explored how listeners from diverse language backgrounds weighed…

  10. Visual Enhancement of Illusory Phenomenal Accents in Non-Isochronous Auditory Rhythms

    PubMed Central

    2016-01-01

    Musical rhythms encompass temporal patterns that often yield regular metrical accents (e.g., a beat). There have been mixed results regarding perception as a function of metrical saliency, namely, whether sensitivity to a deviant was greater in metrically stronger or weaker positions. Besides, effects of metrical position have not been examined in non-isochronous rhythms, or with respect to multisensory influences. This study was concerned with two main issues: (1) In non-isochronous auditory rhythms with clear metrical accents, how would sensitivity to a deviant be modulated by metrical positions? (2) Would the effects be enhanced by multisensory information? Participants listened to strongly metrical rhythms with or without watching a point-light figure dance to the rhythm in the same meter, and detected a slight loudness increment. Both conditions were presented with or without an auditory interference that served to impair auditory metrical perception. Sensitivity to a deviant was found greater in weak beat than in strong beat positions, consistent with the Predictive Coding hypothesis and the idea of metrically induced illusory phenomenal accents. The visual rhythm of dance hindered auditory detection, but more so when the latter was itself less impaired. This pattern suggested that the visual and auditory rhythms were perceptually integrated to reinforce metrical accentuation, yielding more illusory phenomenal accents and thus lower sensitivity to deviants, in a manner consistent with the principle of inverse effectiveness. Results were discussed in the predictive framework for multisensory rhythms involving observed movements and possible mediation of the motor system. PMID:27880850

  11. Accent, Listening Assessment and the Potential for a Shared-L1 Advantage: A DIF Perspective

    ERIC Educational Resources Information Center

    Harding, Luke

    2012-01-01

    This paper reports on an investigation of the potential for a shared-L1 advantage on an academic English listening test featuring speakers with L2 accents. Two hundred and twelve second-language listeners (including 70 Mandarin Chinese L1 listeners and 60 Japanese L1 listeners) completed three versions of the University Test of English as a Second…

  12. An Exploratory Study of Undergraduate College Students' Perceptions and Attitudes toward Foreign Accented Faculty

    ERIC Educational Resources Information Center

    Kavas, Aysel; Kavas, Alican

    2008-01-01

    The findings of an exploratory survey related to students' perceptions of factors, including accent and pronunciation, influencing their learning were presented. Data were collected from students through a self-administered questionnaire at one Southeastern University. A big majority (82.4%) of the respondents indicated that instructors'…

  13. Effects of Strength of Accent on an L2 Interactive Lecture Listening Comprehension Test

    ERIC Educational Resources Information Center

    Ockey, Gary J.; Papageorgiou, Spiros; French, Robert

    2016-01-01

    This article reports on a study which aimed to determine the effect of strength of accent on listening comprehension of interactive lectures. Test takers (N = 21,726) listened to an interactive lecture given by one of nine speakers and responded to six comprehension items. The test taker responses were analyzed with the Rasch computer program…

  14. Neural Correlates of Infant Accent Discrimination: An fNIRS Study

    ERIC Educational Resources Information Center

    Cristia, Alejandrina; Minagawa-Kawai, Yasuyo; Egorova, Natalia; Gervain, Judit; Filippin, Luca; Cabrol, Dominique; Dupoux, Emmanuel

    2014-01-01

    The present study investigated the neural correlates of infant discrimination of very similar linguistic varieties (Quebecois and Parisian French) using functional Near InfraRed Spectroscopy. In line with previous behavioral and electrophysiological data, there was no evidence that 3-month-olds discriminated the two regional accents, whereas…

  15. Reduction of non-native accents through statistical parametric articulatory synthesis.

    PubMed

    Aryal, Sandesh; Gutierrez-Osuna, Ricardo

    2015-01-01

    This paper presents an articulatory synthesis method to transform utterances from a second language (L2) learner to appear as if they had been produced by the same speaker but with a native (L1) accent. The approach consists of building a probabilistic articulatory synthesizer (a mapping from articulators to acoustics) for the L2 speaker, then driving the model with articulatory gestures from a reference L1 speaker. To account for differences in the vocal tract of the two speakers, a Procrustes transform is used to bring their articulatory spaces into registration. In a series of listening tests, accent conversions were rated as being more intelligible and less accented than L2 utterances while preserving the voice identity of the L2 speaker. No significant effect was found between the intelligibility of accent-converted utterances and the proportion of phones outside the L2 inventory. Because the latter is a strong predictor of pronunciation variability in L2 speech, these results suggest that articulatory resynthesis can decouple those aspects of an utterance that are due to the speaker's physiology from those that are due to their linguistic gestures.

  16. A Cross-Linguistic Investigation of the Effect of Raters' Accent Familiarity on Speaking Assessment

    ERIC Educational Resources Information Center

    Huang, Becky; Alegre, Analucia; Eisenberg, Ann

    2016-01-01

    The project aimed to examine the effect of raters' familiarity with accents on their judgments of non-native speech. Participants included three groups of raters who were either from Spanish Heritage, Spanish Non-Heritage, or Chinese Heritage backgrounds (n = 16 in each group) using Winke & Gass's (2013) definition of a heritage learner as…

  17. Effects of Noise and Proficiency on Intelligibility of Chinese-Accented English

    ERIC Educational Resources Information Center

    Rogers, Catherine L.; Dalby, Jonathan; Nishi, Kanae

    2004-01-01

    This study compared the intelligibility of native and foreign-accented English speech presented in quiet and mixed with three different levels of background noise. Two native American English speakers and four native Mandarin Chinese speakers for whom English is a second language each read a list of 50 phonetically balanced sentences (Egan, 1948).…

  18. Mechanisms Underlying Accent Accommodation in Early Word Learning: Evidence for General Expansion

    ERIC Educational Resources Information Center

    Schmale, Rachel; Seidl, Amanda; Cristia, Alejandrina

    2015-01-01

    Previous work reveals that toddlers can accommodate a novel accent after hearing it for only a brief period of time. A common assumption is that children, like adults, cope with nonstandard pronunciations by relying on words they know (e.g. "this person pronounces sock as 'sack', therefore by 'black' she meant 'block'"). In this paper,…

  19. Listening to Accented Speech in a Second Language: First Language and Age of Acquisition Effects

    ERIC Educational Resources Information Center

    Larraza, Saioa; Samuel, Arthur G.; Oñederra, Miren Lourdes

    2016-01-01

    Bilingual speakers must acquire the phonemic inventory of 2 languages and need to recognize spoken words cross-linguistically; a demanding job potentially made even more difficult due to dialectal variation, an intrinsic property of speech. The present work examines how bilinguals perceive second language (L2) accented speech and where…

  20. Finding Referents in Time: Eye-Tracking Evidence for the Role of Contrastive Accents

    ERIC Educational Resources Information Center

    Weber, Andrea; Braun, Bettina; Crocker, Matthew W.

    2006-01-01

    In two eye-tracking experiments the role of contrastive pitch accents during the on-line determination of referents was examined. In both experiments, German listeners looked earlier at the picture of a referent belonging to a contrast pair ("red scissors," given "purple scissors") when instructions to click on it carried a…

  1. THE BACON not the bacon: how children and adults understand accented and unaccented noun phrases.

    PubMed

    Arnold, Jennifer E

    2008-07-01

    Two eye-tracking experiments examine whether adults and 4- and 5-year-old children use the presence or absence of accenting to guide their interpretation of noun phrases (e.g., the bacon) with respect to the discourse context. Unaccented nouns tend to refer to contextually accessible referents, while accented variants tend to be used for less accessible entities. Experiment 1 confirms that accenting is informative for adults, who show a bias toward previously-mentioned objects beginning 300 ms after the onset of unaccented nouns and pronouns. But contrary to findings in the literature, accented words produced no observable bias. In Experiment 2, 4 and 5 year olds were also biased toward previously-mentioned objects with unaccented nouns and pronouns. This builds on findings of limits on children's on-line reference comprehension [Arnold, J. E., Brown-Schmidt, S., & Trueswell, J. C. (2007). Children's use of gender and order-of-mention during pronoun comprehension. Language and Cognitive Processes], showing that children's interpretation of unaccented nouns and pronouns is constrained in contexts with one single highly accessible object.

  2. Morphological Make-up as the Predictor of English Word Accent

    ERIC Educational Resources Information Center

    Salmani-Nodoushan, Mohammad Ali

    2009-01-01

    For years, phoneticians have tried to simplify pronunciation for EFL/ESL learners. Some have identified four degrees of primary, secondary, tertiary, and weak stress, and others only three degrees: primary, secondary, and weak. Still others have concentrated on two stress levels: accented versus unaccented, or stressed versus unstressed (Bowen,…

  3. The Influence of Semantic Context on the Perception of Spanish-Accented American English

    ERIC Educational Resources Information Center

    Behrman, Alison; Akhund, Ali

    2013-01-01

    Purpose: In this article, the authors examine (a) the effect of semantic context on accentedness, comprehensibility, and intelligibility of Spanish-accented American English (AE) as judged by monolingual AE listeners and (b) the interaction of semantic context and accentedness on comprehensibility and intelligibility. Method: Twenty adult native…

  4. Accommodating Variability in Voice and Foreign Accent: Flexibility of Early Word Representations

    ERIC Educational Resources Information Center

    Schmale, Rachel; Seidl, Amanda

    2009-01-01

    In six experiments with English-learning infants, we examined the effects of variability in voice and foreign accent on word recognition. We found that 9-month-old infants successfully recognized words when two native English talkers with dissimilar voices produced test and familiarization items (Experiment 1). When the domain of variability was…

  5. Global Foreign Accent and Voice Onset Time Among Japanese EFL Speakers.

    ERIC Educational Resources Information Center

    Riney, Timothy J.; Takagi, Naoyuki

    1999-01-01

    Investigated the correlation between global foreign accent (GFA) and voice onset time (VOT). VOT values for /p/, /t/, and /k/ were measured at two times, separated by an interval of 42 months. Subjects were 11 Japanese speakers of English as a foreign language; 5 age-matched native speakers of English served as the control group. (Author/VWL)

  6. Accent Priority in a Thai University Context: A Common Sense Revisited

    ERIC Educational Resources Information Center

    Jindapitak, Naratip; Teo, Adisa

    2013-01-01

    In Thailand, there has been much debate regarding what accents should be prioritized and adopted as models for learning and use in the context of English language education. However, it is not a debate in which the voices of English learners have sufficiently been heard. Several world Englishes scholars have maintained that being a denationalized…

  7. The Weckud Wetch of the Wast: Lexical Adaptation to a Novel Accent

    ERIC Educational Resources Information Center

    Maye, Jessica; Aslin, Richard N.; Tanenhaus, Michael K.

    2008-01-01

    Two experiments investigated the mechanism by which listeners adjust their interpretation of accented speech that is similar to a regional dialect of American English. Only a subset of the vowels of English (the front vowels) were shifted during adaptation, which consisted of listening to a 20-min segment of the "Wizard of Oz." Compared…

  8. Beliefs regarding the Impact of Accent within Speech-Language Pathology Practice Areas

    ERIC Educational Resources Information Center

    Levy, Erika S.; Crowley, Catherine J.

    2012-01-01

    With the demographic shifts in the United States, it is increasingly the case that speech-language pathologists (SLPs) come from different language backgrounds from those of their clients and have nonnative accents in their languages of service. An anonymous web-based survey was completed by students and clinic directors in SLP training programs…

  9. The Influence of Second Language Experience and Accent Familiarity on Oral Proficiency Rating: A Qualitative Investigation

    ERIC Educational Resources Information Center

    Winke, Paula; Gass, Susan

    2013-01-01

    This study investigates whether raters' knowledge of test takers' first language (L1) affects how the raters orient themselves to the task of rating oral speech. The authors qualitatively investigated the effects of accent familiarity on raters' score assignment processes. Twenty-six trained raters with a second language of Mandarin Chinese,…

  10. Policies and Practices regarding Students with Accents in Speech-Language Pathology Training Programs

    ERIC Educational Resources Information Center

    Levy, Erika S.; Crowley, Catherine J.

    2012-01-01

    Speech-language pathology (SLP) training programs are the initial gateway for nonnative speakers of English to join the SLP profession. An anonymous web-based survey in New York State examined policies and practices implemented when SLP students have foreign accents in English or in other languages. Responses were elicited from 530 students and 28…

  11. Second Language Accent and Pronunciation Teaching: A Research-Based Approach

    ERIC Educational Resources Information Center

    Derwing, Tracey M.; Munro, Murray J.

    2005-01-01

    Empirical studies are essential to improving our understanding of the relationship between accent and pronunciation teaching. However, the study of pronunciation has been marginalized within the field of applied linguistics. As a result, teachers are often left to rely on their own intuitions with little direction. Although some instructors can…

  12. How to Speak Standard American English without a Foreign Accent. New York Edition.

    ERIC Educational Resources Information Center

    Catran, Jack

    This transcript of and guide to a two-cassette course designed to assist New Yorkers in erasure of their accents can be used for either individual or group study. Narrative and taped demonstrations of Standard American English that pinpoint typical phonological barriers and pronunciation difficulties are outlined. The author's own system of…

  13. How To Speak Standard American English without a Foreign Accent. Scandinavian Edition.

    ERIC Educational Resources Information Center

    Catran, Jack

    This transcript of and guide to a two-cassette course designed to assist Swedish and Norwegian immigrants in erasure of their foreign accents can be used for either individual or group study. Narrative and taped demonstrations of American English that pinpoint typical phonological barriers and pronunciation difficulties are outlined. The author's…

  14. How to Speak English without a Foreign Accent. Black English Edition.

    ERIC Educational Resources Information Center

    Catran, Jack

    The transcript of and guide to a two-cassette course designed to assist speakers of Black English in erasure of their accents includes an introduction on Black and Standard English usage, an explanation of the system used in this course, the pronunciation symbols used, and an explanation of how to change or eliminate trouble spots. The course is…

  15. Stronger Accent Following a Stroke: The Case of a Trilingual with Aphasia

    ERIC Educational Resources Information Center

    Levy, Erika S.; Goral, Mira; De Diesbach, Catharine Castelluccio; Law, Franzo, II

    2011-01-01

    This study documents patterns of change in speech production in a multilingual with aphasia following a cerebrovascular accident (CVA). EC, a right-handed Hebrew-English-French trilingual man, had a left fronto-temporo-parietal CVA, after which he reported that his (native) Hebrew accent became stronger in his (second language) English. Recordings…

  16. Visual Enhancement of Illusory Phenomenal Accents in Non-Isochronous Auditory Rhythms.

    PubMed

    Su, Yi-Huang

    2016-01-01

    Musical rhythms encompass temporal patterns that often yield regular metrical accents (e.g., a beat). There have been mixed results regarding perception as a function of metrical saliency, namely, whether sensitivity to a deviant was greater in metrically stronger or weaker positions. Besides, effects of metrical position have not been examined in non-isochronous rhythms, or with respect to multisensory influences. This study was concerned with two main issues: (1) In non-isochronous auditory rhythms with clear metrical accents, how would sensitivity to a deviant be modulated by metrical positions? (2) Would the effects be enhanced by multisensory information? Participants listened to strongly metrical rhythms with or without watching a point-light figure dance to the rhythm in the same meter, and detected a slight loudness increment. Both conditions were presented with or without an auditory interference that served to impair auditory metrical perception. Sensitivity to a deviant was found greater in weak beat than in strong beat positions, consistent with the Predictive Coding hypothesis and the idea of metrically induced illusory phenomenal accents. The visual rhythm of dance hindered auditory detection, but more so when the latter was itself less impaired. This pattern suggested that the visual and auditory rhythms were perceptually integrated to reinforce metrical accentuation, yielding more illusory phenomenal accents and thus lower sensitivity to deviants, in a manner consistent with the principle of inverse effectiveness. Results were discussed in the predictive framework for multisensory rhythms involving observed movements and possible mediation of the motor system.

  17. THE BACON not the bacon: How children and adults understand accented and unaccented noun phrases

    PubMed Central

    Arnold, Jennifer E.

    2008-01-01

    Two eye-tracking experiments examine whether adults and 4 and 5 year old children use the presence or absence of accenting to guide their interpretation of noun phrases (e.g., the bacon) with respect to the discourse context. Unaccented nouns tend to refer to contextually accessible referents, while accented variants tend to be used for less accessible entities. Experiment 1 confirms that accenting is informative for adults, who show a bias toward previously-mentioned objects beginning 300 msec after the onset of unaccented nouns and pronouns. But contrary to findings in the literature, accented words produced no observable bias. In Experiment 2, 4 and 5 year olds were also biased toward previously-mentioned objects with unaccented nouns and pronouns. This builds on findings of limits on children’s on-line reference comprehension (Arnold, Brown-Schmidt, & Trueswell, in press), showing that children’s interpretation of unaccented nouns and pronouns is constrained in contexts with one single highly accessible object. PMID:18358460

  18. Retrovirally transduced murine T lymphocytes expressing FasL mediate effective killing of prostate cancer cells

    PubMed Central

    Symes, JC; Siatskas, C; Fowler, DH; Medin, JA

    2010-01-01

    Adoptively transferred T cells possess anticancer activities partially mediated by T-cell FasL engagement of Fas tumor targets. However, antigen-induced T-cell activation and clonal expansion, which stimulates FasL activity, is often inefficient in tumors. As a gene therapy approach to overcome this obstacle, we have created oncoretroviral vectors to overexpress FasL or non-cleavable FasL (ncFasL) on murine T cells of a diverse T-cell receptor repertoire. Expression of c-FLIP was also engineered to prevent apoptosis of transduced cells. Retroviral transduction of murine T lymphocytes has historically been problematic, and we describe optimized T-cell transduction protocols involving CD3/CD28 co-stimulation of T cells, transduction on ice using concentrated oncoretrovirus, and culture with IL-15. Genetically modified T cells home to established prostate cancer tumors in vivo. Co-stimulated T cells expressing FasL, ncFasL and ncFasL/c-FLIP each mediated cytotoxicity in vitro against RM-1 and LNCaP prostate cancer cells. To evaluate the compatibility of this approach with current prostate cancer therapies, we exposed RM-1, LNCaP, and TRAMP-C1 cells to radiation, mitoxantrone, or docetaxel. Fas and H-2b expression were upregulated by these methods. We have developed a novel FasL-based immuno-gene therapy for prostate cancer that warrants further investigation given the apparent constitutive and inducible Fas pathway expression in this malignancy. PMID:19096446

  19. Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation

    PubMed Central

    Barthel, Lea; Bednarek, Joseph M.; Yunt, Zulma X.; Henson, Peter M.; Janssen, William J.

    2014-01-01

    Apoptosis of alveolar macrophages and their subsequent clearance by neighboring phagocytes are necessary steps in the resolution of acute pulmonary inflammation. We have recently identified that activation of the Fas death receptor on the cell surface of macrophages drives macrophage apoptosis. However, the source of the cognate ligand for Fas (FasL) responsible for induction of alveolar macrophage apoptosis is not defined. Given their known role in the resolution of inflammation and ability to induce macrophage apoptosis ex vivo, we hypothesized that T lymphocytes represented a critical source of FasL. To address this hypothesis, C57BL/6J and lymphocyte-deficient (Rag-1−/−) mice were exposed to intratracheal lipopolysaccharide to induce pulmonary inflammation. Furthermore, utilizing mice expressing nonfunctional FasL, we adoptively transferred donor lymphocytes into inflamed lymphocyte-deficient mice to characterize the effect of lymphocyte-derived FasL on alveolar macrophage apoptosis in the resolution of inflammation. Herein, evidence is presented that lymphocytes expressing FasL enhance alveolar macrophage apoptosis during the resolution of LPS-induced inflammation. Moreover, lymphocyte induction of alveolar macrophage apoptosis results in contraction of the alveolar macrophage pool, which occurs in a FasL-dependent manner. Specifically, FasL-expressing CD8+ T lymphocytes potently induce alveolar macrophage apoptosis and contraction of the alveolar macrophage pool. Together, these studies identify a novel role for CD8+ T lymphocytes in the resolution of acute pulmonary inflammation. PMID:24838751

  20. A Fashi Lymphoproliferative Phenotype Reveals Non-Apoptotic Fas Signaling in HTLV-1-Associated Neuroinflammation

    PubMed Central

    Menezes, Soraya Maria; Leal, Fabio E.; Dierckx, Tim; Khouri, Ricardo; Decanine, Daniele; Silva-Santos, Gilvaneia; Schnitman, Saul V.; Kruschewsky, Ramon; López, Giovanni; Alvarez, Carolina; Talledo, Michael; Gotuzzo, Eduardo; Nixon, Douglas F.; Vercauteren, Jurgen; Brassat, David; Liblau, Roland; Vandamme, Anne Mieke; Galvão-Castro, Bernardo; Van Weyenbergh, Johan

    2017-01-01

    Human T-cell lymphotropic virus (HTLV)-1 was the first human retrovirus to be associated to cancer, namely adult T-cell leukemia (ATL), but its pathogenesis remains enigmatic, since only a minority of infected individuals develops either ATL or the neuroinflammatory disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A functional FAS -670 polymorphism in an interferon (IFN)-regulated STAT1-binding site has been associated to both ATL and HAM/TSP susceptibility. Fashi T stem cell memory (Tscm) cells have been identified as the hierarchical apex of ATL, but have not been investigated in HAM/TSP. In addition, both FAS and STAT1 have been identified in an IFN-inducible HAM/TSP gene signature, but its pathobiological significance remains unclear. We comprehensively explored Fas expression (protein/mRNA) and function in lymphocyte activation, apoptosis, proliferation, and transcriptome, in PBMC from a total of 47 HAM/TSP patients, 40 asymptomatic HTLV-1-infected individuals (AC), and 58 HTLV-1 -uninfected healthy controls. Fas surface expression followed a two-step increase from HC to AC and from AC to HAM/TSP. In HAM/TSP, Fas levels correlated positively to lymphocyte activation markers, but negatively to age of onset, linking Fashi cells to earlier, more aggressive disease. Surprisingly, increased lymphocyte Fas expression in HAM/TSP was linked to decreased apoptosis and increased lymphoproliferation upon in vitro culture, but not to proviral load. This Fashi phenotype is HAM/TSP-specific, since both ex vivo and in vitro Fas expression was increased as compared to multiple sclerosis (MS), another neuroinflammatory disorder. To elucidate the molecular mechanism underlying non-apoptotic Fas signaling in HAM/TSP, we combined transcriptome analysis with functional assays, i.e., blocking vs. triggering Fas receptor in vitro with antagonist and agonist-, anti-Fas mAb, respectively. Treatment with agonist anti-Fas mAb restored apoptosis, indicating

  1. Myocardial Fas and cytokine expression in end-stage heart failure: impact of LVAD support.

    PubMed

    Bedi, Maninder S; Alvarez, Rene J; Kubota, Toru; Sheppard, Richard; Kormos, Robert L; Siegenthaler, Michael P; Feldman, Arthur M; McTiernan, Charles F; McNamara, Dennis M

    2008-12-01

    Left ventricular assist device (LVAD) support may facilitate myocardial recovery. We evaluated the impact of LVAD support on Fas expression in a cohort with end-stage heart failure. Myocardial gene expression was assessed pre- and post-LVAD by RNase protection assay and compared to control donor hearts. The expression of Fas is markedly elevated at the time of LVAD support and is tightly correlated with TNF expression. While interleukin (IL)-6 was significantly reduced by LVAD support, the impact of support on Fas was highly variable and tightly linked to tumor necrosis factor (TNF). The role of Fas in predicting recovery after LVAD support requires further investigation.

  2. Screening, diagnosing and prevention of fetal alcohol syndrome: is this syndrome treatable?

    PubMed

    Ismail, Sahar; Buckley, Stephanie; Budacki, Ross; Jabbar, Ahmad; Gallicano, G Ian

    2010-07-01

    Prenatal alcohol exposure can lead to a wide range of adverse effects on a developing fetus. As a whole, these teratogenic outcomes are generally known as fetal alcohol spectrum disorders, the most severe of which is fetal alcohol syndrome (FAS). Clinically, children diagnosed with FAS vary greatly in their presentation of symptoms, likely due to the amount of alcohol and timing of exposure, as well as maternal and genetic influences. All these factors play a role in determining the mechanisms through which alcohol damages a developing brain, the details of which are still largely unknown. However, continuing research and recent developments have provided promising results that may lead to screening mechanisms and treatment therapies for children with FAS. Here we review the teratogenic effects of alcohol, strategies for detecting maternal alcohol consumption, identification of fetal biological markers, and prevention methods for FAS.

  3. Th1 CD4+ lymphocytes delete activated macrophages through the Fas/APO-1 antigen pathway.

    PubMed Central

    Ashany, D; Song, X; Lacy, E; Nikolic-Zugic, J; Friedman, S M; Elkon, K B

    1995-01-01

    The Fas/APO-1 cytotoxic pathway plays an important role in the regulation of peripheral immunity. Recent evidence indicates that this regulatory function operates through deletion of activated T and B lymphocytes by CD4+ T cells expressing the Fas ligand. Because macrophages play a key role in peripheral immunity, we asked whether Fas was involved in T-cell-macrophage interactions. Two-color flow cytometry revealed that Fas receptor (FasR) was expressed on resting murine peritoneal macrophages. FasR expression was upregulated after activation of macrophages with cytokines or lipopolysaccharide, although only tumor necrosis factor-alpha rendered macrophages sensitive to anti-FasR antibody-mediated death. To determine the consequence of antigen presentation by macrophages to CD4+ T cells, macrophages were pulsed with antigen and then incubated with either Th1 or Th2 cell lines or clones. Th1, but not Th2, T cells induced lysis of 60-80% of normal macrophages, whereas macrophages obtained from mice with mutations in the FasR were totally resistant to Th1-mediated cytotoxicity. Macrophage cytotoxicity depended upon specific antigen recognition by T cells and was major histocompatibility complex restricted. These findings indicate that, in addition to deletion of activated lymphocytes, Fas plays an important role in deletion of activated macrophages after antigen presentation to Th1 CD4+ T cells. Failure to delete macrophages that constitutively present self-antigens may contribute to the expression of autoimmunity in mice deficient in FasR (lpr) or Fas ligand (gld). PMID:7479970

  4. The dual functions of Fas ligand in the regulation of peripheral CD8+ and CD4+ T cells

    PubMed Central

    Suzuki, Ivy; Fink, Pamela J.

    2000-01-01

    Although Fas ligand (FasL) is well characterized for its capacity to deliver a death signal through its receptor Fas, recent work demonstrates that FasL also can receive signals facilitating antigen (Ag)-specific proliferation of CD8+ T cells. The fact that the gld mutation differentially influences the proliferative capacity of CD8+ and CD4+ T cells presented the intriguing possibility that a single molecule may play opposing roles in these two subpopulations. The present study focuses on how these positive and negative regulatory roles are balanced. We show that naive CD4+ T cells are responsive to FasL-mediated costimulation on encounter with Ag when Fas-mediated death is prevented. Thus, the machinery responsible for transducing the FasL positive reverse signal operates in both CD4+ and CD8+ T cells. Instead, differential control of FasL expression distinguishes the role of FasL in these two T cell subpopulations. FasL costimulation occurs immediately on T cell receptor ligation and correlates with the up-regulation of FasL expression on CD8+ and naive CD4+ T cells, both of which are sensitive to the FasL costimulatory signal. Conversely, FasL-initiated death occurs late in an immune response when high levels of FasL expression are maintained on CD4+ T cells that are sensitive to Fas-mediated death, but not on CD8+ T cells that are relatively insensitive to this signal. This careful orchestration of FasL expression during times of susceptibility to costimulation and conversely, to death, endows FasL with the capacity to both positively and negatively regulate the peripheral T cell compartment. PMID:10677522

  5. Involvement of Fas/Fas-L and Bax/Bcl-2 systems in germ cell death following immunization with syngeneic testicular germ cells in mice.

    PubMed

    Kuerban, Maimaiti; Naito, Munekazu; Hirai, Shuichi; Terayama, Hayato; Qu, Ning; Musha, Muhetaerjiang; Ikeda, Ayumi; Koji, Takehiko; Itoh, Masahiro

    2012-01-01

    Experimental autoimmune orchitis (EAO) is characterized by T cell-dependent lymphocytic inflammation and seminiferous tubule damage, which can result in the death of germ cells. The aim of the present study is to investigate the roles of the Fas/Fas-L and Bax/Bcl-2 systems in the death of germ cells in mice with EAO that is induced by immunization with syngeneic testicular germ cells (TGC). The results using real-time reverse transcription-polymerase chain reaction and immunostaining show that many terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining germ cells were present in seminiferous tubules during the active inflammation stage, and these cells were persistently observed in the seminiferous epithelium until the postactive inflammation stage. Intratesticular mRNA expression levels of both Fas and Bax were increased during the active inflammation stage and were dramatically decreased during the post-active inflammation stage. In contrast, the intratesticular mRNA expression levels of both Fas-L and Bcl-2 did not show significant changes during the active inflammation stage but showed extreme increases during the post-active inflammation stage. Immunohistochemically, some Fas- and Bax-positive germ cells were detected during the active inflammation stage, but these were hardly found during the post-active inflammation stage. In contrast, some Fas-L- and Bcl-2-positive germ cells were found during the active inflammation stage, and many of these were also observed during the post-active inflammation stage. These results indicate that germ cell death during TGC-induced EAO is mediated by the Fas/Fas-L and Bax/Bcl-2 systems during the active inflammation stage but not during the post-active inflammation stage.

  6. FasL and TRAIL Induce Epidermal Apoptosis and Skin Ulceration Upon Exposure to Leishmania major

    PubMed Central

    Eidsmo, Liv; Fluur, Caroline; Rethi, Bence; Eriksson Ygberg, Sofia; Ruffin, Nicolas; De Milito, Angelo; Akuffo, Hannah; Chiodi, Francesca

    2007-01-01

    Receptor-mediated apoptosis is proposed as an important regulator of keratinocyte homeostasis in human epidermis. We have previously reported that Fas/FasL interactions in epidermis are altered during cutaneous leishmaniasis (CL) and that keratinocyte death through apoptosis may play a pathogenic role for skin ulceration. To further investigate the alterations of apoptosis during CL, a keratinocyte cell line (HaCaT) and primary human epidermal keratinocytes were incubated with supernatants from Leishmania major-infected peripheral blood mononuclear cells. An apoptosis-specific microarray was used to assess mRNA expression in HaCaT cells exposed to supernatants derived from L. major-infected cultures. Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA and protein expression were significantly up-regulated, and apoptosis was detected in both HaCaT and human epidermal keratinocyte cells. The keratinocyte apoptosis was partly inhibited through blocking of Fas or FasL and even more efficiently through TRAIL neutralization. Up-regulation of Fas on keratinocytes in epidermis and the presence of FasL-expressing macrophages and T cells in dermis were previously reported by us. In this study, keratinocytes expressing TRAIL, as well as the proapoptotic receptor TRAIL-R2, were detected in skin biopsies from CL cases. We propose that activation of Fas and TRAIL apoptosis pathways, in the presence of inflammatory mediators at the site of infection, leads to tissue destruction and ulceration during CL. PMID:17200196

  7. Inorganic mercury dissociates preassembled Fas/CD95 receptor oligomers in T lymphocytes

    SciTech Connect

    Ziemba, Stamatina E.; McCabe, Michael J.; Rosenspire, Allen J. . E-mail: arosensp@sun.science.wayne.edu

    2005-08-15

    Genetically susceptible rodents exposed to low burdens of inorganic mercury (Hg{sup 2+}) develop autoimmune disease. Previous studies have shown that low, noncytotoxic levels of Hg{sup 2+} inhibit Fas-mediated apoptosis in T cells. These results suggest that inhibition of the Fas death receptor pathway potentially contributes to autoimmune disease after Hg{sup 2+} exposure, as a consequence of disruption of peripheral tolerance. The formation of active death inducing signaling complexes (DISC) following CD95/Fas receptor oligomerization is a primary step in the Fas-mediated apoptotic pathway. Other recent studies have shown that Hg{sup 2+} at concentrations that inhibit apoptosis also inhibit formation of active DISC, suggesting that inhibition of DISC is the mechanism responsible for Hg{sup 2+}-mediated inhibition of apotosis. Preassociated Fas receptors have been implicated as key elements necessary for the production of functional DISC. We present evidence in this study showing that low and nontoxic concentrations of Hg{sup 2+} induce the dissociation of preassembled Fas receptor complexes in Jurkat T cells. Thus, this Hg{sup 2+}-induced event should subsequently decrease the amount of preassembled Fas available for DISC formation, potentially resulting in the attenuation of Fas-mediated apoptosis in T lymphocytes.

  8. The influence of effector T cells and Fas ligand on lupus-associated B cells.

    PubMed

    Fields, Michele L; Nish, Simone A; Hondowicz, Brian D; Metzgar, Michele H; Wharton, Gina N; Caton, Andrew J; Erikson, Jan

    2005-07-01

    Circulating autoantibodies against dsDNA and chromatin are a characteristic of systemic lupus erythematosus in humans and many mouse models of this disease. B cells expressing these autoantibodies are normally regulated in nonautoimmune-prone mice but are induced to secrete Abs following T cell help. Likewise, anti-chromatin autoantibody production is T cell-dependent in Fas/Fas ligand (FasL)-deficient (lpr/lpr or gld/gld) mice. In this study, we demonstrate that Th2 cells promote anti-chromatin B cell survival and autoantibody production in vivo. FasL influences the ability of Th2 cells to help B cells, as Th2-gld/gld cells support higher titers of anti-chromatin Abs than their FasL-sufficient counterparts and promote anti-chromatin B cell participation in germinal centers. Th1 cells induce anti-chromatin B cell germinal centers regardless of FasL status; however, their ability to stimulate anti-chromatin Ab production positively correlates with their level of IFN-gamma production. This distinction is lost if FasL-deficient T cells are used: Th1-gld/gld cells promote significant titers of anti-chromatin Abs regardless of IFN-gamma production levels. Thus, FasL from effector T cells plays an important role in determining the fate of anti-chromatin B cells.

  9. Fas–Fas Ligand: Checkpoint of T Cell Functions in Multiple Sclerosis

    PubMed Central

    Volpe, Elisabetta; Sambucci, Manolo; Battistini, Luca; Borsellino, Giovanna

    2016-01-01

    Fas and Fas Ligand (FasL) are two molecules involved in the regulation of cell death. Their interaction leads to apoptosis of thymocytes that fail to rearrange correctly their T cell receptor (TCR) genes and of those that recognize self-antigens, a process called negative selection; moreover, Fas–FasL interaction leads to activation-induced cell death, a form of apoptosis induced by repeated TCR stimulation, responsible for the peripheral deletion of activated T cells. Both control mechanisms are particularly relevant in the context of autoimmune diseases, such as multiple sclerosis (MS), where T cells exert an immune response against self-antigens. This concept is well demonstrated by the development of autoimmune diseases in mice and humans with defects in Fas or FasL. In recent years, several new aspects of T cell functions in MS have been elucidated, such as the pathogenic role of T helper (Th) 17 cells and the protective role of T regulatory (Treg) cells. Thus, in this review, we summarize the role of the Fas–FasL pathway, with particular focus on its involvement in MS. We then discuss recent advances concerning the role of Fas–FasL in regulating Th17 and Treg cells’ functions, in the context of MS. PMID:27729910

  10. The Fetal Alcohol Syndrome Public Awareness Campaign, 1979: Progress Report Concerning the Advance Notice of Proposed Rulemaking on Warning Labels on Containers of Alcoholic Beverages and Addendum.

    ERIC Educational Resources Information Center

    Department of the Treasury, Washington, DC.

    This report provides expert opinion on the problems of fetal alcohol syndrome (FAS) and ways to inform the public of teratogenic risk of alcohol consumption during pregnancy. In the absence of firm evidence that moderate drinking of alcoholic beverages leads to FAS and uncertainty concerning the effectiveness of labeling of alcoholic beverages, a…

  11. Baicalin protects sertoli cells from heat stress-induced apoptosis via activation of the Fas/FasL pathway and Hsp72 expression.

    PubMed

    Guo, Xiaotong; Chi, Shikai; Cong, Xia; Li, Huatao; Jiang, Zhongling; Cao, Rongfeng; Tian, Wenru

    2015-11-01

    Certain Chinese herbal medicines have antipyretic effects in both animal and human clinical practice. However, no report indicates their antipyretic effects on heat-stressed cells. The present study aimed to identify the protective effects of baicalin on the apoptosis of primary cultured bovine sertoli cells (SCs) subjected to heat stress (HS). The results demonstrated that HS induced apoptosis in the SCs exposed to 43°C for 1h as Fas/FasL was activated and caspase-3 was cleaved, the cells apoptotic rate was decreased. Moreover, the mRNA and protein levels of Hsp72 increased, whereas the cells apoptotic rate and expression of Fas, FasL, caspases 8 and 3 decreased in the SCs pretreated with various concentrations (0.1, 1, 10, 20μg/mL) of baicalin prior to HS. In conclusion, baicalin ameliorates heat stress-induced cell apoptosis via the modulation of the cell survival rate through Fas/FasL pathway activation and the upregulation of Hsp72 expression in bovine SCs.

  12. Novel mechanism of harmaline on inducing G2/M cell cycle arrest and apoptosis by up-regulating Fas/FasL in SGC-7901 cells.

    PubMed

    Wang, Yihai; Wang, Chunhua; Jiang, Chenguang; Zeng, Hong; He, Xiangjiu

    2015-12-18

    Harmaline (HAR), a natural occurrence β-carboline alkaloid, was isolated from the seeds of Peganum harmala and exhibited potent antitumor effect. In this study, the anti-gastric tumor effects of HAR were firstly investigated in vitro and in vivo. The results strongly showed that HAR could inhibit tumor cell proliferation and induce G2/M cell cycle arrest accompanied by an increase in apoptotic cell death in SGC-7901 cancer cells. HAR could up-regulate the expressions of cell cycle-related proteins of p-Cdc2, p21, p-p53, Cyclin B and down-regulate the expression of p-Cdc25C. In addition, HAR could up-regulate the expressions of Fas/FasL, activated Caspase-8 and Caspase-3. Moreover, blocking Fas/FasL signaling could markedly inhibit the apoptosis caused by HAR, suggesting that Fas/FasL mediated pathways were involved in HAR-induced apoptosis. Interestingly, HAR could also exert on antitumor activity with a dose of 15 mg/kg/day in vivo, which was also related with cell cycle arrest. These new findings provided a framework for further exploration of HAR which possess the potential antitumor activity by inducing cell cycle arrest and apoptosis.

  13. Novel mechanism of harmaline on inducing G2/M cell cycle arrest and apoptosis by up-regulating Fas/FasL in SGC-7901 cells

    PubMed Central

    Wang, Yihai; Wang, Chunhua; Jiang, Chenguang; Zeng, Hong; He, Xiangjiu

    2015-01-01

    Harmaline (HAR), a natural occurrence β-carboline alkaloid, was isolated from the seeds of Peganum harmala and exhibited potent antitumor effect. In this study, the anti-gastric tumor effects of HAR were firstly investigated in vitro and in vivo. The results strongly showed that HAR could inhibit tumor cell proliferation and induce G2/M cell cycle arrest accompanied by an increase in apoptotic cell death in SGC-7901 cancer cells. HAR could up-regulate the expressions of cell cycle-related proteins of p-Cdc2, p21, p-p53, Cyclin B and down-regulate the expression of p-Cdc25C. In addition, HAR could up-regulate the expressions of Fas/FasL, activated Caspase-8 and Caspase-3. Moreover, blocking Fas/FasL signaling could markedly inhibit the apoptosis caused by HAR, suggesting that Fas/FasL mediated pathways were involved in HAR-induced apoptosis. Interestingly, HAR could also exert on antitumor activity with a dose of 15 mg/kg/day in vivo, which was also related with cell cycle arrest. These new findings provided a framework for further exploration of HAR which possess the potential antitumor activity by inducing cell cycle arrest and apoptosis. PMID:26678950

  14. [Valoration of the FAS in the contralateral testis after unilateral testicular torsion. Experimental study in rats].

    PubMed

    Paredes Esteban, R M; Ramírez Chamond, R; Carracedo Añón, J; Rodríguez Portillo, M

    2003-01-01

    The role the FAS and BCL-2 in the apoptosis of testicular cells in the contralateral testis after unilateral testicular torsion, was investigated. We compared with control group. These experiments were performed in male Wistar rats prepuberal old. FAS and BCL-2 determination is realized in cells cultures of contralateral testis. Flow cytometry and immunohistochemistry studies, using a FAS and BCL-2 specific monoclonal antibody, were utilized to value FAS y BCL-2 expression on testiculaires cells following unilateral testicular torsion. We observed an increase of expression of FAS and decrease of BCL-2 in the contralateral testis in comparison with control group. The present results may indicate that the expression of this molecules is implicated in cellular apoptosis.

  15. Apoptosis in a Fas-resistant, T-cell receptor-sensitive human leukaemic T-cell clone.

    PubMed Central

    Delehanty, L L; Payne, J A; Farrow, S N; Brown, R; Champion, B R

    1997-01-01

    The Fas (CD95) antigen plays a key role in regulating T-cell activation and survival. We have generated a Fas-resistant subclone of the human T-cell leukaemia line, H9, which is still able to undergo apoptosis in response to T-cell receptor ligation. Molecular analyses revealed that resistance to Fas-mediated apoptosis was due to a heterozygous mutation in the death domain of the Fas gene which generates a stop codon, and thus encodes a truncated Fas molecule. Fas ligation was able to induce apoptosis in the presence of cycloheximide, indicating that the mutant Fas molecule retained some signalling capability, which is death-domain independent. These cells will provide a useful tool for dissecting the complexities of Fas signalling pathways. Images Figure 5 PMID:9155645

  16. Systemic FasL and TRAIL Neutralisation Reduce Leishmaniasis Induced Skin Ulceration

    PubMed Central

    Lieke, Thorsten; Lemu, Befekadu; Meless, Hailu; Ruffin, Nicolas; Wolday, Dawit; Asseffa, Abraham; Yagita, Hideo; Britton, Sven; Akuffo, Hannah

    2010-01-01

    Cutaneous leishmaniasis (CL) is caused by Leishmania infection of dermal macrophages and is associated with chronic inflammation of the skin. L. aethiopica infection displays two clinical manifestations, firstly ulcerative disease, correlated to a relatively low parasite load in the skin, and secondly non-ulcerative disease in which massive parasite infiltration of the dermis occurs in the absence of ulceration of epidermis. Skin ulceration is linked to a vigorous local inflammatory response within the skin towards infected macrophages. Fas ligand (FasL) and Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expressing cells are present in dermis in ulcerative CL and both death ligands cause apoptosis of keratinocytes in the context of Leishmania infection. In the present report we show a differential expression of FasL and TRAIL in ulcerative and non-ulcerative disease caused by L. aethiopica. In vitro experiments confirmed direct FasL- and TRAIL-induced killing of human keratinocytes in the context of Leishmania-induced inflammatory microenvironment. Systemic neutralisation of FasL and TRAIL reduced ulceration in a model of murine Leishmania infection with no effect on parasitic loads or dissemination. Interestingly, FasL neutralisation reduced neutrophil infiltration into the skin during established infection, suggesting an additional proinflammatory role of FasL in addition to direct keratinocyte killing in the context of parasite-induced skin inflammation. FasL signalling resulting in recruitment of activated neutrophils into dermis may lead to destruction of the basal membrane and thus allow direct FasL mediated killing of exposed keratinocytes in vivo. Based on our results we suggest that therapeutic inhibition of FasL and TRAIL could limit skin pathology during CL. PMID:20967287

  17. FINE-GRAINED PITCH ACCENT AND BOUNDARY TONE LABELING WITH PARAMETRIC F0 FEATURES

    PubMed Central

    Ananthakrishnan, Sankaranarayanan; Narayanan, Shrikanth

    2009-01-01

    Motivated by linguistic theories of prosodic categoricity, symbolic representations of prosody have recently attracted the attention of speech technologists. Categorical representations such as ToBI not only bear linguistic relevance, but also have the advantage that they can be easily modeled and integrated within applications. Since manual labeling of these categories is time-consuming and expensive, there has been significant interest in automatic prosody labeling. This paper presents a fine-grained ToBI-style prosody labeling system that makes use of features derived from RFC and TILT parameterization of F0 together with a n-gram prosodic language model for 4-way pitch accent labeling and 2-way boundary tone labeling. For this task, our system achieves pitch accent labeling accuracy of 56.4% and boundary tone labeling accuracy of 67.7% on the Boston University Radio News Corpus. PMID:19180228

  18. Vowel normalization for accent: An investigation of perceptual plasticity in young adults

    NASA Astrophysics Data System (ADS)

    Evans, Bronwen G.; Iverson, Paul

    2004-05-01

    Previous work has emphasized the role of early experience in the ability to accurately perceive and produce foreign or foreign-accented speech. This study examines how listeners at a much later stage in language development-early adulthood-adapt to a non-native accent within the same language. A longitudinal study investigated whether listeners who had had no previous experience of living in multidialectal environments adapted their speech perception and production when attending university. Participants were tested before beginning university and then again 3 months later. An acoustic analysis of production was carried out and perceptual tests were used to investigate changes in word intelligibility and vowel categorization. Preliminary results suggest that listeners are able to adjust their phonetic representations and that these patterns of adjustment are linked to the changes in production that speakers typically make due to sociolinguistic factors when living in multidialectal environments.

  19. H3K9 Trimethylation Silences Fas Expression To Confer Colon Carcinoma Immune Escape and 5-Fluorouracil Chemoresistance.

    PubMed

    Paschall, Amy V; Yang, Dafeng; Lu, Chunwan; Choi, Jeong-Hyeon; Li, Xia; Liu, Feiyan; Figueroa, Mario; Oberlies, Nicholas H; Pearce, Cedric; Bollag, Wendy B; Nayak-Kapoor, Asha; Liu, Kebin

    2015-08-15

    The Fas-FasL effector mechanism plays a key role in cancer immune surveillance by host T cells, but metastatic human colon carcinoma often uses silencing Fas expression as a mechanism of immune evasion. The molecular mechanism under FAS transcriptional silencing in human colon carcinoma is unknown. We performed genome-wide chromatin immunoprecipitation sequencing analysis and identified that the FAS promoter is enriched with H3K9me3 in metastatic human colon carcinoma cells. The H3K9me3 level in the FAS promoter region is significantly higher in metastatic than in primary cancer cells, and it is inversely correlated with Fas expression level. We discovered that verticillin A is a selective inhibitor of histone methyltransferases SUV39H1, SUV39H2, and G9a/GLP that exhibit redundant functions in H3K9 trimethylation and FAS transcriptional silencing. Genome-wide gene expression analysis identified FAS as one of the verticillin A target genes. Verticillin A treatment decreased H3K9me3 levels in the FAS promoter and restored Fas expression. Furthermore, verticillin A exhibited greater efficacy than decitabine and vorinostat in overcoming colon carcinoma resistance to FasL-induced apoptosis. Verticillin A also increased DR5 expression and overcame colon carcinoma resistance to DR5 agonist drozitumab-induced apoptosis. Interestingly, verticillin A overcame metastatic colon carcinoma resistance to 5-fluorouracil in vitro and in vivo. Using an orthotopic colon cancer mouse model, we demonstrated that tumor-infiltrating cytotoxic T lymphocytes are FasL(+) and that FasL-mediated cancer immune surveillance is essential for colon carcinoma growth control in vivo. Our findings determine that H3K9me3 of the FAS promoter is a dominant mechanism underlying FAS silencing and resultant colon carcinoma immune evasion and progression.

  20. Pitch accent alignment in romance: primary and secondary associations with metrical structure.

    PubMed

    Prieto, Pilar; D'Imperio, Mariapaola; Fivela, Barbara Gili

    2005-01-01

    The article describes the contrastive possibilities of alignment of high accents in three Romance varieties, namely, Central Catalan, Neapolitan Italian, and Pisa Italian. The Romance languages analyzed in this article provide crucial evidence that small differences in alignment in rising accents should be encoded phonologically. To account for such facts within the AM model, the article develops the notion of "phonological anchoring" as an extension of the concept of secondary association originally proposed by Pierrehumbert and Beckman (1988), and later adopted by Grice (1995), Grice, Ladd, and Arvaniti (2000), and others to explain the behavior of edge tones. The Romance data represent evidence that not only peripheral edge tones seek secondary associations. We claim that the phonological representation of pitch accents should include two independent mechanisms to encode alignment properties with metrical structure: (1) encoding of the primary phonological association (or affiliation) between the tone and its tone-bearing unit; and (2), for some specific cases, encoding of the secondary phonological anchoring of tones to prosodic edges (moras, syllables, and prosodic words). The Romance data described in the article provide crucial evidence of mora-edge, syllable-edge, and word-edge H tonal associations.

  1. Speech assessment of Chinese-English bilingual children: accent versus developmental level.

    PubMed

    Hack, Jamie; Marinova-Todd, Stefka H; May Bernhardt, B

    2012-12-01

    The study aimed to evaluate the phonological profiles of Chinese-English bilingual children in primary grades relative to those of English monolinguals, and to compare these profiles with speech-language pathologists' (SLPs') ratings of children's speech in terms of accent or developmental level. Participants were 29 Chinese-English bilinguals and 25 English-monolingual children. Speech samples were collected using the Goldman-Fristoe Test of Articulation-2, either a Cantonese or Mandarin phonology test, and three sentences in a delayed repetition task. In addition, 10 SLPs rated each of the randomized sentences on either an accent or developmental level scale. Bilingual children with identified accents had significantly lower standard scores than monolingual children on the GFTA-2, but on the Chinese phonological assessments the same children showed age-expected speech. The differences in the bilingual children's scores on phonology tests in English vs Chinese highlight the need for phonological assessment in both languages. The SLP listener results further suggest that perceptual judgement may be a useful complement in phonological assessment of bilingual children but not a replacement for more formal testing.

  2. Listening with a foreign-accent: The interlanguage speech intelligibility benefit in Mandarin speakers of English.

    PubMed

    Xie, Xin; Fowler, Carol A

    2013-09-01

    This study examined the intelligibility of native and Mandarin-accented English speech for native English and native Mandarin listeners. In the latter group, it also examined the role of the language environment and English proficiency. Three groups of listeners were tested: native English listeners (NE), Mandarin-speaking Chinese listeners in the US (M-US) and Mandarin listeners in Beijing, China (M-BJ). As a group, M-US and M-BJ listeners were matched on English proficiency and age of acquisition. A nonword transcription task was used. Identification accuracy for word-final stops in the nonwords established two independent interlanguage intelligibility effects. An interlanguage speech intelligibility benefit for listeners (ISIB-L) was manifest by both groups of Mandarin listeners outperforming native English listeners in identification of Mandarin-accented speech. In the benefit for talkers (ISIB-T), only M-BJ listeners were more accurate identifying Mandarin-accented speech than native English speech. Thus, both Mandarin groups demonstrated an ISIB-L while only the M-BJ group overall demonstrated an ISIB-T. The English proficiency of listeners was found to modulate the magnitude of the ISIB-T in both groups. Regression analyses also suggested that the listener groups differ in their use of acoustic information to identify voicing in stop consonants.

  3. Voice onset time and global foreign accent in mature Japanese-English bilinguals

    NASA Astrophysics Data System (ADS)

    Riney, Timothy J.

    2004-05-01

    Experiment 1 investigates to what degree the phonetic category established in childhood for an L1 sound may evolve gradually [Flege, Speech Learning Model (1995)]. VOT is assessed in two groups of five bilingual (English and Japanese) speakers, one L1 English and the other L1 Japanese, ages 35-60 with little or no L2 exposure before age 15, but working in the L2 regularly for 15-35 years in adulthood. Both groups read lists of English and Japanese words containing word initial /p/, /t/, and /k/; 880 tokens (10 speakers × 2 languages × 44 tokens per language) were examined. The findings for both groups were that (a) the L1 VOT values did not change much over time and (b) the L2 VOT values were halfway between the L1 and target language values. Experiment 2 investigates the relationship between individual VOT and accent. The ten speakers were asked to read five Japanese sentences, now digitized. Ten additional L1 Japanese participants will rate these sentences for accent in March 2004. The prediction is that the American speakers who have the most Japanese accents will also have VOT values that are closest to L1 Japanese values.

  4. Listening with a foreign-accent: The interlanguage speech intelligibility benefit in Mandarin speakers of English

    PubMed Central

    Xie, Xin; Fowler, Carol A.

    2013-01-01

    This study examined the intelligibility of native and Mandarin-accented English speech for native English and native Mandarin listeners. In the latter group, it also examined the role of the language environment and English proficiency. Three groups of listeners were tested: native English listeners (NE), Mandarin-speaking Chinese listeners in the US (M-US) and Mandarin listeners in Beijing, China (M-BJ). As a group, M-US and M-BJ listeners were matched on English proficiency and age of acquisition. A nonword transcription task was used. Identification accuracy for word-final stops in the nonwords established two independent interlanguage intelligibility effects. An interlanguage speech intelligibility benefit for listeners (ISIB-L) was manifest by both groups of Mandarin listeners outperforming native English listeners in identification of Mandarin-accented speech. In the benefit for talkers (ISIB-T), only M-BJ listeners were more accurate identifying Mandarin-accented speech than native English speech. Thus, both Mandarin groups demonstrated an ISIB-L while only the M-BJ group overall demonstrated an ISIB-T. The English proficiency of listeners was found to modulate the magnitude of the ISIB-T in both groups. Regression analyses also suggested that the listener groups differ in their use of acoustic information to identify voicing in stop consonants. PMID:24293741

  5. Acquisition of stress and pitch accent in English-Spanish bilingual children

    NASA Astrophysics Data System (ADS)

    Kim, Sahyang; Andruski, Jean; Nathan, Geoffrey S.; Casielles, Eugenia; Work, Richard

    2005-09-01

    Although understanding of prosodic development is considered crucial for understanding of language acquisition in general, few studies have focused on how children develop native-like prosody in their speech production. This study will examine the acquisition of lexical stress and postlexical pitch accent in two English-Spanish bilingual children. Prosodic characteristics of English and Spanish are different in terms of frequent stress patterns (trochaic versus penultimate), phonetic realization of stress (reduced unstressed vowel versus full unstressed vowel), and frequent pitch accent types (H* versus L*+H), among others. Thus, English-Spanish bilingual children's prosodic development may provide evidence of their awareness of language differences relatively early during language development, and illustrate the influence of markedness or input frequency in prosodic acquisition. For this study, recordings from the children's one-word stage are used. Durations of stressed and unstressed syllables and F0 peak alignment are measured, and pitch accent types in different accentual positions (nuclear versus prenuclear) are transcribed using American English ToBI and Spanish ToBI. Prosodic development is compared across ages within each language and across languages at each age. Furthermore, the bilingual children's productions are compared with monolingual English and Spanish parents' productions.

  6. Increased levels of soluble Fas ligand in CSF of rapidly progressive HTLV-1-associated myelopathy/tropical spastic paraparesis patients.

    PubMed

    Saito, M; Nakamura, N; Nagai, M; Shirakawa, K; Sato, H; Kawahigashi, N; Furukawa, Y; Usuku, K; Nakagawa, M; Izumo, S; Osame, M

    1999-08-03

    The interaction of Fas ligand (FasL) with Fas-bearing cells induces apoptosis and contributes to the negative regulation of peripheral T-cell responses. Membrane-bound FasL is cleaved by a matrix metalloproteinase-like enzyme and converted to a soluble form (sFasL). Recent studies suggest that such sFasL can cause systemic tissue damage. Here we report that serum and CSF levels of soluble FasL (sFasL) are markedly higher in three active phase patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). All of these patients showed higher sFasL levels in CSF than in serum. Although the HTLV-1 proviral load of patients showed no correlation with serum or with CSF sFasL, CSF sFasL levels of 14 HAM/TSP patients correlated with the anti-HTLV-1 antibody titer and neopterin concentration in CSF. These results indicate that sFasL mediated mechanisms may contribute to the inflammatory process and subsequent spinal tissue damage seen in HAM/TSP patients.

  7. Fetal Alcohol Syndrome in Adolescents and Adults.

    ERIC Educational Resources Information Center

    Bert, Cynthia R. Greene; Bert, Minnie

    Persons with fetal alcohol syndrome (FAS) may be diagnosed at birth based on specific symptoms and anomalies. These are history of prenatal alcohol exposure, mental retardation, central nervous system dysfunctions, growth deficiency, particular physical anomalies, and speech and language anomalies. With aging, cranial and skeletal anomalies become…

  8. Fetal Alcohol Syndrome: An International Concern.

    ERIC Educational Resources Information Center

    Asetoyer, Charon

    1987-01-01

    Describes Fetal Alcohol Effects (FAE) and Fetal Alcohol Syndrome (FAS) in infants, caused by mothers' consumption of alcohol during pregnancy. Both disabilities found in relatively high proportions of American Indian children. Discusses impact of disabilities on education. Discusses parent education programs in United States and abroad. (TES)

  9. MicroRNA-25 Negatively Regulates Cerebral Ischemia/Reperfusion Injury-Induced Cell Apoptosis Through Fas/FasL Pathway.

    PubMed

    Zhang, Jun-Feng; Shi, Li-Li; Zhang, Li; Zhao, Zhao-Hua; Liang, Fei; Xu, Xi; Zhao, Ling-Yu; Yang, Peng-Bo; Zhang, Jian-Shui; Tian, Ying-Fang

    2016-04-01

    MicroRNA-25 (miR-25) has been reported to be a major miRNA marker in neural cells and is strongly expressed in ischemic brain tissues. However, the precise mechanism and effect of miR-25 in cerebral ischemia/reperfusion (I/R) injury needs further investigations. In the present study, the oxygen-glucose deprivation (OGD) model was constructed in human SH-SY5Y and IMR-32 cells to mimic I/R injury and to evaluate the role of miR-25 in regulating OGD/reperfusion (OGDR)-induced cell apoptosis. We found that miR-25 was downregulated in the OGDR model. Overexpression of miR-25 via miRNA-mimics transfection remarkably inhibited OGDR-induced cell apoptosis. Moreover, Fas was predicted as a target gene of miR-25 through bioinformatic analysis. The interaction between miR-25 and 3'-untranslated region (UTR) of Fas mRNA was confirmed by dual-luciferase reporter assay. Fas protein expression was downregulated by miR-25 overexpression in OGDR model. Subsequently, the small interfering RNA (siRNA)-mediated knockdown of Fas expression also inhibited cell apoptosis induced by OGDR model; in contrast, Fas overexpression abrogated the protective effects of miR-25 on OGDR-induced cells. Taken together, our results indicate that the upregulation of miR-25 inhibits cerebral I/R injury-induced apoptosis through downregulating Fas/FasL, which will provide a promising therapeutic target.

  10. CD3(+) CD8(+) NKG2D(+) T Lymphocytes Induce Apoptosis and Necroptosis in HLA-negative Cells via FasL-Fas Interaction.

    PubMed

    Ivanova, O K; Sharapova, T N; Romanova, E A; Sashchenko, L P; Yashin, D V

    2017-03-15

    An important problem in cellular immunology is to identify new populations of cytotoxic lymphocytes capable of killing tumor cells that have lost classical components of MHC-machinery and to understand mechanisms of the death of these cells. We have previously found that CD4(+) CD25(+) lymphocytes appear in the lymphokine-activated killer (LAK) cell culture, which carry Tag7 (PGRP-S) and FasL proteins on their surface and can kill Hsp70- and Fas-expressing HLA-negative cells. In this work, we have continued to study the mechanisms of killing of the HLA-negative tumor cells, focusing this time on the CD8+ lymphocytes. We show that after a tumor antigen contact the IL-2 activated CD8+ lymphocytes acquire ability to lyse tumor cells bearing this antigen. However, activation of the CD8+ lymphocytes in the absence of antigen causes appearance of a cytotoxic population of CD8 + NKG2D+ lymphocytes, which are able to lyse HLA-negative cancer cells that have lost the classic mechanism of antigen presentation. These cells recognize the noncanonical MicA antigen on the surface of HLA-negative K562 cells but kill them via the FasL-Fas interaction, as do cytotoxic T lymphocytes. FasL presented on the lymphocyte surface can trigger both apoptosis and necroptosis. Unlike in the case of TNFR1, another cell death receptor, no switching to alternative processes has been observed upon induction of Fas-dependent cell death. It may well be that the apoptotic and necroptotic signals are transduced separately in the latter case, with the ability of FasL(+) lymphocytes to induce necroptosis allowing them to kill tumor cells that escape apoptosis. This article is protected by copyright. All rights reserved.

  11. Tissue plasminogen activator is required for the development of fetal alcohol syndrome in mice.

    PubMed

    Noel, Melissa; Norris, Erin H; Strickland, Sidney

    2011-03-22

    Ethanol exposure during developmental synaptogenesis can lead to brain defects referred to as fetal alcohol syndrome (FAS), which can include mental health problems such as cognitive deficits and mental retardation. In FAS, widespread neuronal death and brain mass loss precedes behavioral and cognitive impairments in adulthood. Because tissue plasminogen activator (tPA) has been implicated in neurodegeneration, we examined whether it mediates FAS. Neonatal WT and tPA-/- mice were injected with ethanol to mimic FAS in humans. In WT mice, ethanol elicited caspase-3 activation, significant forebrain neurodegeneration, and decreased contextual fear conditioning in adults. However, tPA-deficient mice were protected from these neurotoxicities, and this protection could be abrogated by exogenous tPA. Selective pharmacological modulators of NMDA and GABAA receptor pathways revealed that the effects of tPA were mediated by the NR2B subunit of the NMDA receptor. This study identifies tPA as a critical signaling component in FAS.

  12. Fetal Alcohol Syndrome in Sudden Unexpected Death in Infancy: A Case Report in Medicolegal Autopsy.

    PubMed

    Tangsermkijsakul, Aphinan

    2016-03-01

    Fetal alcohol spectrum disorder is a range of birth defects associated with prenatal alcohol exposure. Fetal alcohol syndrome (FAS) is the most serious form of fetal alcohol spectrum disorder. Infants with FAS are prone to death because of various physical abnormalities. Consequently, infants with FAS may be presented in the medicolegal investigation as a form of sudden unexpected death in infancy. The author reported a 6-month-old male infant who was found dead at home. The history of maternal ethanol consumption during pregnancy was obtained. The infant was diagnosed with FAS at the autopsy because he was presented with postnatal growth retardation, multiple facial abnormalities, and abnormal brain structures, which met the criteria of FAS. The cause of death was severe aspiration pneumonia. The purposes of this case report are to show an uncommon manifestation of sudden unexpected death in infancy case for the forensic pathologists and to emphasize on the national healthcare problem.

  13. MicroRNA 196B regulates FAS-mediated apoptosis in colorectal cancer cells

    PubMed Central

    Kang, In-Hong; Park, Won Cheol; Seo, Geom-Seog; Choi, Suck-Chei; Kim, Hun-Soo; Moon, Hyung-Bae; Yun, Ki-Jung; Chae, Soo-Cheon

    2015-01-01

    Using miRNA microarray analysis, we identified 31 miRNAs that were significantly up-regulated or down-regulated in colon cancer tissues. We chose MIR196B, which was specifically up-regulated in colon cancer, for further study. We identified 18 putative MIR196B target genes by comparing between the mRNAs down-regulated in MIR196B-overexpressed cells and the assumed MIR196B target genes predicted by public bioinformatics tools. The association between MIR196B and FAS was verified in this study. FAS expression was constitutively elevated in normal human colorectal tissues. However, its expression was often reduced in human colorectal cancer. The decrease in FAS expression could be responsible for the reduction of apoptosis in colorectal cancer cells. In colorectal cancer tissue, we showed that MIR196B up-regulation was mutually followed by down regulation of FAS expression. We also showed that MIR196B directly repressed FAS expression in colorectal cells. Furthermore, anti-MIR196B up-regulated FAS expression and increased apoptosis in colorectal cancer cell lines. Our results suggest that the up-regulation of MIR196B modulates apoptosis in colorectal cancer cells by partially repressing FAS expression and that anti-MIR196B could be a potential candidate as an anti-cancer drug in colorectal cancer therapy. PMID:25605245

  14. Fas/APO-1 protein is increased in spaceflown lymphocytes (Jurkat)

    NASA Technical Reports Server (NTRS)

    Cubano, L. A.; Lewis, M. L.

    2000-01-01

    Human lymphocytes flown on the Space Shuttle respond poorly to mitogen stimulation and populations of the lymphoblastoid T cell line, Jurkat, manifest growth arrest, increase in apoptosis and time- and microgravity-dependent increases in the soluble form of the cell death factor, Fas/APO-1 (sFas). The potential role of apoptosis in population dynamics of space-flown lymphocytes has not been investigated previously. We flew Jurkat cells on Space Transportation System (STS)-80 and STS-95 to determine whether apoptosis and the apparent microgravity-related release of sFas are characteristic of lymphocytes in microgravity. The effects of spaceflight and ground-based tests simulating spaceflight experimental conditions, including high cell density and low serum concentration, were assessed. Immunofluorescence microscopy showed increased cell associated Fas in flown cells. Results of STS-80 and STS-95 confirmed increase in apoptosis during spaceflight and the release of sFas as a repeatable, time-dependent and microgravity-related response. Ground-based tests showed that holding cells at 1.5 million/ml in medium containing 2% serum before launch did not increase sFas. Reports of increased Fas in cells of the elderly and the increases in spaceflown cells suggest possible similarities between aging and spaceflight effects on lymphocytes.

  15. Sevoflurane induces neurotoxicity in young mice through FAS/FASL signaling.

    PubMed

    Song, Q; Ma, Y L; Song, J Q; Chen, Q; Xia, G S; Ma, J Y; Feng, F; Fei, X J; Wang, Q M

    2015-12-22

    Sevoflurane, the most widely used anesthetic in clinical practice, has been shown to induce apoptosis, inhibit neurogenesis, and cause learning and memory impairment in young mice. However, the underlying mechanism is still unknown. In this study, wild-type and the FAS- or FAS ligand (FASL)-knockout mice (age 7 days) were exposed to sevoflurane or pure oxygen. Western blotting was used to examine the expression of FAS protein. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and bromodeoxyuridine (BrdU) staining were employed to quantify the apoptotic cells and newborn cells in the hippocampus and Morris water maze (MWM) in order to evaluate learning and memory status. Sevoflurane significantly increased the expression of FAS protein in wild-type mice. Compared to FAS- and FASL-knockout mice treated with sevoflurane, sevoflurane-treated wild-type mice exhibited more TUNEL-positive hippocampal cells and less BrdU-positive hippocampal cells. The MWM showed that compared with FAS- and FASL-knockout mice treated with sevoflurane, sevoflurane treatment of wild-type mice significantly prolonged the escape latency and reduced platform crossing times. These data suggest that sevoflurane induces neurotoxicity in young mice through FAS-FASL signaling.

  16. Evaluation of Fas2-ELISA for the serological detection of Fasciola hepatica infection in humans.

    PubMed

    Espinoza, Jose R; Maco, Vicente; Marcos, Luis; Saez, Sandra; Neyra, Victor; Terashima, Angelica; Samalvides, Frine; Gotuzzo, Eduardo; Chavarry, Elizabeth; Huaman, Maria Cecilia; Bargues, M Dolores; Valero, M Adela; Mas-Coma, Santiago

    2007-05-01

    The performance of Fas2-ELISA for the diagnosis of Fasciola hepatica infection in children living in areas of high endemicity for fascioliasis in the Peruvian Andes is analyzed. Fas2-ELISA is based on the detection of circulating IgG antibodies elicited in infected individuals against a F. hepatica antigen termed Fas2. The study was conducted in three Andean localities, Huertas-Julcan in Junin, Asillo in Puno, and Cajamarca, with a total population of 634 children in an age range 1 to 16 years old. Child fascioliasis prevalence was 21.1% in Huertas-Julcan, 25.4% in Asillo, and 24% in Cajamarca, estimated by coprological inspection. The seroprevalence of F. hepatica infection, determined by Fas2-ELISA, was 27.8% in Huertas-Julcan, 44.6% in Asillo, and 29.1% in Cajamarca. The overall sensitivity of Fas2-ELISA was 92.4%, the specificity 83.6%, and the negative predictive value 97.2%. No association between OD(450) Fas2-ELISA and infection intensity measured by egg counting was observed. Results show that Fas2-ELISA is a highly sensitive immunodiagnostic test for the detection of F. hepatica infection in children living in human fascioliasis endemic areas.

  17. Rhodococcus fascians impacts plant development through the dynamic fas-mediated production of a cytokinin mix.

    PubMed

    Pertry, Ine; Václavíková, Katerina; Gemrotová, Markéta; Spíchal, Lukás; Galuszka, Petr; Depuydt, Stephen; Temmerman, Wim; Stes, Elisabeth; De Keyser, Annick; Riefler, Michael; Biondi, Stefania; Novák, Ondrej; Schmülling, Thomas; Strnad, Miroslav; Tarkowski, Petr; Holsters, Marcelle; Vereecke, Danny

    2010-09-01

    The phytopathogenic actinomycete Rhodococcus fascians D188 relies mainly on the linear plasmid-encoded fas operon for its virulence. The bacteria secrete six cytokinin bases that synergistically redirect the developmental program of the plant to stimulate proliferation of young shoot tissue, thus establishing a leafy gall as a niche. A yeast-based cytokinin bioassay combined with cytokinin profiling of bacterial mutants revealed that the fas operon is essential for the enhanced production of isopentenyladenine, trans-zeatin, cis-zeatin, and the 2-methylthio derivatives of the zeatins. Cytokinin metabolite data and the demonstration of the enzymatic activities of FasD (isopentenyltransferase), FasE (cytokinin oxidase/dehydrogenase), and FasF (phosphoribohydrolase) led us to propose a pathway for the production of the cytokinin spectrum. Further evaluation of the pathogenicity of different fas mutants and of fas gene expression and cytokinin signal transduction upon infection implied that the secretion of the cytokinin mix is a highly dynamic process, with the consecutive production of a tom initiation wave followed by a maintenance flow.

  18. Lipid rafts mediate ultraviolet light-induced Fas aggregation in M624 melanoma cells.

    PubMed

    Elyassaki, Walid; Wu, Shiyong

    2006-01-01

    Ultraviolet light (UV) induces aggregation of Fas-receptor through a Fas-ligand-independent pathway. However, the mechanism of ultraviolet light-induced Fas-receptor aggregation is not known. In this report, we show that lipid rafts mediate ultraviolet light-induced aggregation of Fas. Our data show that UV induces a redistribution of Fas-receptor in a 25-5% Optiprep continuous gradient. The amount of Fas-receptorS is significantly increased in a gradient fraction that contain lipid rafts and is associated with an increase of FADD and caspase-8. Our data also show that the active dimeric form of caspase-8 (p44/p41) is increased in the lipid raft fraction. In addition, our data show that cholesterol, a major component of lipid rafts, is significantly reduced in only the lipid raft fractions after UV-irradiation. However, ceramide, another major lipid raft component, is increased evenly in all gradient fractions after UV-irradiation. These results suggest that UV alters the composition of major lipid raft components, which leads to the recruitment of Fas-receptor and FADD, with subsequent activation of caspase-8. Based on our results, we propose a novel mechanism by which UV induces apoptosis through a membrane lipid raft-mediated signaling pathway.

  19. Organization and Dynamics of Fas Transmembrane Domain in Raft Membranes and Modulation by Ceramide

    PubMed Central

    Castro, Bruno M.; de Almeida, Rodrigo F.M.; Goormaghtigh, Erik; Fedorov, Aleksander; Prieto, Manuel

    2011-01-01

    To comprehend the molecular processes that lead to the Fas death receptor clustering in lipid rafts, a 21-mer peptide corresponding to its single transmembrane domain (TMD) was reconstituted into mammalian raft model membranes composed of an unsaturated glycerophospholipid, sphingomyelin, and cholesterol. The peptide membrane lateral organization and dynamics, and its influence on membrane properties, were studied by steady-state and time-resolved fluorescence techniques and by attenuated total reflection Fourier transformed infrared spectroscopy. Our results show that Fas TMD is preferentially localized in liquid-disordered membrane regions and undergoes a strong reorganization as the membrane composition is changed toward the liquid-ordered phase. This results from the strong hydrophobic mismatch between the length of the peptide hydrophobic stretch and the hydrophobic thickness of liquid-ordered membranes. The stability of nonclustered Fas TMD in liquid-disordered domains suggests that its sequence may have a protective function against nonligand-induced Fas clustering in lipid rafts. It has been reported that ceramide induces Fas oligomerization in lipid rafts. Here, it is shown that neither Fas TMD membrane organization nor its conformation is affected by ceramide. These results are discussed within the framework of Fas membrane signaling events. PMID:21961589

  20. Thymineless Death in F10-Treated AML Cells Occurs via Lipid Raft Depletion and Fas/FasL co-Localization in the Plasma Membrane with Activation of the Extrinsic Apoptotic Pathway

    PubMed Central

    Gmeiner, William H.; Jennings-Gee, Jamie; Stuart, Christopher H.; Pardee, Timothy S.

    2014-01-01

    The polymeric fluoropyrimidine F10 displays excellent anti-leukemia activity in pre-clinical models of acute myelogenous leukemia (AML) through dual targeting of thymidylate synthase and DNA topoisomerase 1. Here we report that F10 activates the extrinsic apoptotic pathway in AML cells by enhancing localization of Fas and Fas ligand (FasL) at the plasma membrane and while reducing overall lipid raft levels promotes Fas/FasL co-localization in remaining lipid rafts. The HMG-CoA synthase inhibitor simvastatin was synergistic with F10 and induced cell death via similar apoptotic processes. Our results are consistent with diverse processes activating a common apoptotic pathway characterized by reduced overall levels of lipid rafts and Fas/FasL co-localization in the plasma membrane, including in remaining lipid rafts which may play a role in both cell-survival and cell death signaling. PMID:25510486

  1. Thymineless death in F10-treated AML cells occurs via lipid raft depletion and Fas/FasL co-localization in the plasma membrane with activation of the extrinsic apoptotic pathway.

    PubMed

    Gmeiner, William H; Jennings-Gee, Jamie; Stuart, Christopher H; Pardee, Timothy S

    2015-02-01

    The polymeric fluoropyrimidine F10 displays excellent anti-leukemia activity in pre-clinical models of acute myelogenous leukemia (AML) through dual targeting of thymidylate synthase and DNA topoisomerase 1. Here we report that F10 activates the extrinsic apoptotic pathway in AML cells by enhancing localization of Fas and Fas ligand (FasL) at the plasma membrane and while reducing overall lipid raft levels promotes Fas/FasL co-localization in remaining lipid rafts. The HMG-CoA synthase inhibitor simvastatin was synergistic with F10 and induced cell death via similar apoptotic processes. Our results are consistent with diverse processes activating a common apoptotic pathway characterized by reduced overall levels of lipid rafts and Fas/FasL co-localization in the plasma membrane, including in remaining lipid rafts which may play a role in both cell-survival and cell death signaling.

  2. Positive regulation of Fas gene expression by MSSP and abrogation of Fas-mediated apoptosis induction in MSSP-deficient mice.

    PubMed

    Nomura, Jun; Matsumoto, Ken-ichi; Iguchi-Ariga, Sanae M M; Ariga, Hiroyoshi

    2005-05-01

    MSSP has been identified as a transcription factor that regulates the c-myc gene. MSSP was later found to positively or negatively regulate a variety of genes, including alpha-smooth actin, MHC class I, MHC class 2 and the thyrotropin receptor. The knockout mice for the Mssp gene developed by us revealed that these mice became partially embryonic lethal due to a low concentration of progesterone at E2.5. In this study, we further analyzed Mssp-knockout mice and found that the expression of the Fas gene was repressed, resulting in abrogation of Fas-mediated induction of apoptosis both in Mssp-knockout mice and primary thymocytes. MSSP was then found to stimulate promoter activity of the Fas gene by binding to a region spanning -1035 to -635 in chromatin immunoprecipitation assays. Binding of MSSP in the MSSP-binding sequence, TCTAAT, located in this region was confirmed by mobility shift assays, and deletion of this sequence from the Fas promoter was found to result in loss of MSSP-dependent stimulating activity. The results suggest that MSSP is an important mediator for Fas-induced apoptosis in vivo and in vitro.

  3. BCR engagement induces Fas resistance in primary B cells in the absence of functional Bruton's tyrosine kinase.

    PubMed

    Tumang, Joseph R; Negm, Robert S; Solt, Laura A; Schneider, Thomas J; Colarusso, Thomas P; Hastings, William D; Woodland, Robert T; Rothstein, Thomas L

    2002-03-15

    B cell susceptibility to Fas-mediated apoptosis is regulated in a receptor-specific fashion. CD40 engagement produces marked sensitivity to Fas killing, whereas surface Ig (sIg) engagement blocks Fas signaling for cell death in otherwise sensitive, CD40-stimulated B cell targets, and thus, induces a state of Fas resistance. The signaling mediator, Bruton's tyrosine kinase (Btk), is required for certain sIg-triggered responses, and Btk is reported to directly bind Fas and block Fas-mediated apoptosis. For these reasons, the role of Btk as a mediator of sIg-induced Fas resistance was examined. Dysfunction of Btk through mutation, and absence of Btk through deletion did not interfere with induction of Fas resistance by anti-Ig. This may be due, at least in part, to induction of Btk-dependent Bcl-2 family members by anti-Ig after CD40 ligand treatment. However, the susceptibility to Fas-mediated apoptosis of B cell targets stimulated by CD40 ligand alone was increased in the absence of Btk. These results indicate that Fas resistance produced by sIg triggering does not require Btk, but suggests that in certain situations Btk modulates B cell susceptibility to Fas killing.

  4. NFκB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP

    PubMed Central

    Kreuz, Sebastian; Siegmund, Daniela; Rumpf, Jost-Julian; Samel, Dierk; Leverkus, Martin; Janssen, Ottmar; Häcker, Georg; Dittrich-Breiholz, Oliver; Kracht, Michael; Scheurich, Peter; Wajant, Harald

    2004-01-01

    Fas (APO-1/CD95) is the prototypic death receptor, and the molecular mechanisms of Fas-induced apoptosis are comparably well understood. Here, we show that Fas activates NFκB via a pathway involving RIP, FADD, and caspase-8. Remarkably, the enzymatic activity of the latter was dispensable for Fas-induced NFκB signaling pointing to a scaffolding-related function of caspase-8 in nonapoptotic Fas signaling. NFκB was activated by overexpressed FLIPL and FLIPS in a cell type–specific manner. However, in the context of Fas signaling both isoforms blocked FasL-induced NFκB activation. Moreover, down-regulation of both endogenous FLIP isoforms or of endogenous FLIPL alone was sufficient to enhance FasL-induced expression of the NFκB target gene IL8. As NFκB signaling is inhibited during apoptosis, FasL-induced NFκB activation was most prominent in cells that were protected by Bcl2 expression or caspase inhibitors and expressed no or minute amounts of FLIP. Thus, protection against Fas-induced apoptosis in a FLIP-independent manner converted a proapoptotic Fas signal into an inflammatory NFκB-related response. PMID:15289496

  5. Fas Versatile Signaling and Beyond: Pivotal Role of Tyrosine Phosphorylation in Context-Dependent Signaling and Diseases

    PubMed Central

    Chakrabandhu, Krittalak; Hueber, Anne-Odile

    2016-01-01

    The Fas/FasL system is known, first and foremost, as a potent apoptosis activator. While its proapoptotic features have been studied extensively, evidence that the Fas/FasL system can elicit non-death signals has also accumulated. These non-death signals can promote survival, proliferation, migration, and invasion of cells. The key molecular mechanism that determines the shift from cell death to non-death signals had remained unclear until the recent identification of the tyrosine phosphorylation in the death domain of Fas as the reversible signaling switch. In this review, we present the connection between the recent findings regarding the control of Fas multi-signals and the context-dependent signaling choices. This information can help explain variable roles of Fas signaling pathway in different pathologies. PMID:27799932

  6. Fas signal promotes lung cancer growth by recruiting myeloid-derived suppressor cells via cancer cell-derived PGE2.

    PubMed

    Zhang, Yongliang; Liu, Qiuyan; Zhang, Minggang; Yu, Yizhi; Liu, Xia; Cao, Xuetao

    2009-03-15

    Fas/FasL system has been extensively investigated with respect to its capacity to induce cellular apoptosis. However, accumulated evidences show that Fas signaling also exhibits nonapoptotic functions, such as induction of cell proliferation and differentiation. Lung cancer is one of cancer's refractory to the immunotherapy, however, the underlying mechanisms remain to be fully understood. In this study, we show that Fas overexpression does not affect in vitro growth of 3LL cells, but promotes lung cancer growth in vivo. However, such tumor-promoting effect is not observed in FasL-deficient (gld) mice, and also not observed in the immune competent mice once inoculation with domain-negative Fas-overexpressing 3LL cells, suggesting the critical role of Fas signal in the promotion of lung cancer growth in vivo. More accumulation of myeloid-derived suppressor cells (MDSC) and Foxp3(+) regulatory T cells is found in tumors formed by inoculation with Fas-overexpressing 3LL cells, but not domain-negative Fas-overexpressing 3LL cells. Accordingly, Fas-ligated 3LL lung cancer cells can chemoattract more MDSC but not regulatory T cells in vitro. Furthermore, Fas ligation induces 3LL lung cancer cells to produce proinflammatory factor PGE(2) by activating p38 pathway, and in turn, 3LL cells-derived PGE(2) contribute to the Fas ligation-induced MDSC chemoattraction. Furthermore, in vivo administration of cyclooxygenase-2 inhibitor can significantly reduce MDSC accumulation in the Fas-overexpressing tumor. Therefore, our results demonstrate that Fas signal can promote lung cancer growth by recruiting MDSC via cancer cell-derived PGE(2), thus providing new mechanistic explanation for the role of inflammation in cancer progression and immune escape.

  7. Prevention of fetal alcohol syndrome

    PubMed Central

    Fröschl, Barbara; Brunner-Ziegler, Sophie; Wirl, Charlotte

    2013-01-01

    The fetal alcohol syndrome (FAS) is the most avoidable handicap of newborns. It describes prenatal damages which result from the alcohol consumption of the mother. These can be: reduced body length and weight (pre- and postnatal), microcephaly, musculoskeletal, mental and statomotoric developmental retardations and impaired coordinative ability. There are preventive measures of which the efficiency is examined. Already, short counseling interviews, so-called short interventions, increase the abstinence of pregnant women. PMID:24009646

  8. Prevalence and Characteristics of Fetal Alcohol Syndrome and Partial Fetal Alcohol Syndrome in a Rocky Mountain Region City

    PubMed Central

    Keaster, Carol; Bozeman, Rosemary; Goodover, Joelene; Blankenship, Jason; Kalberg, Wendy O.; Buckley, David; Brooks, Marita; Hasken, Julie; Gossage, J. Phillip; Robinson, Luther K.; Manning, Melanie; Hoyme, H. Eugene

    2015-01-01

    Background The prevalence and characteristics of fetal alcohol syndrome (FAS) and partial FAS (PFAS) in the United States (US) are not well known. Methods This active case ascertainment study in a Rocky Mountain Region City assessed the prevalence and traits of children with FAS and PFAS and linked them to maternal risk factors. Diagnoses made by expert clinical dysmorphologists in multidisciplinary case conferences utilized all components of the study: dysmorphology and physical growth; neurobehavior; and maternal risk interviews. Results Direct parental (active) consent was obtained for 1,278 children. Averages for key physical diagnostic traits and several other minor anomalies were significantly different among FAS, PFAS, and randomly-selected, normal controls. Cognitive tests and behavioral checklists discriminated the diagnostic groups from controls on 12 of 14 instruments. Mothers of children with FAS and PFAS were significantly lower in educational attainment, shorter, later in pregnancy recognition, and suffered more depression, and used marijuana and methamphetamine during their pregnancy. Most pre-pregnancy and pregnancy drinking measures were worse for mothers of FAS and PFAS. Excluding a significant difference in simply admitting drinking during the index pregnancy (FAS and PFAS = 75% vs. 39.4% for controls), most quantitative intergroup differences merely approached significance. This community’s prevalence of FAS is 2.9 to 7.5 per 1,000, PFAS is 7.9 to 17.7 per 1,000, and combined prevalence is 10.9 to 25.2 per 1,000 or 1.1% to 2.5%. Conclusions Comprehensive, active case ascertainment methods produced rates of FAS and PFAS higher than predicted by long-standing, popular estimates. PMID:26321671

  9. Cell cycle specificity of Fas-mediated apoptosis in WIL-2 cells.

    PubMed

    Beletskaya, I V; Nikonova, L V; Beletsky, I P

    1997-07-21

    Antibodies to Fas/APO1 receptor induce effective apoptosis in WIL-2 cells of the human B-lymphoid line. Quantitative assessment of the extent of the death in cells synchronized by thymidine block revealed a significant increase in their sensitivity to the cytocidal effect mediated by Fas/APO1 during the G1 phase of the cell cycle. Western analysis of the content of the p53 antigen in the cytoplasm and nuclei of the cells showed that the Fas/APO1-induced death is accompanied by massive translocation of the p53 from the cytoplasm to the nucleus. These findings suggest that cell vulnerability to the Fas/APO1-mediated apoptosis is subjected to regulation by cell cycle-dependent mechanisms, one of which is probably the function of the p53 antigen.

  10. Loss of FAS/FASL signaling does not reduce apoptosis in Sharpin null mice.

    PubMed

    Potter, Christopher S; Silva, Kathleen A; Kennedy, Victoria E; Stearns, Timothy M; HogenEsch, Harm; Sundberg, John P

    2017-01-17

    Mice with mutations in SHANK-associated RH domain interactor (Sharpin) develop a hypereosinophilic auto-inflammatory disease known as chronic proliferative dermatitis. Affected mice have increased apoptosis in the keratinocytes of the skin, esophagus, and forestomach driven by extrinsic TNF receptor mediated apoptotic signaling pathways. FAS receptor signaling is an extrinsic apoptotic signaling mechanism frequently involved in inflammatory skin diseases. Compound mutations in Sharpin and Fas or Fasl were created to determine if these death domain proteins influenced the cutaneous phenotype in Sharpin null mice. Both Sharpin/Fas and Sharpin/Fasl compound mutant mice developed an auto-inflammatory phenotype similar to that seen in Sharpin null mice indicating that initiation of apoptosis by FAS signaling is likely not involved in the pathogenesis of this disease. This article is protected by copyright. All rights reserved.

  11. Role of dioxin response element and nuclear factor-kappaB motifs in 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated regulation of Fas and Fas ligand expression.

    PubMed

    Singh, Narendra P; Nagarkatti, Mitzi; Nagarkatti, Prakash S

    2007-01-01

    We have demonstrated previously that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) up-regulates Fas and FasL in immune cells, although the molecular mechanisms remain unknown. We investigated the regulation of Fas or FasL promoter by TCDD in EL4 T cells using luciferase reporter constructs. We observed 20 +/- 5- and 14 +/- 4-fold induction of promoter activity for Fas and FasL, respectively, after TCDD exposure. The induction of luciferase was significantly reduced (2 +/- 1-fold) in the presence of alpha-naphthoflavone, an aryl hydrocarbon receptor (AhR) antagonist. We noted the presence of a dioxin response element (DRE) and five nuclear factor-kappaB (NF-kappaB) motifs on Fas promoter, and no DRE but two NF-kappaB motifs on FasL promoter. When we investigated the role of DRE and NF-kappaB, we observed varying levels of luciferase induction (9 +/- 2-fold for DRE and 8 +/- 2-fold for NF-kappaBs of Fas promoter and 6 +/- 3-fold for NF-kappaBs of FasL promoter). Mutations in DRE of Fas promoter or NF-kappaBs of FasL promoter led to decreased luciferase induction, further supporting our results. Probes for DRE or NF-kappaB motifs of Fas and/or FasL promoters demonstrated mobility shift in the presence of nuclear extract from TCDD-treated EL4 cells. Furthermore, we observed supershift in mobility when DRE and NF-kappaB probes were incubated in the presence of anti-mouse AhR, and anti-NF-kappaB (RelA/p65 and p50) antibodies, respectively. Administration of TCDD into mice caused significant increase in Fas and FasL transcripts in thymus and liver. These data demonstrate that TCDD regulates Fas and FasL promoters through DRE and/or NF-kappaB motifs via AhR.

  12. The Influence of Information Structure on the Depth of Semantic Processing: How Focus and Pitch Accent Determine the Size of the N400 Effect

    ERIC Educational Resources Information Center

    Wang, Lin; Bastiaansen, Marcel; Yang, Yufang; Hagoort, Peter

    2011-01-01

    To highlight relevant information in dialogues, both wh-question context and pitch accent in answers can be used, such that focused information gains more attention and is processed more elaborately. To evaluate the relative influence of context and pitch accent on the depth of semantic processing, we measured event-related potentials (ERPs) to…

  13. Speech motor brain regions are differentially recruited during perception of native and foreign-accented phonemes for first and second language listeners.

    PubMed

    Callan, Daniel; Callan, Akiko; Jones, Jeffery A

    2014-01-01

    Brain imaging studies indicate that speech motor areas are recruited for auditory speech perception, especially when intelligibility is low due to environmental noise or when speech is accented. The purpose of the present study was to determine the relative contribution of brain regions to the processing of speech containing phonetic categories from one's own language, speech with accented samples of one's native phonetic categories, and speech with unfamiliar phonetic categories. To that end, native English and Japanese speakers identified the speech sounds /r/ and /l/ that were produced by native English speakers (unaccented) and Japanese speakers (foreign-accented) while functional magnetic resonance imaging measured their brain activity. For native English speakers, the Japanese accented speech was more difficult to categorize than the unaccented English speech. In contrast, Japanese speakers have difficulty distinguishing between /r/ and /l/, so both the Japanese accented and English unaccented speech were difficult to categorize. Brain regions involved with listening to foreign-accented productions of a first language included primarily the right cerebellum, left ventral inferior premotor cortex PMvi, and Broca's area. Brain regions most involved with listening to a second-language phonetic contrast (foreign-accented and unaccented productions) also included the left PMvi and the right cerebellum. Additionally, increased activity was observed in the right PMvi, the left and right ventral superior premotor cortex PMvs, and the left cerebellum. These results support a role for speech motor regions during the perception of foreign-accented native speech and for perception of difficult second-language phonetic contrasts.

  14. Fetal alcohol syndrome prevention in American Indian communities of Michigan's upper peninsula.

    PubMed

    Plaisier, K J

    1989-01-01

    Attitudes and knowledge about Fetal Alcohol Syndrome (FAS) were examined among American Indian communities of Michigan's Upper Peninsula. Indian health workers and community women were interviewed. Education about FAS was provided in each community. The results indicate that information on FAS is reaching many women in these communities and that traditional cultural patterns can support the development of a strong Indian women's health program. At the same time, more must be done in the near term to help those women who are at greatest risk.

  15. Examining differences in nurses' language, accent, and comprehensibility in nursing home settings based on birth origin and country of education.

    PubMed

    Wagner, Laura M; Brush, Barbara L; Castle, Nicholas G; Eaton, Michelle; Capezuti, Elizabeth

    2015-01-01

    As nursing homes turn abroad to fill vacancies, the diverse linguistic backgrounds of nurse hires are creating new challenges in comprehensibility between nurses, providers, and residents. Accents are a natural part of spoken language that may present difficulty even when the parties involved are speaking the same language. We surveyed 1,629 nurses working in 98 nursing homes (NHs) in five U.S. states to determine if and how language difficulties were perceived by nurses and others (e.g. physicians, residents and family members). We found that when participants were asked how often other care team members and residents/families had difficulty understanding them due to language use or accent, foreign born nurses were significantly more likely to report that they experienced difficulty at least some of the time across all groups. This study supports an assessment of nurses' language, accents, and comprehensibility in these settings.

  16. Genetic disruption of oncogenic Kras sensitizes lung cancer cells to Fas receptor-mediated apoptosis.

    PubMed

    Mou, Haiwei; Moore, Jill; Malonia, Sunil K; Li, Yingxiang; Ozata, Deniz M; Hough, Soren; Song, Chun-Qing; Smith, Jordan L; Fischer, Andrew; Weng, Zhiping; Green, Michael R; Xue, Wen

    2017-04-04

    Genetic lesions that activate KRAS account for ∼30% of the 1.6 million annual cases of lung cancer. Despite clinical need, KRAS is still undruggable using traditional small-molecule drugs/inhibitors. When oncogenic Kras is suppressed by RNA interference, tumors initially regress but eventually recur and proliferate despite suppression of Kras Here, we show that tumor cells can survive knockout of oncogenic Kras, indicating the existence of Kras-independent survival pathways. Thus, even if clinical KRAS inhibitors were available, resistance would remain an obstacle to treatment. Kras-independent cancer cells exhibit decreased colony formation in vitro but retain the ability to form tumors in mice. Comparing the transcriptomes of oncogenic Kras cells and Kras knockout cells, we identified 603 genes that were specifically up-regulated in Kras knockout cells, including the Fas gene, which encodes a cell surface death receptor involved in physiological regulation of apoptosis. Antibodies recognizing Fas receptor efficiently induced apoptosis of Kras knockout cells but not oncogenic Kras-expressing cells. Increased Fas expression in Kras knockout cells was attributed to decreased association of repressive epigenetic marks at the Fas promoter. Concordant with this observation, treating oncogenic Kras cells with histone deacetylase inhibitor and Fas-activating antibody efficiently induced apoptosis, thus bypassing the need to inhibit Kras. Our results suggest that activation of Fas could be exploited as an Achilles' heel in tumors initiated by oncogenic Kras.

  17. Fas/CD95-induced chemokines can serve as "find-me" signals for apoptotic cells.

    PubMed

    Cullen, Sean P; Henry, Conor M; Kearney, Conor J; Logue, Susan E; Feoktistova, Maria; Tynan, Graham A; Lavelle, Ed C; Leverkus, Martin; Martin, Seamus J

    2013-03-28

    Apoptosis is commonly thought to represent an immunologically silent or even anti-inflammatory mode of cell death, resulting in cell clearance in the absence of explicit activation of the immune system. However, here we show that Fas/CD95-induced apoptosis is associated with the production of an array of cytokines and chemokines, including IL-6, IL-8, CXCL1, MCP-1, and GMCSF. Fas-induced production of MCP-1 and IL-8 promoted chemotaxis of phagocytes toward apoptotic cells, suggesting that these factors serve as "find-me" signals in this context. We also show that RIPK1 and IAPs are required for optimal production of cytokines and chemokines in response to Fas receptor stimulation. Consequently, a synthetic IAP antagonist potently suppressed Fas-dependent expression of multiple proinflammatory mediators and inhibited Fas-induced chemotaxis. Thus, in addition to provoking apoptosis, Fas receptor stimulation can trigger the secretion of chemotactic factors and other immunologically active proteins that can influence immune responsiveness toward dying cells.

  18. Glucocorticoids impair oocyte developmental potential by triggering apoptosis of ovarian cells via activating the Fas system

    PubMed Central

    Yuan, Hong-Jie; Han, Xiao; He, Nan; Wang, Guo-Liang; Gong, Shuai; Lin, Juan; Gao, Min; Tan, Jing-He

    2016-01-01

    Previous studies indicate that stress damages oocytes with increased secretion of glucorticoids. However, although injection of female mice with cortisol decreased oocyte competence, exposure of mouse oocytes directly to physiological or stress-induced concentrations of glucorticoids did not affect oocyte maturation and embryo development. This study has explored the mechanisms by which glucocorticoids impair oocyte competence. Female mice were injected with cortisol and the effects of cortisol-injection on oocyte competence, ovarian cell apoptosis and Fas/FasL activation were observed. The results showed that cortisol-injection decreased (a) oocyte developmental potential, (b) the E2/P4 ratio in serum and ovaries, and (c) expression of insulin-like growth factor 1, brain-derived neurotrophic factor and glucocorticoid receptor in mural granulosa cells (MGCs), while increasing levels of (a) cortisol in serum and ovaries, (b) apoptosis in MGCs and cumulus cells (CCs), (c) FasL secretion in ovaries and during oocyte maturation in vitro, and (d) Fas in MGCs, CCs and oocytes. The detrimental effects of cortisol-injection on oocyte competence and apoptosis of MGCs and CCs were significantly relieved when the gld (generalized lymphoproliferative disorder) mice harboring FasL mutations were observed. Together, the results suggested that glucocorticoids impair oocyte competence by triggering apoptosis of ovarian cells via activating the Fas system. PMID:27040909

  19. Corneal graft rejection occurs despite Fas ligand expression and apoptosis of infiltrating cells

    PubMed Central

    Williams, K A; Standfield, S D; Smith, J R; Coster, D J

    2005-01-01

    Background/aims: Constitutive expression of Fas ligand (CD95L) protects the eye against cell mediated immune responses by inducing apoptosis in infiltrating Fas bearing T cells. This study was designed to examine Fas ligand expression on acutely rejecting rat corneal grafts and to investigate the kinetics of induction of apoptosis in infiltrating leucocytes. Methods: Orthotopic penetrating corneal transplantation was performed between genetically disparate inbred rats. Fas ligand expression and the phenotype of infiltrating leucocytes were examined by immunohistochemistry. Apoptotic nuclei were visualised in sections of normal rat cornea, rejecting allografts, and time matched isografts by terminal deoxynucleotidyl transferase mediated dUTP biotin nick end labelling (TUNEL) and quantified by video image analysis. Staining with Hoechst dye 33258 was used to confirm the presence of apoptotic nuclei. Results: Fas ligand was expressed on corneal endothelial and epithelial cells during acute corneal graft rejection. At all time points examined, including as early as the fifth postoperative day, the cells infiltrating both corneal isografts and allografts were TUNEL positive. By the 15th postoperative day, over 90% of all nuclei, many of which were T cells, were apoptotic. Conclusion: Expression of Fas ligand is not downregulated on the cornea during allograft rejection and infiltrating leucocytes in both isografts and allografts die rapidly in situ. Despite the death of the cells believed to be responsible for rejection, isografts survive indefinitely whereas allografts are irreparably damaged. PMID:15834099

  20. Glucocorticoids impair oocyte developmental potential by triggering apoptosis of ovarian cells via activating the Fas system.

    PubMed

    Yuan, Hong-Jie; Han, Xiao; He, Nan; Wang, Guo-Liang; Gong, Shuai; Lin, Juan; Gao, Min; Tan, Jing-He

    2016-04-04

    Previous studies indicate that stress damages oocytes with increased secretion of glucorticoids. However, although injection of female mice with cortisol decreased oocyte competence, exposure of mouse oocytes directly to physiological or stress-induced concentrations of glucorticoids did not affect oocyte maturation and embryo development. This study has explored the mechanisms by which glucocorticoids impair oocyte competence. Female mice were injected with cortisol and the effects of cortisol-injection on oocyte competence, ovarian cell apoptosis and Fas/FasL activation were observed. The results showed that cortisol-injection decreased (a) oocyte developmental potential, (b) the E2/P4 ratio in serum and ovaries, and (c) expression of insulin-like growth factor 1, brain-derived neurotrophic factor and glucocorticoid receptor in mural granulosa cells (MGCs), while increasing levels of (a) cortisol in serum and ovaries, (b) apoptosis in MGCs and cumulus cells (CCs), (c) FasL secretion in ovaries and during oocyte maturation in vitro, and (d) Fas in MGCs, CCs and oocytes. The detrimental effects of cortisol-injection on oocyte competence and apoptosis of MGCs and CCs were significantly relieved when the gld (generalized lymphoproliferative disorder) mice harboring FasL mutations were observed. Together, the results suggested that glucocorticoids impair oocyte competence by triggering apoptosis of ovarian cells via activating the Fas system.

  1. Chronic methamphetamine exposure induces cardiac fas-dependent and mitochondria-dependent apoptosis.

    PubMed

    Liou, Cher-Ming; Tsai, Shiow-Chwen; Kuo, Chia-Hua; Williams, Timothy; Ting, Hua; Lee, Shin-Da

    2014-06-01

    Very limited information regarding the influence of chronic methamphetamine exposure on cardiac apoptosis is available. In this study, we evaluate whether chronic methamphetamine exposure will increase cardiac Fas-dependent (type I) and mitochondria-dependent (type II) apoptotic pathways. Thirty-two male Wistar rats at 3-4 months of age were randomly divided into a vehicle-treated group [phosphate-buffered saline (PBS) 0.5 ml SQ per day] and a methamphetamine-treated group (MA 10 mg/kg SQ per day) for 3 months. We report that after 3 months of exposure, abnormal myocardial architecture, more minor cardiac fibrosis and cardiac TUNEL-positive apoptotic cells were observed at greater frequency in the MA group than in the PBS group. Protein levels of TNF-α, Fas ligand, Fas receptor, Fas-associated death domain, activated caspase-8, and activated caspase-3 (Fas-dependent apoptosis) extracted from excised hearts were significantly increased in the MA group, compared to the PBS group. Protein levels of cardiac Bak, t-Bid, Bak to Bcl-xL ratio, activated caspase-9, and activated caspase-3 (mitochondria-dependent apoptosis) were significantly increased in the MA group, compared with the PBS group. The results from this study reveal that chronic methamphetamine exposure will activate cardiac Fas-dependent and mitochondria-dependent apoptotic pathways, which may indicate a possible mechanism for developing cardiac abnormalities in humans with chronic methamphetamine abuse.

  2. Deficient leptin signaling ameliorates systemic lupus erythematosus lesions in MRL/Mp-Fas lpr mice.

    PubMed

    Fujita, Yoshimasa; Fujii, Takao; Mimori, Tsuneyo; Sato, Tomomi; Nakamura, Takuji; Iwao, Haruka; Nakajima, Akio; Miki, Miyuki; Sakai, Tomoyuki; Kawanami, Takafumi; Tanaka, Masao; Masaki, Yasufumi; Fukushima, Toshihiro; Okazaki, Toshiro; Umehara, Hisanori

    2014-02-01

    Leptin is secreted by adipocytes, the placenta, and the stomach. It not only controls appetite through leptin receptors in the hypothalamus, it also regulates immunity. In the current study, we produced leptin-deficient MRL/Mp-Fas(lpr) mice to investigate the potential role of leptin in autoimmunity. C57BL/6J-ob/ob mice were backcrossed with MRL/Mp-Fas(lpr) mice, which develop human systemic lupus erythematosus (SLE)-like lesions. The effects of leptin deficiency on various SLE-like manifestations were investigated in MRL/Mp-Fas(lpr) mice. The regulatory T cell population in the spleen was analyzed by flow cytometry, and the effects of leptin on regulatory T cells and Th17 cells were evaluated in vitro. Compared with leptin-producing MRL/Mp-Fas(lpr) mice, leptin-deficient MRL/Mp-Fas(lpr) mice showed less marked splenomegaly and a particularly low population of CD3(+)CD4(-)CD8(-)B220(+) T cells (lpr cells). Their serum concentrations of Abs to dsDNA were lower, and renal histological changes at age 20 wk were ameliorated. Regulatory T cells were increased in the spleens of leptin-deficient MRL/Mp-Fas(lpr) mice. Leptin suppressed regulatory T cells and enhanced Th17 cells in vitro. In conclusion, blockade of leptin signaling may be of therapeutic benefit in patients with SLE and other autoimmune diseases.

  3. Kupffer cells of cirrhotic rat livers sensitize colon cancer cells to Fas-mediated apoptosis.

    PubMed

    Song, E; Chen, J; Ouyang, N; Wang, M; Exton, M S; Heemann, U

    2001-05-04

    Metastasis of colorectal carcinomas rarely occurs in cirrhotic livers. Our study investigated the influence of activated Kupffer cells from cirrhotic rat livers on hepatic colonization and FasR-mediated apoptosis of colon cancer cells. A rat colon cancer cell line, RCN-9, was used to inoculate rat livers. Treatment with conditioned media of Kupffer cells isolated from CCl(4)-induced cirrhotic rat livers (cirrhotic KCM) significantly reduced the incidence of hepatic colonization of RCN-9 cells. In vitro cytotoxicity of Kupffer cells and tumour infiltrating lymphocytes (TILs) on RCN-9 cells was evaluated using [(3)H]-release assay. RCN-9 cells were resistant to cytotoxicity mediated by cirrhotic Kupffer cells, but were sensitized to TIL-mediated killing after treatment with cirrhotic KCM. The specific killing induced by TILs was FasR-mediated, as it was inhibited by ZB4, an antagonistic anti-FasR antibody. In agreement, cirrhotic KCM increased recombinant Fas ligand-induced apoptosis of RCN-9 cells, and up-regulated FasR expression on RCN-9 cells as evaluated by RT-PCR and flow cytometry. These findings suggest that Kupffer cells in cirrhotic livers sensitize metastatic colon cancer cells to FasR-mediated apoptosis by up-regulating the receptors, which thus prepare them to be eliminated by infiltrating lymphocytes.

  4. Expression of fas protein on CD4+T cells irradiated by low level He-Ne

    NASA Astrophysics Data System (ADS)

    Nie, Fan; Zhu, Jing; Zhang, Hui-Guo

    2005-07-01

    Objective: To investigate the influence on the Expression of Fas protein on CD4+ T cells irradiated by low level He-Ne laser in the cases of psoriasis. Methods:the expression of CD4+ T Fas protein was determined in the casee of psoriasis(n=5) pre and post-low level laser irradiation(30 min、60min and 120min)by flow cytometry as compared withthe control(n=5). Results:In the cases of psoriasis,the expression of CD4+T FAS protein 21.4+/-3.1% was increased significantly than that of control group 16.8+/-2.1% pre-irradiation, p<0.05in the control,there is no difference between pre and post- irradiation,p>0.05in the cases , the expression of CD4+T Fas protein wae positively corelated to the irradiation times, when the energy density arrived to 22.92J/cm2(60 minutes)and 45.84J/cm2(120minutes), the expression of CD4+ T Fas protein was increased significantly as compared with pre-irradiation,p<0.05.Conclusion: The expression of CD4+T Fas protein may be increased by low level He-Ne laser irradiation ,the uncontrolled status of apoptosis could be corrected.

  5. Fas (CD95) expression in myeloid cells promotes obesity-induced muscle insulin resistance

    PubMed Central

    Wueest, Stephan; Mueller, Rouven; Blüher, Matthias; Item, Flurin; Chin, Annie S H; Wiedemann, Michael S F; Takizawa, Hitoshi; Kovtonyuk, Larisa; Chervonsky, Alexander V; Schoenle, Eugen J; Manz, Markus G; Konrad, Daniel

    2014-01-01

    Low-grade inflammation in adipose tissue and liver has been implicated in obesity-associated insulin resistance and type 2 diabetes. Yet, the contribution of inflammatory cells to the pathogenesis of skeletal muscle insulin resistance remains elusive. In a large cohort of obese human individuals, blood monocyte Fas (CD95) expression correlated with systemic and skeletal muscle insulin resistance. To test a causal role for myeloid cell Fas expression in the development of skeletal muscle insulin resistance, we generated myeloid/haematopoietic cell-specific Fas-depleted mice. Myeloid/haematopoietic Fas deficiency prevented the development of glucose intolerance in high fat-fed mice, in ob/ob mice, and in mice acutely challenged by LPS. In vivo, ex vivo and in vitro studies demonstrated preservation of muscle insulin responsiveness with no effect on adipose tissue or liver. Studies using neutralizing antibodies demonstrated a role for TNFα as mediator between myeloid Fas and skeletal muscle insulin resistance, supported by significant correlations between monocyte Fas expression and circulating TNFα in humans. In conclusion, our results demonstrate an unanticipated crosstalk between myeloid cells and skeletal muscle in the development of obesity-associated insulin resistance. PMID:24203314

  6. Tumor Endothelium FasL Establishes a Selective Immune Barrier Promoting Tolerance in Tumors

    PubMed Central

    Motz, Gregory T.; Santoro, Stephen P.; Wang, Li-Ping; Garrabrant, Tom; Lastra, Ricardo R.; Hagemann, Ian S.; Lal, Priti; Feldman, Michael D.; Benencia, Fabian; Coukos, George

    2014-01-01

    We describe a novel mechanism regulating the tumor endothelial barrier and T cell homing to tumors. Selective expression of the death mediator Fas ligand (FasL/CD95L) was detected in the vasculature of many human and mouse solid tumors but not in normal vasculature, and in these tumors it was associated with scarce CD8+ infiltration and predominance of FoxP3+ T regulatory (Treg) cells. Tumor-derived vascular endothelial growth factor A (VEGF-A), interleukin 10 (IL-10) and prostaglandin E2 (PGE2) cooperatively induced FasL expression on endothelial cells, which acquired the ability to kill effector CD8+ T cells, but not Treg cells, due to higher levels of cFLIP expression in Tregs. In the mouse, genetic or pharmacologic suppression of FasL produced a significant increase in the influx of tumor-rejecting CD8+ over FoxP3+ T cells. Pharmacologic inhibition of VEGF and PGE2 attenuated tumor endothelial FasL expression, produced a significant increase in the influx of tumor-rejecting CD8+ over FoxP3+ T cells, which was FasL-dependent, and led to CD8-dependent tumor growth suppression. Thus, tumor paracrine mechanisms establish a tumor endothelial death barrier, which plays a critical role in establishing immune tolerance and determining the fate of tumors. PMID:24793239

  7. Increased FasL expression correlates with apoptotic changes in granulocytes cultured with oxidized clozapine

    SciTech Connect

    Husain, Zaheed; Almeciga, Ingrid; Delgado, Julio C.; Clavijo, Olga P.; Castro, Januario E.; Belalcazar, Viviana; Pinto, Clara; Zuniga, Joaquin; Romero, Viviana; Yunis, Edmond J. . E-mail: edmond_yunis@dfci.harvard.edu

    2006-08-01

    Clozapine has been associated with a 1% incidence of agranulocytosis. The formation of an oxidized intermediate clozapine metabolite has been implicated in direct polymorphonuclear (PMN) toxicity. We utilized two separate systems to analyze the role of oxidized clozapine in inducing apoptosis in treated cells. Human PMN cells incubated with clozapine (0-10 {mu}M) in the presence of 0.1 mM H{sub 2}O{sub 2} demonstrated a progressive decrease of surface CD16 expression along with increased apoptosis. RT-PCR analysis showed decreased CD16 but increased FasL gene expression in clozapine-treated PMN cells. No change in constitutive Fas expression was observed in treated cells. In HL-60 cells induced to differentiate with retinoic acid (RA), a similar increase in FasL expression, but no associated changes in CD16 gene expression, was observed following clozapine treatments. Our results demonstrate increased FasL gene expression in oxidized clozapine-induced apoptotic neutrophils suggesting that apoptosis in granulocytes treated with clozapine involves Fas/FasL interaction that initiates a cascade of events leading to clozapine-induced agranulocytosis.

  8. A hypothesis on improving foreign accents by optimizing variability in vocal learning brain circuits.

    PubMed

    Simmonds, Anna J

    2015-01-01

    Rapid vocal motor learning is observed when acquiring a language in early childhood, or learning to speak another language later in life. Accurate pronunciation is one of the hardest things for late learners to master and they are almost always left with a non-native accent. Here, I propose a novel hypothesis that this accent could be improved by optimizing variability in vocal learning brain circuits during learning. Much of the neurobiology of human vocal motor learning has been inferred from studies on songbirds. Jarvis (2004) proposed the hypothesis that as in songbirds there are two pathways in humans: one for learning speech (the striatal vocal learning pathway), and one for production of previously learnt speech (the motor pathway). Learning new motor sequences necessary for accurate non-native pronunciation is challenging and I argue that in late learners of a foreign language the vocal learning pathway becomes inactive prematurely. The motor pathway is engaged once again and learners maintain their original native motor patterns for producing speech, resulting in speaking with a foreign accent. Further, I argue that variability in neural activity within vocal motor circuitry generates vocal variability that supports accurate non-native pronunciation. Recent theoretical and experimental work on motor learning suggests that variability in the motor movement is necessary for the development of expertise. I propose that there is little trial-by-trial variability when using the motor pathway. When using the vocal learning pathway variability gradually increases, reflecting an exploratory phase in which learners try out different ways of pronouncing words, before decreasing and stabilizing once the "best" performance has been identified. The hypothesis proposed here could be tested using behavioral interventions that optimize variability and engage the vocal learning pathway for longer, with the prediction that this would allow learners to develop new motor

  9. A hypothesis on improving foreign accents by optimizing variability in vocal learning brain circuits

    PubMed Central

    Simmonds, Anna J.

    2015-01-01

    Rapid vocal motor learning is observed when acquiring a language in early childhood, or learning to speak another language later in life. Accurate pronunciation is one of the hardest things for late learners to master and they are almost always left with a non-native accent. Here, I propose a novel hypothesis that this accent could be improved by optimizing variability in vocal learning brain circuits during learning. Much of the neurobiology of human vocal motor learning has been inferred from studies on songbirds. Jarvis (2004) proposed the hypothesis that as in songbirds there are two pathways in humans: one for learning speech (the striatal vocal learning pathway), and one for production of previously learnt speech (the motor pathway). Learning new motor sequences necessary for accurate non-native pronunciation is challenging and I argue that in late learners of a foreign language the vocal learning pathway becomes inactive prematurely. The motor pathway is engaged once again and learners maintain their original native motor patterns for producing speech, resulting in speaking with a foreign accent. Further, I argue that variability in neural activity within vocal motor circuitry generates vocal variability that supports accurate non-native pronunciation. Recent theoretical and experimental work on motor learning suggests that variability in the motor movement is necessary for the development of expertise. I propose that there is little trial-by-trial variability when using the motor pathway. When using the vocal learning pathway variability gradually increases, reflecting an exploratory phase in which learners try out different ways of pronouncing words, before decreasing and stabilizing once the “best” performance has been identified. The hypothesis proposed here could be tested using behavioral interventions that optimize variability and engage the vocal learning pathway for longer, with the prediction that this would allow learners to develop new motor

  10. Autoimmune lymphoproliferative syndrome misdiagnosed as hemophagocytic lymphohistiocytosis.

    PubMed

    Rudman Spergel, Amanda; Walkovich, Kelly; Price, Susan; Niemela, Julie E; Wright, Dowain; Fleisher, Thomas A; Rao, V Koneti

    2013-11-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a rare inherited disorder of apoptosis, most commonly due to mutations in the FAS (TNFRSF6) gene. It presents with chronic lymphadenopathy, splenomegaly, and symptomatic multilineage cytopenias in an otherwise healthy child. Unfortunately, these clinical findings are also noted in other childhood lymphoproliferative conditions, such as leukemia, lymphoma, and hemophagocytic lymphohistiocytosis, which can confound the diagnosis. This report describes a 6-year-old girl with symptoms misdiagnosed as hemophagocytic lymphohistiocytosis and treated with chemotherapy before the recognition that her symptoms and laboratory values were consistent with a somatic FAS mutation leading to ALPS. This case should alert pediatricians to include ALPS in the differential diagnosis of a child with lymphadenopathy, splenomegaly, and cytopenias; obtain discriminating screening laboratory biomarkers, such as serum vitamin B-12 and ferritin levels; and, in the setting of a highly suspicious clinical scenario for ALPS, pursue testing for somatic FAS mutations when germ-line mutation testing is negative.

  11. ApoE-/-Fas-/- C57BL/6 mice: a novel murine model simultaneously exhibits lupus nephritis, atherosclerosis, and osteopenia.

    PubMed

    Feng, Xuebing; Li, Hongyun; Rumbin, Alexis A; Wang, Xuping; La Cava, Antonio; Brechtelsbauer, Katherine; Castellani, Lawrence W; Witztum, Joseph L; Lusis, Aldons J; Tsao, Betty P

    2007-04-01

    To establish a mouse model of accelerated atherosclerosis in lupus, we generated apolipoprotein E-deficient (apoE(-/-)) and Fas(lpr/lpr) (Fas(-/-)) C57BL/6 mice. On a normal chow diet, 5 month old apoE(-/-)Fas(-/-) mice had enlarged glomerular tuft areas, severe proteinuria, increased circulating autoantibody levels, and increased apoptotic cells in renal and vascular lesions compared with either single knockout mice. Also, double knockout mice developed increased atherosclerotic lesions but decreased serum levels of total and non-HDL cholesterol compared with apoE(-/-)Fas(+/+) littermates. Moreover, female apoE(-/-)Fas(-/-) mice had lower vertebral bone mineral density (BMD) and bone volume density (BV/TV) than age-matched female apoE(-/-)Fas(+/+) mice. Compared with apoE(-/-)Fas(+/+) and apoE(+/+)Fas(-/-) mice, apoE(-/-)Fas(-/-) mice had decreased circulating oxidized phospholipid (OxPL) content on apoB-100 containing lipoprotein particles and increased serum IgG antibodies to OxPL, which were significantly correlated with aortic lesion areas (r = 0.58), glomerular tuft areas (r = 0.87), BMD (r = -0.57), and BV/TV (r = -0.72). These results suggest that the apoE(-/-)Fas(-/-) mouse model might be used to study atherosclerosis and osteopenia in lupus. Correlations of IgG anti-OxPL with lupus-like disease, atherosclerosis, and bone loss suggested a shared pathway of these disease processes.

  12. Improved isolation and purification of functional human Fas receptor extracellular domain using baculovirus-silkworm expression system.

    PubMed

    Muraki, Michiro; Honda, Shinya

    2011-11-01

    To achieve an efficient isolation of human Fas receptor extracellular domain (hFasRECD), a fusion protein of hFasRECD with human IgG1 heavy chain Fc domain containing thrombin cleavage sequence at the junction site was overexpressed using baculovirus-silkworm larvae expression system. The hFasRECD part was separated from the fusion protein by the effective cleavage of the recognition site with bovine thrombin. Protein G column treatment of the reaction mixture and the subsequent cation-exchange chromatography provided purified hFasRECD with a final yield of 13.5mg from 25.0 ml silkworm hemolymph. The functional activity of the product was examined by size-exclusion chromatography analysis. The isolated hFasRECD less strongly interacted with human Fas ligand extracellular domain (hFasLECD) than the Fc domain-bridged counterpart, showing the contribution of antibody-like avidity in the latter case. The purified glycosylated hFasRECD presented several discrete bands in the disulphide-bridge non-reducing SDS-PAGE analysis, and virtually all of the components were considered to participate in the binding to hFasLECD. The attached glycans were susceptible to PNGase F digestion, but mostly resistant to Endo Hf digestion under denaturing conditions. One of the components exhibited a higher susceptibility to PNGase F digestion under non-denaturing conditions.

  13. Rho-ROCK-dependent ezrin-radixin-moesin phosphorylation regulates Fas-mediated apoptosis in Jurkat cells.

    PubMed

    Hébert, Marylise; Potin, Sophie; Sebbagh, Michaël; Bertoglio, Jacques; Bréard, Jacqueline; Hamelin, Jocelyne

    2008-11-01

    Upon engagement by its ligand, the Fas receptor (CD95/APO-1) is oligomerized in a manner dependent on F-actin. It has been shown that ezrin, a member of the ERM (ezrin-radixin-moesin) protein family can link Fas to the actin cytoskeleton. We show herein that in Jurkat cells, not only ezrin but also moesin can associate with Fas. The same observation was made in activated human peripheral blood T cells. Fas/ezrin or moesin (E/M) association increases in Jurkat cells following Fas triggering and occurs concomitantly with the formation of SDS- and 2-ME-stable high molecular mass Fas aggregates. Ezrin and moesin have to be present together for the formation of Fas aggregates since down-regulation of either ezrin or moesin expression with small interfering RNAs completely inhibits Fas aggregate formation. Although FADD (Fas-associated death domain protein) and caspase-8 associate with Fas in the absence of E/M, subsequent events such as caspase-8 activation and sensitivity to apoptosis are decreased. During the course of Fas stimulation, ezrin and moesin become phosphorylated, respectively, on T567 and on T558. This phosphorylation is mediated by the kinase ROCK (Rho-associated coiled coil-containing protein kinase) I subsequently to Rho activation. Indeed, inhibition of either Rho or ROCK prevents ezrin and moesin phosphorylation, abrogates the formation of Fas aggregates, and interferes with caspase-8 activation. Thus, phosphorylation of E/M by ROCK is involved in the early steps of apoptotic signaling following Fas triggering and regulates apoptosis induction.

  14. The Effect of Perceived Regional Accents on Individual Economic Behavior: A Lab Experiment on Linguistic Performance, Cognitive Ratings and Economic Decisions

    PubMed Central

    Heblich, Stephan; Lameli, Alfred; Riener, Gerhard

    2015-01-01

    Does it matter if you speak with a regional accent? Speaking immediately reveals something of one’s own social and cultural identity, be it consciously or unconsciously. Perceiving accents involves not only reconstructing such imprints but also augmenting them with particular attitudes and stereotypes. Even though we know much about attitudes and stereotypes that are transmitted by, e.g. skin color, names or physical attractiveness, we do not yet have satisfactory answers how accent perception affects human behavior. How do people act in economically relevant contexts when they are confronted with regional accents? This paper reports a laboratory experiment where we address this question. Participants in our experiment conduct cognitive tests where they can choose to either cooperate or compete with a randomly matched male opponent identified only via his rendering of a standardized text in either a regional accent or standard accent. We find a strong connection between the linguistic performance and the cognitive rating of the opponent. When matched with an opponent who speaks the accent of the participant’s home region—the in-group opponent –, individuals tend to cooperate significantly more often. By contrast, they are more likely to compete when matched with an accent speaker from outside their home region, the out-group opponent. Our findings demonstrate, firstly, that the perception of an out-group accent leads not only to social discrimination but also influences economic decisions. Secondly, they suggest that this economic behavior is not necessarily attributable to the perception of a regional accent per se, but rather to the social rating of linguistic distance and the in-group/out-group perception it evokes. PMID:25671607

  15. Fetal alcohol syndrome: overview of pathogenesis.

    PubMed

    Henderson, G I; Patwardhan, R V; Hoyumpa, A M; Schenker, S

    1981-01-01

    The pathogenesis of Fetal Alcohol Syndrome (FAS) has been reviewed briefly in terms of factors which can influence its development and specific mechanisms. FAS was defined arbitrarily to include a wide spectrum ranging from the fully expressed clinical syndrome to growth and developmental impairment seen in fetal and neonatal animals exposed to ethanol. The available evidence suggests that ethanol per se in the absence of nutritional deficit can cause some from of FAS. Acetaldehyde may contribute to the FAS, but there is lack of knowledge concerning the levels of acetaldehyde needed to achieve fetal damage and the effect of this agent on the placenta and its placental transfer to the fetal organs. There is no specific data at this time to incriminate nutritional impairment, although further studies in animal models and man of the role of possible deficiencies of certain vitamins (i.e., folate) and of trace minerals (i.e., zinc) are needed. There is some evidence that alcohol or its metabolites may alter placental transport function. The relevance of this to FAS needs further investigation. The possible additive roles of caffeine, nicotine and other drugs on fetal development and viability deserve more consideration. The specific mechanism(s) of FAS are unknown. Of those considered--mutagenic (paternal) effect, abnormal protein synthesis, altered cerebral neurotransmitter balance, hormonal and other effects--impairment of protein synthesis at present seems best documented, but all clearly require further evaluation. When specific mechanisms are investigated it will be essential also to determine the dose-response relationship and the effects of a given dose of alcohol at various stages of gestation.

  16. GABA tea prevents cardiac fibrosis by attenuating TNF-alpha and Fas/FasL-mediated apoptosis in streptozotocin-induced diabetic rats.

    PubMed

    Cherng, Shur-Hueih; Huang, Chih-Yang; Kuo, Wei-Wen; Lai, Shue-Er; Tseng, Chien-Yu; Lin, Yueh-Min; Tsai, Fuu-Jen; Wang, Hsueh-Fang

    2014-03-01

    GABA tea is a tea product that contains a high level of gamma-aminobutyric acid (GABA). This study investigated the effects of GABA tea on the heart in a diabetic rat model. Male Wistar rats were injected with 55mg/kg streptozotocin (STZ) to induce diabetes for 2weeks and then orally given dosages of 4.55 and 45.5mg/kg/day GABA tea extract for 6weeks. The results revealed that fasting blood glucose levels returned to normal levels in GABA tea-treated diabetic rats, but not in the untreated diabetic rats. Additionally, GABA tea effectively inhibited cardiac fibrosis induced by STZ. Further experiments showed that the STZ-induced protein levels of tumor necrosis factor-alpha (TNF-alpha), Fas, activated caspase-8 and caspase-3 were significantly inhibited by the GABA tea treatment. Therefore, our data suggest that the inhibiting effect of GABA tea on STZ-induced cardiac fibrosis in diabetic rats may be mediated by reducing blood glucose and further attenuating TNF-alpha expression and/or Fas/Fas ligand (FasL)-mediated apoptosis. These findings will provide implications for the potential anti-diabetic properties of GABA tea.

  17. Exploring the intelligibilty of foreign-accented English vowels when ``English'' is ill-defined

    NASA Astrophysics Data System (ADS)

    Bundgaard-Nielsen, Rikke Louise; Bohn, Ocke-Schwen

    2004-05-01

    Many studies of foreign-accented speech have been conducted in second language settings in which learners are assumed to be exposed to a relatively homogeneous non-native sound system. However, foreign language learners, who learn an additional language in a setting where this language is not the primary medium of communication, are frequently exposed to a range of varieties of the target language which may differ considerably with respect to their sound systems. The present study examined and compared the intelligibility of English monophthongs produced by two speaker groups: Native Danes who had learned English as a foreign language (with exposure to different native and non-native varieties) and native English speakers from Australia, the US, and the UK. Ten native Canadian-English listeners, who were familiar with native and non-native accents of English, identified the 11 monophthongs of English produced by the speaker groups in a /bVt/ context. As expected, the listeners' error patterns were specific for each speaker group. However, reduced intelligibility was observed for much the same vowels irrespective of speaker group. Our results suggest that one source of problems in learning the sounds of English is the heterogeneity of English vowel systems in addition to transfer from the native language.

  18. Listeners' perceptions of and attitudes toward Hispanic-, Asian-, and Arabic-accented English speakers

    NASA Astrophysics Data System (ADS)

    Lass, Norman; Atkins, Traci; Squires, Rebekah

    2002-05-01

    A master tape containing the randomized recordings of 20 Hispanic-, Asian-, and Arabic-accented English speakers reading a standard prose passage was presented to a group of 22 native English-speaking listeners who participated in two listening sessions. In the first session they were asked to use a 5-point listening preference rating scale. In the second session they heard the same speakers and were asked to determine the presence or absence of an accent and, if present, the type (Asian, Hispanic, Arabic, or other) and degree (mild, moderate, or severe) of accentedness. A scattergram plotting listeners' mean listening preference ratings and degree of accentedness ratings for each of the speakers in the study revealed a strong inverse relationship which yielded a statistically significant (p <0.01) correlation coefficient.Thus, the higher the degree of severity of the listeners' judged accentedness of speakers, the more negative their listening preference rating judgments of the speakers. Implications of these findings and suggestions for future research are discussed.

  19. Intelligibility of foreign-accented speech: Effects of listening condition, listener age, and listener hearing status

    NASA Astrophysics Data System (ADS)

    Ferguson, Sarah Hargus

    2005-09-01

    It is well known that, for listeners with normal hearing, speech produced by non-native speakers of the listener's first language is less intelligible than speech produced by native speakers. Intelligibility is well correlated with listener's ratings of talker comprehensibility and accentedness, which have been shown to be related to several talker factors, including age of second language acquisition and level of similarity between the talker's native and second language phoneme inventories. Relatively few studies have focused on factors extrinsic to the talker. The current project explored the effects of listener and environmental factors on the intelligibility of foreign-accented speech. Specifically, monosyllabic English words previously recorded from two talkers, one a native speaker of American English and the other a native speaker of Spanish, were presented to three groups of listeners (young listeners with normal hearing, elderly listeners with normal hearing, and elderly listeners with hearing impairment; n=20 each) in three different listening conditions (undistorted words in quiet, undistorted words in 12-talker babble, and filtered words in quiet). Data analysis will focus on interactions between talker accent, listener age, listener hearing status, and listening condition. [Project supported by American Speech-Language-Hearing Association AARC Award.

  20. Beat Processing Is Pre-Attentive for Metrically Simple Rhythms with Clear Accents: An ERP Study

    PubMed Central

    Bouwer, Fleur L.; Van Zuijen, Titia L.; Honing, Henkjan

    2014-01-01

    The perception of a regular beat is fundamental to music processing. Here we examine whether the detection of a regular beat is pre-attentive for metrically simple, acoustically varying stimuli using the mismatch negativity (MMN), an ERP response elicited by violations of acoustic regularity irrespective of whether subjects are attending to the stimuli. Both musicians and non-musicians were presented with a varying rhythm with a clear accent structure in which occasionally a sound was omitted. We compared the MMN response to the omission of identical sounds in different metrical positions. Most importantly, we found that omissions in strong metrical positions, on the beat, elicited higher amplitude MMN responses than omissions in weak metrical positions, not on the beat. This suggests that the detection of a beat is pre-attentive when highly beat inducing stimuli are used. No effects of musical expertise were found. Our results suggest that for metrically simple rhythms with clear accents beat processing does not require attention or musical expertise. In addition, we discuss how the use of acoustically varying stimuli may influence ERP results when studying beat processing. PMID:24870123

  1. In vivo Effects in Melanoma of ROCK Inhibition-Induced FasL Overexpression.

    PubMed

    Teiti, Iotefa; Florie, Bertrand; Pich, Christine; Gence, Rémi; Lajoie-Mazenc, Isabelle; Rochaix, Philippe; Favre, Gilles; Tilkin-Mariamé, Anne-Françoise

    2015-01-01

    Ectopic Fas-ligand (FasL) expression in tumor cells is responsible for both tumor escape through tumor counterattack of Fas-positive infiltrating lymphocytes and tumor rejection though inflammatory and immune responses. We have previously shown that RhoA GTPase and its effector ROCK negatively control FasL membrane expression in murine melanoma B16F10 cells. In this study, we found that B16F10 treatment with the ROCK inhibitor H1152 reduced melanoma development in vivo through FasL membrane overexpression. Although H1152 treatment did not reduce tumor growth in vitro, pretreatment of tumor cells with this inhibitor delayed tumor appearance, and slowed tumor growth in C57BL/6 immunocompetent mice. Thanks to the use of mice-bearing mutated Fas receptors (B6/lpr), we found that reduced tumor growth, observed in immunocompetent mice, was linked to FasL overexpression induced by H1152 treatment. Tumor growth analysis in immunosuppressed NUDE and IFN-γ-KO mice highlighted major roles for T lymphocytes and IFN-γ in the H1152-induced tumor growth reduction. Histological analyses of subcutaneous tumors, obtained from untreated versus H1152-treated B16F10 cells, showed that H1152 pretreatment induced a strong intratumoral infiltration of leukocytes. Cytofluorometric analysis showed that among these leukocytes, the number of activated CD8 lymphocytes was increased. Moreover, their antibody-induced depletion highlighted their main responsibility in tumor growth reduction. Subcutaneous tumor growth was also reduced by repeated intravenous injections of a clinical ROCK inhibitor, Fasudil. Finally, H1152-induced ROCK inhibition also reduced pulmonary metastasis implantation independently of T cell-mediated immune response. Altogether, our data suggest that ROCK inhibitors could become interesting pharmacological molecules for melanoma immunotherapy.

  2. Growth factor protection against cytokine-induced apoptosis in neonatal rat islets of Langerhans: role of Fas.

    PubMed

    Harrison, M; Dunger, A M; Berg, S; Mabley, J; John, N; Green, M H; Green, I C

    1998-09-18

    Treatment of neonatal rat islets of Langerhans with combined cytokines (interleukin-1beta 10(-10) M, tumour necrosis factor-alpha 10(-10) M, interferon-gamma 5 U/ml) led to extensive cell death, which was potentiated by Fas activation with the anti-Fas cytolytic antibody JO2. Pre-treatment with insulin (25 ng/ml) or insulin-like growth factor-1 (10(-8)M) gave only partial protection against cell killing, but prevented the Fas-mediated component. In the absence of cytokine treatment, Fas-mediated killing was not observed.

  3. Engagement of Fas on Macrophages Modulates Poly I:C induced cytokine production with specific enhancement of IP-10.

    PubMed

    Lyons, Caitriona; Fernandes, Philana; Fanning, Liam J; Houston, Aileen; Brint, Elizabeth

    2015-01-01

    Viral double-stranded RNA (dsRNA) is recognised by pathogen recognition receptors such as Toll-Like Receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I), and results in cytokine and interferon production. Fas, a well characterised death receptor, has recently been shown to play a role in the inflammatory response. In this study we investigated the role of Fas in the anti-viral immune response. Stimulation of Fas on macrophages did not induce significant cytokine production. However, activation of Fas modified the response of macrophages to the viral dsRNA analogue poly I:C. In particular, poly I:C-induced IP-10 production was significantly enhanced. A similar augmentation of IP-10 by Fas was observed following stimulation with both poly A:U and Sendai virus. Fas activation suppressed poly I:C-induced phosphorylation of the MAP kinases p38 and JNK, while overexpression of the Fas adaptor protein, Fas-associated protein with death domain (FADD), activated AP-1 and inhibited poly I:C-induced IP-10 production. Consistent with an inhibitory role for AP-1 in IP-10 production, mutation of the AP-1 binding site on the IP-10 promoter resulted in augmented poly I:C-induced IP-10. These results demonstrate that engagement of the Fas receptor plays a role in modifying the innate immune response to viral RNA.

  4. NaCS-PDMDAAC immobilized cultivation of recombinant Dictyostelium discoideum for soluble human Fas ligand production.

    PubMed

    Zheng, Chao; Zeng, Xianhai; Danquah, Michael K; Lu, Yinghua

    2015-01-01

    Dictyostelium discoideum is a promising eukaryotic host for the expression of heterologous proteins requiring post-translational modifications. However, the dilute nature of D. discoideum cell culture limits applications for high value proteins production. D. discoideum cells, entrapped in sodium cellulose sulfate/poly-dimethyl-diallyl-ammonium chloride (NaCS-PDMDAAC) capsules were used for biosynthesis of the heterologous protein, soluble human Fas ligand (hFasL). Semi-continuous cultivations with capsules recycling were carried out in shake flasks. Also, a scaled-up cultivation of immobilized D. discoideum for hFasL production in a customized vitreous airlift bioreactor was conducted. The results show that NaCS-PDMDAAC capsules have desirable biophysical properties including biocompatibility with the D. discoideum cells and good mechanical stability throughout the duration of cultivation. A maximum cell density of 2.02 × 10(7) cells mL(-1) (equivalent to a maximum cell density of 2.22 × 10(8) cells mL(-1) in capsules) and a hFasL concentration of 130.40 μg L(-1) (equivalent to a hFasL concentration of 1434.40 μg L(-1) in capsules) were obtained in shake flask cultivation with capsules recycling. Also, a maximum cell density of 1.72 × 10(7) cells mL(-1) (equivalent to a maximum cell density of 1.89 × 10(8) cells mL(-1) in capsules) and a hFasL concentration of 106.10 μg L(-1) (equivalent to a hFasL concentration of 1167.10 μg L(-1) in capsules) were obtained after ∼170 h cultivation in the airlift bioreactor (with a working volume of 200 mL in a 315 mL bioreactor). As the article presents a premier work in the application of NaCS-PDMDAAC immobilized D. discoideum cells for the production of hFasL, more work is required to further optimize the system to generate higher cell densities and hFasL titers for large-scale applications.

  5. On Voice-Onset Time as a Cue to Foreign Accent in Spanish: Native and Nonnative Perceptions

    ERIC Educational Resources Information Center

    Schoonmaker-Gates, Elena

    2015-01-01

    Although previous research has documented the relationship between voice-onset time (VOT) and the production of foreign accent in English and Spanish, less is known about the role of this cue in perception. VOT refers to the aspiration that occurs between the release of a stop consonant and the beginning of the following segment. In Spanish and…

  6. In the Right Place at the Right Time: Asian English Accents in a Listening Test for Healthcare Professions

    ERIC Educational Resources Information Center

    Suebsook, Khwanchanok; Adunyarittigun, Dumrong

    2016-01-01

    The rise of medical tourism and the increasing number of international patients from Asian countries have led Thai healthcare professionals to serve a lot of Asian patients and to encounter a complexity of language use in their workplace. There is a necessity for these professionals to strive for an understanding of Asian accents spoken by the…

  7. Perceived Foreign Accent in First Language Attrition and Second Language Acquisition: The Impact of Age of Acquisition and Bilingualism

    ERIC Educational Resources Information Center

    Hopp, Holger; Schmid, Monika S.

    2013-01-01

    This study investigates constraints on ultimate attainment in second language (L2) pronunciation in a direct comparison of perceived foreign accent of 40 late L2 learners and 40 late first language (L1) attriters of German. Both groups were compared with 20 predominantly monolingual controls. Contrasting participants who acquired the target…

  8. Accent and Identity: Exploring the Perceptions among Bilingual Speakers of English as a Lingua Franca in Hong Kong

    ERIC Educational Resources Information Center

    Sung, Chit Cheung Matthew

    2014-01-01

    This paper reports on a study that investigated the perceptions of a group of bilingual speakers of English and Chinese in Hong Kong concerning issues surrounding accent, identity and English as a lingua franca (ELF). Data were primarily collected via in-depth interviews with 28 university students in Hong Kong who are also regular users of…

  9. Anglo-Australians' and Immigrants' Attitudes toward Language and Accent: A Review of Experimental and Survey Research.

    ERIC Educational Resources Information Center

    Callan, Victor J.; Gallois, Cynthia

    1987-01-01

    Anglo-Australians remain monolingual and Anglophile in their attitudes. They show preference for standard or prestige varieties of English. Second generation members of immigrant groups are under strong pressure to assimilate and to abandon their community languages. They may have more negative attitudes toward non-standard accents in English than…

  10. Theoretical Analysis of Fas Ligand-Induced Apoptosis with an Ordinary Differential Equation Model.

    PubMed

    Shi, Zhimin; Li, Yan; Liu, Zhihai; Mi, Jun; Wang, Renxiao

    2012-12-01

    Upon the treatment of Fas ligand, different types of cells exhibit different apoptotic mechanisms, which are determined by a complex network of biological pathways. In order to derive a quantitative interpretation of the cell sensitivity and apoptosis pathways, we have developed an ordinary differential equation model. Our model is intended to include all of the known major components in apoptosis pathways mediated by Fas receptor. It is composed of 29 equations using a total of 49 rate constants and 13 protein concentrations. All parameters used in our model were derived through nonlinear fitting to experimentally measured concentrations of four selected proteins in Jurkat T-cells, including caspase-3, caspase-8, caspase-9, and Bid. Our model is able to correctly interpret the role of kinetic parameters and protein concentrations in cell sensitivity to FasL. It reveals the possible reasons for the transition between type-I and type-II pathways and also provides some interesting predictions, such as the more decisive role of Fas over Bax in apoptosis pathway and a possible feedback mechanism between type-I and type-II pathways. But our model failed in predicting FasL-induced apoptotic mechanism of NCI-60 cells from their gene-expression levels. Limitations in our model are also discussed.

  11. Cardiac Fas-dependent and mitochondria-dependent apoptosis after chronic cocaine abuse.

    PubMed

    Liou, Cher-Ming; Tsai, Shiow-Chwen; Kuo, Chia-Hua; Ting, Hua; Lee, Shin-Da

    2014-04-09

    To evaluate whether chronic cocaine abuse will increase cardiac Fas-dependent and mitochondria-dependent apoptotic pathways, thirty-two male Wistar rats at 3-4 months of age were randomly divided into a vehicle-treated group (phosphate-buffered saline, PBS, 0.5 mL, SQ per day) and a cocaine-treated group (Cocaine, 10 mg/kg, SQ per day). After 3 months of treatment, the excised left ventricles were measured by H&E staining, Western blotting, DAPI staining and TUNEL assays. More cardiac TUNEL-positive apoptotic cells were observed in the Cocaine group than the PBS group. Protein levels of TNF-alpha, Fas ligand, Fas death receptor, FADD, activated caspase-8, and activated caspase-3 (Fas-dependent apoptosis) extracted from excised hearts in the Cocaine group were significantly increased, compared to the PBS group. Protein levels of cardiac Bax, cytosolic cytochrome c, t-Bid-to-Bid, Bak-to-Bcl-xL, Bax-to-Bcl-2 ratio, activated caspase-9, and activated caspase-3 (mitochondria-dependent apoptosis) were significantly increased in the Cocaine group, compared to the PBS group. Chronic cocaine exposure appeared to activate the cardiac Fas-dependent and mitochondria-dependent apoptosis, which may indicate a possible mechanism for the development of cardiac abnormalities in humans with chronic cocaine abuse.

  12. Toll-like receptor 9 suppresses lupus disease in Fas-sufficient MRL Mice

    PubMed Central

    Wang, Yujuan; Bastacky, Sheldon; Shlomchik, Mark J.

    2017-01-01

    Genetic deficiency in TLR9 accelerates pathogenesis in the spontaneous polygenic MRL.Faslpr murine model of systemic lupus erythematosus, despite the absence of anti-nucleosome autoantibodies. However, it could be argued that this result was dependent on Fas-deficiency rather than lupus-promoting genes in the MRL genetic background. Here we report the effects of TLR9 deficiency on autoimmune disease independent of the lpr mutation in Fas by characterizing Tlr9-/- and Tlr9+/+ mice on the Fas-intact MRL/+ genetic background. By 30 weeks of age, Tlr9-deficient MRL/+ had more severe renal disease, increased T cell activation, and higher titers of anti-Sm and anti-RNA autoantibodies than Tlr9-intact animals, as had been the case in the MRL.Faslpr model. In addition, Tlr9-deficient MRL/+ mice had increased numbers of germinal center phenotype B cells and an increase in splenic neutrophils and conventional dendritic cell populations. Thus, the disease accelerating effects of Tlr9 deficiency are separable from those mediated by the Fas mutation in the lupus-prone MRL genetic background. Nonetheless, disease acceleration in Tlr9-deficient MRL/+ mice was phenotypically distinct from that in Fas-deficient counterparts, which has important implications. PMID:28278279

  13. The Fas pathway is involved in pancreatic β cell secretory function

    PubMed Central

    Schumann, Desiree M.; Maedler, Kathrin; Franklin, Isobel; Konrad, Daniel; Størling, Joachim; Böni-Schnetzler, Marianne; Gjinovci, Asllan; Kurrer, Michael O.; Gauthier, Benoit R.; Bosco, Domenico; Andres, Axel; Berney, Thierry; Greter, Melanie; Becher, Burkhard; Chervonsky, Alexander V.; Halban, Philippe A.; Mandrup-Poulsen, Thomas; Wollheim, Claes B.; Donath, Marc Y.

    2007-01-01

    Pancreatic β cell mass and function increase in conditions of enhanced insulin demand such as obesity. Failure to adapt leads to diabetes. The molecular mechanisms controlling this adaptive process are unclear. Fas is a death receptor involved in β cell apoptosis or proliferation, depending on the activity of the caspase-8 inhibitor FLIP. Here we show that the Fas pathway also regulates β cell secretory function. We observed impaired glucose tolerance in Fas-deficient mice due to a delayed and decreased insulin secretory pattern. Expression of PDX-1, a β cell-specific transcription factor regulating insulin gene expression and mitochondrial metabolism, was decreased in Fas-deficient β cells. As a consequence, insulin and ATP production were severely reduced and only partly compensated for by increased β cell mass. Up-regulation of FLIP enhanced NF-κB activity via NF-κB-inducing kinase and RelB. This led to increased PDX-1 and insulin production independent of changes in cell turnover. The results support a previously undescribed role for the Fas pathway in regulating insulin production and release. PMID:17299038

  14. FLIP switches Fas-mediated glucose signaling in human pancreatic cells from apoptosis to cell replication

    NASA Astrophysics Data System (ADS)

    Maedler, Kathrin; Fontana, Adriano; Ris, Frédéric; Sergeev, Pavel; Toso, Christian; Oberholzer, José; Lehmann, Roger; Bachmann, Felix; Tasinato, Andrea; Spinas, Giatgen A.; Halban, Philippe A.; Donath, Marc Y.

    2002-06-01

    Type 2 diabetes mellitus results from an inadequate adaptation of the functional pancreatic cell mass in the face of insulin resistance. Changes in the concentration of glucose play an essential role in the regulation of cell turnover. In human islets, elevated glucose concentrations impair cell proliferation and induce cell apoptosis via up-regulation of the Fas receptor. Recently, it has been shown that the caspase-8 inhibitor FLIP may divert Fas-mediated death signals into those for cell proliferation in lymphatic cells. We observed expression of FLIP in human pancreatic cells of nondiabetic individuals, which was decreased in tissue sections of type 2 diabetic patients. In vitro exposure of islets from nondiabetic organ donors to high glucose levels decreased FLIP expression and increased the percentage of apoptotic terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL)-positive cells; FLIP was no longer detectable in such TUNEL-positive cells. Up-regulation of FLIP, by incubation with transforming growth factor or by transfection with an expression vector coding for FLIP, protected cells from glucose-induced apoptosis, restored cell proliferation, and improved cell function. The beneficial effects of FLIP overexpression were blocked by an antagonistic anti-Fas antibody, indicating their dependence on Fas receptor activation. The present data provide evidence for expression of FLIP in the human cell and suggest a novel approach to prevent and treat diabetes by switching Fas signaling from apoptosis to proliferation.

  15. Foetal alcohol syndrome: a cephalometric analysis of patients and controls.

    PubMed

    Naidoo, Sudeshni; Harris, Angela; Swanevelder, Sonja; Lombard, Carl

    2006-06-01

    Foetal alcohol syndrome (FAS) consists of multi-system abnormalities and is caused by the excessive intake of alcohol during pregnancy. The teratogenic effect of alcohol on the human foetus has now been established beyond reasonable doubt and FAS is the most important human teratogenic condition known today. The purpose of this study was to analyse the craniofacial parameters of children with FAS and compare them with matched controls. Ninety children diagnosed with FAS (45 males, 45 females) and 90 controls were matched for age, gender, and social class. The mean age of the FAS children was 8.9 years with the controls slightly older at 9.1 years. This age difference was not significant (P = 0.34). A standard lateral cephalometric radiograph of each subject was taken. The radiographs were digitized for 20 linear and 17 angular measurements. These 37 variables were formulated to assess the size, shape, and relative position of three craniofacial complexes: (1) the cranial base, (2) midface, and (3) mandible. In addition, nine variables were computed to compare the soft tissue profiles. The study showed that measurements related to face height and mandibular size appear to be the most important features when distinguishing FAS children. Overall, the FAS children in the present study presented with vertically and horizontally underdeveloped maxillae, together with features of long face syndrome with large gonial angles and a short ramus in relation to total face height. There was also a tendency for the development of an anterior open bite, which appears to be compensated for by an increase in the vertical dimension of the anterior alveolar process to bring the incisor teeth into occlusion. The latter adaptation occurred mainly in the mandible.

  16. Fetal Alcohol Syndrome: Diagnostic Features and Psychoeducational Risk Factors.

    ERIC Educational Resources Information Center

    Phelps, LeAdelle; Grabowski, Jo-Anne

    1992-01-01

    Discusses Fetal Alcohol Syndrome (FAS), accepted as leading known cause of mental retardation. Relates chronicity, timing, and severity of alcohol exposure to age-specific developmental and behavioral consequences. Delineates specific interventions with infants, preschoolers, school-age children, and adolescents. Advocates for accurate diagnosis…

  17. The Effect of Intensity and Age on the Perception of Accent in Isochronous Sequences of a Snare Drum Timbre

    NASA Astrophysics Data System (ADS)

    Walls, Kimberly Kyle Curley

    1992-01-01

    Musical expression is largely dependent upon accentuation, yet there have been few attempts to study the perception of dynamic accent in music or to relate the results of psychoacoustical research in intensity to realistic musical situations. The purpose of the experiment was to estimate the relationships among (a) the intensity increment in dB(A) required to meet an 80% correct criterion in the perception of one accented tone embedded within a seven -tone isochronous series of identical 87 dB(A) snare drum timbre stimuli of 333 ms onsets (accent level, or AL), (b) the different limen (DL) for intensity increase to meet a 75% correct criterion in a 2AFC task for pairs for the stimuli, and (c) the age of the subjects, all of whom have normal audiograms. The 51 subjects (N = 51) were female nonmusicians ranging in age from 9 to 33 years (M = 17.98, SD = 5.21). The response tasks involved saying whether the second tone of each pair was louder or softer and circling the accented note in notated quarter notes. The stimuli production, the headphone calibration process, and their rationales were detailed. The global regression model was significant (F(2, 48) = 5.505, p =.007, R^2 =.187), and the relationship between AL and DL was not significant (F(1, 48) = 5.505, p =.197, R^2 change =.029), the relationship between AL and age was significant (F(1, 48) = 5.732, p =.021, R ^2 change =.098) at an alpha level of.05 and power calculated at.66 for a medium ES. It was concluded that accented sounds are easier to perceive in tone pairs than they are in a musical setting and that subject maturation improves performance of intensity judgement tasks. Suggestions for further research include shortening the length of the experimental session for younger subjects and increasing the number of intensity increments as well as using smaller increments to accommodate individual differences in perception.

  18. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation.

    PubMed

    Neven, Bénédicte; Magerus-Chatinet, Aude; Florkin, Benoit; Gobert, Delphine; Lambotte, Olivier; De Somer, Lien; Lanzarotti, Nina; Stolzenberg, Marie-Claude; Bader-Meunier, Brigitte; Aladjidi, Nathalie; Chantrain, Christophe; Bertrand, Yves; Jeziorski, Eric; Leverger, Guy; Michel, Gérard; Suarez, Felipe; Oksenhendler, Eric; Hermine, Olivier; Blanche, Stéphane; Picard, Capucine; Fischer, Alain; Rieux-Laucat, Frédéric

    2011-11-03

    Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder characterized by early-onset, chronic, nonmalignant lymphoproliferation, autoimmune manifestations, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline (ALPS-FAS) or somatic mutations (ALPS-sFAS) of the TNFRSF6 gene coding for FAS. Although the clinical features of ALPS have been described previously, long-term follow-up data on morbidity and mortality are scarce. We performed a retrospective analysis of clinical and genetic features of 90 ALPS-FAS and ALPS-sFAS patients monitored over a median period of 20.5 years. Heterozygous germline mutations of TNFRSF6 were identified in 83% of probands. Somatic TNFRSF6 mutations were found in 17% of index cases (all located within the intracellular domain of FAS). Sixty percent of the ALPS-FAS patients with mutations in the extracellular domain had a somatic mutation affecting the second allele of TNFRSF6; age at onset was later in these patients. No other genotype-phenotype correlations could be found. Long-term analysis confirmed a trend toward spontaneous remission of lymphoproliferation in adulthood but mixed outcomes for autoimmune manifestations. We observed significant and potentially life-threatening disease and treatment-related morbidity, including a high risk of sepsis after splenectomy that calls for careful long-term monitoring of ALPS patients. We also noted a significantly greater occurrence of disease-related symptoms in male than in female patients.

  19. The fas operon of Rhodococcus fascians encodes new genes required for efficient fasciation of host plants.

    PubMed

    Crespi, M; Vereecke, D; Temmerman, W; Van Montagu, M; Desomer, J

    1994-05-01

    Three virulence loci (fas, att, and hyp) of Rhodococcus fascians D188 have been identified on a 200-kb conjugative linear plasmid (pFiD188). The fas locus was delimited to a 6.5-kb DNA fragment by insertion mutagenesis, single homologous disruptive recombination, and in trans complementation of different avirulent insertion mutants. The locus is arranged as a large operon containing six open reading frames whose expression is specifically induced during the interaction with host plants. One predicted protein is homologous to P-450 cytochromes from actinomycetes. The putative ferredoxin component is of a novel type containing additional domains homologous to transketolases from chemoautotrophic, photosynthetic, and methylotrophic microorganisms. Genetic analysis revealed that fas encodes, in addition to the previously identified ipt, at least two new genes that are involved in fasciation development, one of which is only required on older tobacco plants.

  20. Fas involvement in Ca(2+)-independent T cell-mediated cytotoxicity.

    PubMed

    Rouvier, E; Luciani, M F; Golstein, P

    1993-01-01

    Mechanisms of T cell-mediated cytotoxicity remain poorly defined at the molecular level. To investigate some of these mechanisms, we used as target cells, on the one hand, thymocytes from lpr and gld mouse mutants, and on the other hand, L1210 cells transfected or not with the apoptosis-inducing Fas molecule. These independent mutant or transfectant-based approaches both led to the conclusion that Fas was involved in the Ca(2+)-independent component of cytotoxicity mediated by at least two sources of T cells, namely nonantigen-specific in vitro activated hybridoma cells, and antigen-specific in vivo raised peritoneal exudate lymphocytes. Thus, in these cases, T cell-mediated cytotoxicity involved transduction via Fas of the target cell death signal.

  1. Control of Mitochondrial Dynamics by Fas-induced Caspase-8 Activation in Hippocampal Neurons

    PubMed Central

    Cho, Hyo Min

    2015-01-01

    Cells undergo apoptosis mainly via two pathways-the mitochondrial pathway and the cytosolic pathway. It has been well documented that activation of the mitochondrial pathway promotes mitochondrial fragmentation and inhibition of mitochondrial fragmentation partly represses cell death. However, the mitochondrial events following activation of the cytosolic pathway are less understood. In this study, we treated Fas-activating antibody and found mitochondrial fragmentation without cell death in hippocampal primary neurons and HT-22 cell lines. Fas antibody treatment, in fact, promoted rapid activation of caspase-8, while executioner caspase-3 activation was not observed. Furthermore, blockage of caspase-8 efficiently prevented Fas antibody-induced mitochondrial fragmentation. These results suggest that the cytosolic pathway induced by death receptor activation promotes caspase-8-dependent mitochondrial fission. PMID:26412971

  2. Chloral Hydrate Treatment Induced Apoptosis of Macrophages via Fas Signaling Pathway

    PubMed Central

    Cai, Jun; Peng, Yanxia; Chen, Ting; Liao, Huanjin; Zhang, Lifang; Chen, Qiuhua; He, Yiming; Wu, Ping; Xie, Tong; Pan, Qingjun

    2016-01-01

    Background There are recent reports on several anesthetics that have anti-inflammatory and anti-infective effects apart from their uses for pain relief and muscle relaxation. Chloral hydrate is a clinical anesthetic drug and sedative that has also been reported to attenuate inflammatory response, but the mechanisms are not clearly understood. Material/Methods This study investigated the effect of chloral hydrate treatment on the apoptosis of macrophages and explored the underlying mechanisms. RAW264.7 macrophages were treated with various concentrations of chloral hydrate for various lengths of time. Morphological changes were observed under a light microscope and apoptosis was detected with annexin-V-FITC/PI double-staining assay, Hochest 33258 and DNA ladder assay, the expression of Fas/FasL was detected with a flow cytometer, and the Fas signaling pathway was assessed by Western blotting. Results The results showed that chloral hydrate treatment induced the morphology of RAW264.7 macrophages to change shape from typical fusiform to round in a concentration- and time-dependent manner, and was finally suspended in the supernatant. For the induction of apoptosis, chloral hydrate treatment induced the apoptosis of RAW264.7 macrophages from early-to-late stage apoptosis in a concentration- and time-dependent manner. For the mechanism, chloral hydrate treatment induced higher expression of Fas on RAW264.7 macrophages, and was also associated with changes in the expression of proteins involved in Fas signaling pathways. Conclusions Chloral hydrate treatment can induce the apoptosis of RAW264.7 macrophages through the Fas signaling pathway, which may provide new options for adjunctive treatment of acute inflammation. PMID:27941708

  3. Chloral Hydrate Treatment Induced Apoptosis of Macrophages via Fas Signaling Pathway.

    PubMed

    Cai, Jun; Peng, Yanxia; Chen, Ting; Liao, Huanjin; Zhang, Lifang; Chen, Qiuhua; He, Yiming; Wu, Ping; Xie, Tong; Pan, Qingjun

    2016-12-10

    BACKGROUND There are recent reports on several anesthetics that have anti-inflammatory and anti-infective effects apart from their uses for pain relief and muscle relaxation. Chloral hydrate is a clinical anesthetic drug and sedative that has also been reported to attenuate inflammatory response, but the mechanisms are not clearly understood. MATERIAL AND METHODS This study investigated the effect of chloral hydrate treatment on the apoptosis of macrophages and explored the underlying mechanisms. RAW264.7 macrophages were treated with various concentrations of chloral hydrate for various lengths of time. Morphological changes were observed under a light microscope and apoptosis was detected with annexin-V-FITC/PI double-staining assay, Hochest 33258 and DNA ladder assay, the expression of Fas/FasL was detected with a flow cytometer, and the Fas signaling pathway was assessed by Western blotting. RESULTS The results showed that chloral hydrate treatment induced the morphology of RAW264.7 macrophages to change shape from typical fusiform to round in a concentration- and time-dependent manner, and was finally suspended in the supernatant. For the induction of apoptosis, chloral hydrate treatment induced the apoptosis of RAW264.7 macrophages from early-to-late stage apoptosis in a concentration- and time-dependent manner. For the mechanism, chloral hydrate treatment induced higher expression of Fas on RAW264.7 macrophages, and was also associated with changes in the expression of proteins involved in Fas signaling pathways. CONCLUSIONS Chloral hydrate treatment can induce the apoptosis of RAW264.7 macrophages through the Fas signaling pathway, which may provide new options for adjunctive treatment of acute inflammation.

  4. Isolation of vascular smooth muscle antigen-reactive CD4(+)αβTh1 clones that induce pulmonary vasculitis in MRL/Mp-Fas(+/+) mice.

    PubMed

    Fujita, Yoshimasa; Fujii, Takao; Shimizu, Hironori; Sato, Tomomi; Nakamura, Takuji; Iwao, Haruka; Nakajima, Akio; Miki, Miyuki; Sakai, Tomoyuki; Kawanami, Takafumi; Tanaka, Masao; Masaki, Yasufumi; Fukushima, Toshihiro; Okazaki, Toshiro; Umehara, Hisanori; Mimori, Tsuneyo

    2016-05-01

    Here, we established CD4(+)αβTh1 clones specific for rat vascular smooth muscle antigen (VSMAg) that induced vasculitis lesions in the lungs of MRL/Mp-Fas(+/+) mice following adoptive transfer. Six different T cell clones, MV1b1 (Vβ1), MV1b4 (Vβ4), MV1b8.3 (Vβ8.3), MV1b61 (Vβ6), MV1b62 (Vβ6), and MV1b63 (Vβ6), were isolated from the MV1 T cell line from the regional lymph nodes of immunized MRL/Mp-Fas(+/+) mice; the three (Vβ6) clones had unique CDR3 amino acid sequences. Following stimulation with VSMAg-pulsed antigen presenting cells, MV1b61 and MV1b62 failed to secrete interferon-γ and tumor necrosis factor-α, although the other four clones secreted high levels of both cytokines. In adoptive transfer experiments, MV1b61 and MV1b62 did not induce organ involvement including pulmonary vasculitis. In contrast, MV1b1, MV1b4, MV1b8.3, and MV1b63 induced perivascular mononuclear cell infiltration in pulmonary small arteries. These clones may provide useful tools for investigating the underlying mechanisms of vasculitis syndromes and for developing therapeutic strategies.

  5. The onset of Fas expression parallels the acquisition of CD8 and CD4 in fetal and adult alpha beta thymocytes.

    PubMed

    Andjelić, S; Drappa, J; Lacy, E; Elkon, K B; Nikolić-Zugić, J

    1994-01-01

    Fas is an apoptosis-related cell surface molecule whose defective transcription results in the lpr defect and autoimmunity. Recent analysis of Fas mRNA and protein expression in normal mice showed high expression in the thymus, on activated T cells, and on 5-10% of peripheral T cells. To investigate the role of Fas in the thymus, we analyzed its expression in fetal and adult thymocyte subsets. Fas was not expressed on fetal nor adult CD8-CD4- (double-negative, DN) T cell precursors. The earliest precursors that expressed low levels of FAS were the immediate precursors of DP thymocytes that bear the CD44-CD25-CD8loCD4loTCRlo phenotype. Other DN cells that expressed Fas appeared to be either non-T cells or mature alpha beta + DN thymocytes. The onset of Fas expression followed the onset of expression of CD8 and CD4 and Fas expression reached its peak in CD8+CD4+ double-positive (DP) thymocytes. Both single-positive (SP) subsets were largely Fas+ (CD8 SP < CD4 SP) but expressed lower levels of Fas than DP cells. However, a majority (> 60%) of the most mature HSA(lo) SP cells (2-5% of all SP thymocytes) were Fas- and the remainder of the HSA(lo) SP cells was Fas(lo). We observed two main differences between Fas expression on fetal versus adult thymocytes. First, up to 90% of fetal gamma delta + DN cells expressed high levels of Fas, in contrast to the very low expression (< 7% Fas+ cells) among adult gamma delta + thymocytes. Second, whereas virtually all adult DP cells were Fas+, up to 75% of fetal day 16 DP cells were Fas-.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. 4-Nonylphenol induces disruption of spermatogenesis associated with oxidative stress-related apoptosis by targeting p53-Bcl-2/Bax-Fas/FasL signaling.

    PubMed

    Duan, Peng; Hu, Chunhui; Butler, Holly J; Quan, Chao; Chen, Wei; Huang, Wenting; Tang, Sha; Zhou, Wei; Yuan, Meng; Shi, Yuqin; Martin, Francis L; Yang, Kedi

    2017-03-01

    4-Nonylphenol (NP) is a ubiquitous environmental chemical with estrogenic activity. Our aim was to test the hypothesis that pubertal exposure to NP leads to testicular dysfunction. Herein, 24 7-week-old rats were randomly divided into four groups and treated with NP (0, 25, 50, or 100 mg/kg body weight every 2 days for 20 consecutive days) by intraperitoneal injection. Compared to untreated controls, the parameters of sperm activation rate, curvilinear velocity, average path velocity, and swimming velocity were significantly lower at doses of 100 mg/kg, while sperm morphological abnormalities were higher, indicating functional disruption and reduced fertilization potential. High exposure to NP (100 mg/kg) resulted in disordered arrangement of spermatoblasts and reduction of spermatocytes in seminiferous tubules, while tissues exhibited a marked decline in testicular fructose content and serum FSH, LH, and testosterone levels. Oxidative stress was induced by NP (50 or 100 mg/kg) as evidenced by elevated MDA, decreased SOD and GSH-Px, and inhibited antioxidant gene expression (CAT, GPx, SOD1, and CYP1B1). In addition, NP treatment decreased proportions of Ki-67-positive cells and increased apoptosis in a dose-dependent manner. Rats treated with 100 mg/kg NP exhibited significantly increased mRNA expression of caspase-1, -2, -9, and -11, decreased caspase-8 and PCNA1 mRNA expression, downregulation of Bcl-2/Bax ratios and upregulation of Fas, FasL, and p53 at the protein and mRNA levels. Taken together, NP-induced apoptosis, hormonal deficiencies, and depletion of fructose potentially impairs spermatogenesis and sperm function. p53-independent Fas/FasL-Bax/Bcl-2 pathways may be involved in NP-induced oxidative stress-related apoptosis. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 739-753, 2017.

  7. Listening to accented speech in a second language: First language and age of acquisition effects.

    PubMed

    Larraza, Saioa; Samuel, Arthur G; Oñederra, Miren Lourdes

    2016-11-01

    Bilingual speakers must acquire the phonemic inventory of 2 languages and need to recognize spoken words cross-linguistically; a demanding job potentially made even more difficult due to dialectal variation, an intrinsic property of speech. The present work examines how bilinguals perceive second language (L2) accented speech and where accommodation to dialectal variation takes place. Dialectal effects were analyzed at different levels: An AXB discrimination task tapped phonetic-phonological representations, an auditory lexical-decision task tested for effects in accessing the lexicon, and an auditory priming task looked for semantic processing effects. Within that central focus, the goal was to see whether perceptual adjustment at a given level is affected by 2 main linguistic factors: bilinguals' first language and age of acquisition of the L2. Taking advantage of the cross-linguistic situation of the Basque language, bilinguals with different first languages (Spanish or French) and ages of acquisition of Basque (simultaneous, early, or late) were tested. Our use of multiple tasks with multiple types of bilinguals demonstrates that in spite of very similar discrimination capacity, French-Basque versus Spanish-Basque simultaneous bilinguals' performance on lexical access significantly differed. Similarly, results of the early and late groups show that the mapping of phonetic-phonological information onto lexical representations is a more demanding process that accentuates non-native processing difficulties. L1 and AoA effects were more readily overcome in semantic processing; accented variants regularly created priming effects in the different groups of bilinguals. (PsycINFO Database Record

  8. Predominant expression of Fas ligand mRNA in CD8+ T lymphocytes in patients with HTLV-1 associated myelopathy.

    PubMed

    Kawahigashi, N; Furukawa, Y; Saito, M; Usuku, K; Osame, M

    1998-10-01

    To determine if Fas ligand (FasL) mediated apoptosis is involved in the pathogenesis of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), we examined the expression of FasL mRNA in fresh uncultured peripheral blood mononuclear cells (PBMC) from 17 Japanese patients with HAM/TSP, four adult T-cell leukemia/lymphoma (ATL) patients, three asymptomatic HTLV-1 carriers and three normal individuals. Using competitive PCR with primers specific for FasL mRNA, we demonstrated that nine of 17 HAM/TSP and one of four ATL patients expressed significant levels of FasL mRNA, whereas asymptomatic carriers, normal controls and both HTLV-1 infected and uninfected T-cell lines did not. Cell separation analysis following PCR revealed that FasL mRNA was expressed in CD8 + T lymphocytes. FasL mRNA was preferentially expressed in patients with increased proviral load and longer duration of clinical illness. These results suggest that FasL mediated mechanisms contribute to the pathogenesis of HAM/TSP.

  9. Daxx plays a novel role in T cell survival but is dispensable in Fas-induced apoptosis

    PubMed Central

    Dowling, John P.; Curcione, Christine; Kurup, Drishya; Zhang, Jianke

    2017-01-01

    Daxx was originally isolated as a Fas-binding protein. However, the in vivo function of Daxx in Fas-induced apoptosis has remained enigmatic. Fas plays an important role in homeostasis in the immune system. Fas gene mutations lead to autoimmune-lymphoproliferation (lpr) diseases characterized by hyperplasia of secondary lymphoid organs. It is well established that the FADD adaptor binds to Fas, and recruits/activates caspase 8. However, additional proteins including Daxx have also been indicated to associate with Fas. It was proposed that Daxx mediates a parallel apoptotic pathway that is independent of FADD and caspase 8, but signals through ASK1-mediated apoptotic pathway. However, because the deletion of Daxx leads to embryonic lethality, the in vivo function of Daxx has not been properly analyzed. In the current study, analysis was performed using a conditional mutant mouse in which Daxx was deleted specifically in T cells. The data show that Daxx-/- T cells were able to undergo normal Fas-induced apoptosis. While containing normal thymocyte populations, the T cell-specific Daxx-/- mice have a reduced peripheral T cell pool. Importantly, Daxx-deficient T cells displayed increased death responses upon activation through TCR stimulation. These results unequivocally demonstrated that Daxx does not mediate Fas-induced apoptosis, but rather that it plays a critical role in survival responses in primary mature T cells. PMID:28301594

  10. Crystal Structure of the Complex of Human FasL and Its Decoy Receptor DcR3.

    PubMed

    Liu, Weifeng; Ramagopal, Udupi; Cheng, Huiyong; Bonanno, Jeffrey B; Toro, Rafael; Bhosle, Rahul; Zhan, Chenyang; Almo, Steven C

    2016-11-01

    The apoptotic effect of FasL:Fas signaling is disrupted by DcR3, a unique secreted member of the tumor necrosis factor receptor superfamily, which also binds and neutralizes TL1A and LIGHT. DcR3 is highly elevated in patients with various tumors and contributes to mechanisms by which tumor cells to evade host immune surveillance. Here we report the crystal structure of FasL in complex with DcR3. Comparison of FasL:DcR3 structure with our earlier TL1A:DcR3 and LIGHT:DcR3 structures supports a paradigm involving the recognition of invariant main-chain and conserved side-chain functionalities, which is responsible for the recognition of multiple TNF ligands exhibited by DcR3. The FasL:DcR3 structure also provides insight into the FasL:Fas recognition surface. We demonstrate that the ability of recombinant FasL to induce Jurkat cell apoptosis is significantly enhanced by native glycosylation or by structure-inspired mutations, both of which result in reduced tendency to aggregate. All of these activities are efficiently inhibited by recombinant DcR3.

  11. Ionizing Radiation and Chemotherapeutic Drugs Induce Apoptosis in Lymphocytes in the Absence of FAS or Fadd/Mort1 Signaling

    PubMed Central

    Newton, Kim; Strasser, Andreas

    2000-01-01

    Ionizing radiation and cytotoxic drugs used in the treatment of cancer induce apoptosis in many cell types, including tumor cells. It has been reported that tumor cells treated with anticancer drugs increase surface expression of Fas ligand (FasL) and are killed by autocrine or paracrine apoptosis signaling through Fas (Friesen, C., I. Herr, P.H. Krammer, and K.-M. Debatin. 1996. Nat. Med. 2:574–577). We show that lymphocytes that cannot be killed by FasL, such as those from Fas-deficient lpr mice or transgenic mice expressing a dominant negative mutant of Fas-associated death domain protein (FADD/MORT1), are as sensitive as normal lymphocytes to killing by gamma radiation or the cytotoxic drugs cis-platin, doxorubicin, and etoposide. In contrast, p53 deficiency or constitutive expression of Bcl-2 markedly increased the resistance of lymphocytes to gamma radiation or anticancer drugs but had no effect on killing by FasL. Consistent with these observations, lpr and wild-type T cells both had a reduced capacity for mitogen-induced proliferation after drug treatment, whereas bcl-2 transgenic or p53-deficient T cells retained significant clonogenic potential. These results demonstrate that apoptosis induced by ionizing radiation or anticancer drugs requires p53 and is regulated by the Bcl-2 protein family but does not require signals transduced by Fas and FADD/MORT1. PMID:10620618

  12. The dual role of Fas-ligand as an injury effector and defense strategy in diabetes and islet transplantation.

    PubMed

    Pearl-Yafe, Michal; Yolcu, Esma S; Yaniv, Isaac; Stein, Jerry; Shirwan, Haval; Askenasy, Nadir

    2006-02-01

    The exact process that leads to the eruption of autoimmune reactions against beta cells and the evolution of diabetes is not fully understood. Macrophages and T cells may launch an initial immune reaction against the pancreatic islets of Langerhans, provoking inflammation and destructive insulitis. The information on the molecular mechanisms of the emergence of beta cell injury is controversial and points to possibly important roles for the perforin-granzyme, Fas-Fas-ligand (FasL) and tumor-necrosis-factor-mediated apoptotic pathways. FasL has several unique features that make it a potentially ideal immunomodulatory tool. Most important, FasL is selectively toxic to cytotoxic T cells and less harmful to regulatory T cells. This review discusses the intrinsic sensitivity of beta cells to FasL-mediated apoptosis, the conditions that underlie this beta cell sensitivity, and the feasibility of using FasL to arrest autoimmunity and prevent islet allograft rejection. In both the autoimmune and transplant settings, it is imperative to progress from the administration of nonspecific immunosuppressive therapy to the concept of beta-cell-specific immunomodulation. FasL evolves as a prime candidate for antigen-specific immunomodulation.

  13. Accessory spleen: differential diagnosis for lymphoma in autoimmune lymphoproliferative syndrome.

    PubMed

    Georgin-Lavialle, Sophie; Aouba, Achille; Canioni, Danielle; Rieux-Laucat, Frédéric; Fischer, Alain; Hermine, Olivier

    2010-07-01

    Mutations of Fas or, less frequently, Fas ligand genes result in a rare inherited lymphoid disorder called autoimmune lymphoproliferative syndrome (ALPS) in which lymphoma frequency is increased. We report on a patient with ALPS who had been splenectomized for giant splenomegaly and progressively developed a voluminous abdominal tumor. The histology of the removed tumor revealed that it was an accessory spleen exhibiting typical features of ALPS involvement, as shown by the presence of a large excess of CD3+CD4-CD8- T cells and plasma cells without a detectable monoclonal population. This observation highlights the lymphoma's differential diagnosis in this context.

  14. Health Care Burden and Cost Associated with Fetal Alcohol Syndrome: Based on Official Canadian Data

    PubMed Central

    Popova, Svetlana; Lange, Shannon; Burd, Larry; Rehm, Jürgen

    2012-01-01

    Background Fetal Alcohol Spectrum Disorder (FASD) is a group of disorders caused by prenatal alcohol exposure. From this group, Fetal Alcohol Syndrome (FAS) is the only disorder coded in the International Classification of Diseases, version 10 (ICD-10). This coding was used to gain an understanding on the health care utilization and the mortality rate for individuals diagnosed with FAS, as well as to estimate the associated health care costs in Canada for the most recent available fiscal year (2008–2009). Methods Health care utilization data associated with a diagnosis of FAS were directly obtained from the Canadian Institute for Health Information (CIHI). Mortality data associated with a diagnosis of FAS were obtained from Statistics Canada. Results The total direct health care cost of acute care, psychiatric care, day surgery, and emergency department services associated with FAS in Canada in 2008–2009, based on the official CIHI data, was about $6.7 million. The vast majority of the most responsible diagnoses, which account for the majority of a patient’s length of stay in hospital, fall within the ICD-10 category Mental and Behavioural Disorders (F00–F99). It was evident that the burden and cost of acute care hospitalizations due to FAS is increasing −1.6 times greater in 2008–2009, compared to 2002–2003. The mortality data due to FAS, obtained from Statistics Canada (2000–2008), may be underreported, and are likely invalid. Discussion The official data on the utilization of health care services by individuals diagnosed with FAS are likely to be underreported and therefore, the reported cost figures are most likely underestimated. The quantification of the health care costs associated with FAS is crucial for policy developers and decision makers alike, of the impact of prenatal alcohol exposure, with the ultimate goal of initiating preventive interventions to address FASD. PMID:22900084

  15. Deep-sea Rhodococcus sp. BS-15, lacking the phytopathogenic fas genes, produces a novel glucotriose lipid biosurfactant.

    PubMed

    Konishi, Masaaki; Nishi, Shinro; Fukuoka, Tokuma; Kitamoto, Dai; Watsuji, Tomo-O; Nagano, Yuriko; Yabuki, Akinori; Nakagawa, Satoshi; Hatada, Yuji; Horiuchi, Jun-Ichi

    2014-08-01

    Glycolipid biosurfactant-producing bacteria were isolated from deep-sea sediment collected from the Okinawa Trough. Isolate BS15 produced the largest amount of the glycolipid, generating up to 6.31 ± 1.15 g l(-1) after 4 days at 20 °C. Glucose was identified in the hydrolysate of the purified major component of the biosurfactant glycolipid. According to gas chromatography/mass spectrometry analysis, the hydrophobic moieties in the major component were hexadecanoate, octadecanoate, 3-hydroxyhexadecanoate, 2-hydroxyoctanoate, and succinate. The molecular weight of the purified major glycolipid was calculated to be 1,211, while (1)H and (13)C nuclear magnetic resonance spectra confirmed that the major component consisted of 2 mol of α-glucoside and 1 mol of β-glucoside. The molecular structure was assigned as novel trisaccharide-type glycolipid biosurfactant, glucotriose lipids. The critical micelle concentration of the purified major glycolipid was 2.3 × 10(-6) M, with a surface tension of 29.5 mN m(-1). Phylogenetic analysis showed isolate BS15 was closely related to a Rhodococcus strains isolated from Antarctica, and to Rhodococcus fascians, a phytopathogen. PCR analysis showed that the fasA, fasB, fasC, fasD, fasE, and fasF genes, which are involved in phytohormone-like cytokinin production, were not present in the genome of BS15; however, analysis of a draft genome sequence of BS15 (5.5 Mb) identified regions with 31 %, 53 %, 46 %, 30 %, and 31 % DNA sequence identity to the fasA, fasB, fasC, and fasD genes, respectively.

  16. An Evolution-Guided Analysis Reveals a Multi-Signaling Regulation of Fas by Tyrosine Phosphorylation and its Implication in Human Cancers

    PubMed Central

    Chakrabandhu, Krittalak; Huault, Sébastien; Durivault, Jérôme; Lang, Kévin; Ta Ngoc, Ly; Bole, Angelique; Doma, Eszter; Dérijard, Benoit; Gérard, Jean-Pierre; Pierres, Michel; Hueber, Anne-Odile

    2016-01-01

    Demonstrations of both pro-apoptotic and pro-survival abilities of Fas (TNFRSF6/CD95/APO-1) have led to a shift from the exclusive “Fas apoptosis” to “Fas multisignals” paradigm and the acceptance that Fas-related therapies face a major challenge, as it remains unclear what determines the mode of Fas signaling. Through protein evolution analysis, which reveals unconventional substitutions of Fas tyrosine during divergent evolution, evolution-guided tyrosine-phosphorylated Fas proxy, and site-specific phosphorylation detection, we show that the Fas signaling outcome is determined by the tyrosine phosphorylation status of its death domain. The phosphorylation dominantly turns off the Fas-mediated apoptotic signal, while turning on the pro-survival signal. We show that while phosphorylations at Y232 and Y291 share some common functions, their contributions to Fas signaling differ at several levels. The findings that Fas tyrosine phosphorylation is regulated by Src family kinases (SFKs) and the phosphatase SHP-1 and that Y291 phosphorylation primes clathrin-dependent Fas endocytosis, which contributes to Fas pro-survival signaling, reveals for the first time the mechanistic link between SFK/SHP-1-dependent Fas tyrosine phosphorylation, internalization route, and signaling choice. We also demonstrate that levels of phosphorylated Y232 and Y291 differ among human cancer types and differentially respond to anticancer therapy, suggesting context-dependent involvement of Fas phosphorylation in cancer. This report provides a new insight into the control of TNF receptor multisignaling by receptor phosphorylation and its implication in cancer biology, which brings us a step closer to overcoming the challenge in handling Fas signaling in treatments of cancer as well as other pathologies such as autoimmune and degenerative diseases. PMID:26942442

  17. 7 CFR 1580.203 - Determination of eligibility and certification by the Administrator (FAS).

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 10 2011-01-01 2011-01-01 false Determination of eligibility and certification by the Administrator (FAS). 1580.203 Section 1580.203 Agriculture Regulations of the Department of Agriculture (Continued) FOREIGN AGRICULTURAL SERVICE, DEPARTMENT OF AGRICULTURE TRADE ADJUSTMENT ASSISTANCE FOR...

  18. 7 CFR 1484.21 - How does FAS determine which Cooperator program applications are approved?

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 10 2013-01-01 2013-01-01 false How does FAS determine which Cooperator program applications are approved? 1484.21 Section 1484.21 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT CORPORATION, DEPARTMENT OF AGRICULTURE EXPORT PROGRAMS PROGRAMS TO HELP...

  19. 7 CFR 1484.30 - How does FAS formalize its working relationship with approved Cooperators?

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 10 2014-01-01 2014-01-01 false How does FAS formalize its working relationship with approved Cooperators? 1484.30 Section 1484.30 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT CORPORATION, DEPARTMENT OF AGRICULTURE EXPORT PROGRAMS PROGRAMS TO HELP...

  20. 7 CFR 1484.21 - How does FAS determine which Cooperator program applications are approved?

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 10 2014-01-01 2014-01-01 false How does FAS determine which Cooperator program applications are approved? 1484.21 Section 1484.21 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT CORPORATION, DEPARTMENT OF AGRICULTURE EXPORT PROGRAMS PROGRAMS TO HELP...

  1. 7 CFR 1484.30 - How does FAS formalize its working relationship with approved Cooperators?

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 10 2013-01-01 2013-01-01 false How does FAS formalize its working relationship with approved Cooperators? 1484.30 Section 1484.30 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT CORPORATION, DEPARTMENT OF AGRICULTURE EXPORT PROGRAMS PROGRAMS TO HELP...

  2. 7 CFR 1484.57 - Will FAS make advance payments to a Cooperator?

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 10 2013-01-01 2013-01-01 false Will FAS make advance payments to a Cooperator? 1484.57 Section 1484.57 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT CORPORATION, DEPARTMENT OF AGRICULTURE EXPORT PROGRAMS PROGRAMS TO HELP DEVELOP FOREIGN...

  3. 7 CFR 1484.30 - How does FAS formalize its working relationship with approved Cooperators?

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 10 2012-01-01 2012-01-01 false How does FAS formalize its working relationship with approved Cooperators? 1484.30 Section 1484.30 Agriculture Regulations of the Department of Agriculture (Continued) COMMODITY CREDIT CORPORATION, DEPARTMENT OF AGRICULTURE EXPORT PROGRAMS PROGRAMS TO HELP...

  4. XIAP acts as a switch between type I and type II FAS-induced apoptosis signalling

    PubMed Central

    Jost, Philipp J.; Grabow, Stephanie; Gray, Daniel; McKenzie, Mark D.; Nachbur, Ueli; Huang, David C.S.; Bouillet, Philippe; Thomas, Helen E.; Borner, Christoph; Silke, John; Strasser, Andreas; Kaufmann, Thomas

    2010-01-01

    FAS (APO-1/CD95) and its physiological ligand, FASL, regulate apoptotic death of unwanted or dangerous cells in many tissues, functioning as a guardian against autoimmunity and cancer development1-4. Distinct cell types differ in the mechanisms by which the ‘death receptor’ FAS triggers their apoptosis1-4. In type I cells, such as lymphocytes, activation of ‘effector caspases’ by FAS-induced activation of caspase-8 suffices for cell killing whereas in type II cells, including hepatocytes and pancreatic β-cells, amplification of the caspase cascade through caspase-8 mediated activation of the pro-apoptotic BCL-2 family member BID5 is essential6-8. Here we show, that loss of X-chromosome linked inhibitor of apoptosis (XIAP)9,10 function by gene-targeting or treatment with a second mitochondria-derived activator of caspases (SMAC11, also called DIABLO12: direct IAP binding protein with low pI) mimetic drug rendered hepatocytes independent of BID for FAS-induced apoptosis signalling. These results show that XIAP is the critical discriminator between type I versus type II apoptosis signalling and suggest that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions. PMID:19626005

  5. XIAP discriminates between type I and type II FAS-induced apoptosis.

    PubMed

    Jost, Philipp J; Grabow, Stephanie; Gray, Daniel; McKenzie, Mark D; Nachbur, Ueli; Huang, David C S; Bouillet, Philippe; Thomas, Helen E; Borner, Christoph; Silke, John; Strasser, Andreas; Kaufmann, Thomas

    2009-08-20

    FAS (also called APO-1 and CD95) and its physiological ligand, FASL, regulate apoptosis of unwanted or dangerous cells, functioning as a guardian against autoimmunity and cancer development. Distinct cell types differ in the mechanisms by which the 'death receptor' FAS triggers their apoptosis. In type I cells, such as lymphocytes, activation of 'effector caspases' by FAS-induced activation of caspase-8 suffices for cell killing, whereas in type II cells, including hepatocytes and pancreatic beta-cells, caspase cascade amplification through caspase-8-mediated activation of the pro-apoptotic BCL-2 family member BID (BH3 interacting domain death agonist) is essential. Here we show that loss of XIAP (X-chromosome linked inhibitor of apoptosis protein) function by gene targeting or treatment with a second mitochondria-derived activator of caspases (SMAC, also called DIABLO; direct IAP-binding protein with low pI) mimetic drug in mice rendered hepatocytes and beta-cells independent of BID for FAS-induced apoptosis. These results show that XIAP is the critical discriminator between type I and type II apoptosis signalling and suggest that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions.

  6. 75 FR 13329 - Implications of Financial Accounting System (FAS) 166 on SBA Guaranteed Loan Programs

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-19

    ... ADMINISTRATION Implications of Financial Accounting System (FAS) 166 on SBA Guaranteed Loan Programs AGENCY... Administration (SBA) is soliciting information and views from the public on: (1) The effect that the accounting changes mandated by the Financial Accounting Standards Board (FASB) in Financial Accounting Standard...

  7. 7 CFR 1484.21 - How does FAS determine which Cooperator program applications are approved?

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... PROGRAMS TO HELP DEVELOP FOREIGN MARKETS FOR AGRICULTURAL COMMODITIES Application and Fund Allocation... to the effective creation, expansion, or maintenance of foreign markets, FAS seeks to identify those projects that would demonstrate a clear, long-term agricultural trade strategy by market or product and...

  8. The Effectiveness of Peer-Led FAS/FAE Prevention Presentations in Middle and High Schools

    ERIC Educational Resources Information Center

    Boulter, Lyn

    2007-01-01

    Pregnant women and women who might become pregnant, including middle school- and high school-age adolescents, continue to consume alcohol, placing themselves at risk of having a child with the effects of prenatal alcohol exposure. However, most prevention programs that attempt to increase public awareness and knowledge of FAS and related disorders…

  9. 7 CFR 1484.21 - How does FAS determine which Cooperator program applications are approved?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... PROGRAMS TO HELP DEVELOP FOREIGN MARKETS FOR AGRICULTURAL COMMODITIES Application and Fund Allocation... Government Performance and Results Act (GPRA) of 1993. In deciding whether a proposed project will contribute to the effective creation, expansion, or maintenance of foreign markets, FAS seeks to identify...

  10. Activation of TIM1 induces colon cancer cell apoptosis via modulating Fas ligand expression.

    PubMed

    Wang, Hao; Zhang, Xueyan; Sun, Wenjing; Hu, Xiaocui; Li, Xiaolin; Fu, Songbin; Liu, Chen

    2016-04-29

    The pathogenesis of colon cancer is unclear. It is proposed that TIM1 has an association with human cancer. The present study aims to investigate the role of TIM1 activation in the inhibition of human colon cancer cells. In this study, human colon cancer cell line, HT29 and T84 cells were cultured. The expression of TIM1 was assessed by real time RT-PCR and Western blotting. The TIM1 on the cancer cells was activated in the culture by adding recombinant TIM4. The chromatin structure at the FasL promoter locus was assessed by chromatin immunoprecipitation. The apoptosis of the cancer cells was assessed by flow cytometry. The results showed that human colon cancer cell lines, HT29 cells and T84 cells, expressed TIM1. Activation of TIM1 by exposing the cells to TIM4 significantly increased the frequency of apoptotic colon cancer cells. The expression of FasL was increased in the cancer cells after treating by TIM4. Blocking Fas or FasL abolished the exposure to TIM4-induced T84 cell apoptosis. In conclusion, HT29 cells and T84 cells express TIM1; activation TIM1 can induce the cancer cell apoptosis. TIM1 may be a novel therapeutic target of colon cancer.

  11. Molecular Cloning and Function of FAS/APO1 Associated Protein in Breast Cancer.

    DTIC Science & Technology

    1996-06-01

    UNCLASSIFIED AD NUMBER ADB221278 NEW LIMITATION CHANGE TO Approved for public release, distribution unlimited FROM Distribution authorized to U.S...levels of Fas antigen 8. N. Itoh and S. Nagata, J. Biof . Chem. 268, 10932 Sepharose in 50 mM tris (pH 8.0), 150 mM NaCI, 5 (1993). mM dithiothreitol (DTT

  12. Prevalence of Fetal Alcohol Syndrome and Maternal Characteristics in a Sample of Schoolchildren from a Rural Province of Croatia

    PubMed Central

    Petković, Giorgie; Barišić, Ingeborg

    2013-01-01

    Fetal alcohol syndrome (FAS) is a congenital syndrome caused by maternal alcohol consumption during pregnancy and is entirely preventable by abstinence from alcohol drinking during this time. Little is known about the prevalence of FAS and maternal alcohol consumption during pregnancy in Western countries. We present the results of FAS/partial fetal alcohol syndrome (PFAS) prevalence study and maternal characteristics in a sample of schoolchildren from a rural province of Croatia. This study involved seven elementary schools with 1,110 enrolled children attending 1st to 4th grade and their mothers. We used an active case ascertainment method with passive parental consent and Clarified IOM criteria. The investigation protocol involved maternal data collection and clinical examination of children. Out of 1,110 mothers, 917 (82.6%) answered the questionnaire. Alcohol exposure during pregnancy was admitted by 11.5%, regular drinking by 4.0% and binge drinking by 1.4% of questioned mothers. Clinical examination involved 824 (74.2%) schoolchildren and disclosed 14 (1.7%) with clinical signs of FAS and 41 (5.0%) of PFAS. The observed FAS prevalence, based on 74.2% participation rate, was 16.9, PFAS 49.7 and combined prevalence was 66.7/1,000 examined schoolchildren. This is the first FAS prevalence study based on active ascertainment among schoolchildren and pregnancy alcohol drinking analysis performed in a rural community of Croatia and Europe. High prevalence of FAS/PFAS and pregnancy alcohol consumption observed in this study revealed that FAS is serious health problem in rural regions as well as a need to develop future studies and preventive measures for pregnancy alcohol drinking and FASD. PMID:23591786

  13. The Fas death pathway controls coordinated expansions of type 1 CD8 and type 2 CD4 T cells in Trypanosoma cruzi infection.

    PubMed

    Guillermo, Landi V Costilla; Silva, Elisabeth M; Ribeiro-Gomes, Flávia L; De Meis, Juliana; Pereira, Wânia F; Yagita, Hideo; DosReis, George A; Lopes, Marcela F

    2007-04-01

    We investigated the role of the Fas ligand (FasL)/Fas death pathway on apoptosis and cytokine production by T cells in Trypanosoma cruzi infection. Anti-FasL, but not anti-TNF-alpha or anti-TRAIL, blocked activation-induced cell death of CD8 T cells and increased secretion of IL-10 and IL-4 by CD4 T cells from T. cruzi-infected mice. CD4 and CD8 T cells up-regulated Fas/FasL expression during T. cruzi infection. However, Fas expression increased earlier in CD8 T cells, and a higher proportion of CD8 T cells was activated and expressed IFN-gamma compared with CD4 T cells. Injection of anti-FasL in infected mice reduced parasitemia and CD8 T cell apoptosis and increased the ratio of CD8:CD4 T cells recovered from spleen and peritoneum. FasL blockade increased the number of activated T cells, enhanced NO production, and reduced parasite loads in peritoneal macrophages. Injection of anti-FasL increased IFN-gamma secretion by splenocytes responding to T. cruzi antigens but also exacerbated production of type 2 cytokines IL-10 and IL-4 at a late stage of acute infection. These results indicate that the FasL/Fas death pathway regulates apoptosis and coordinated cytokine responses by type 1 CD8 and type 2 CD4 T cells in T. cruzi infection.

  14. Marijuana smoke and Delta(9)-tetrahydrocannabinol promote necrotic cell death but inhibit Fas-mediated apoptosis.

    PubMed

    Sarafian, T A; Tashkin, D P; Roth, M D

    2001-08-01

    Marijuana smoke shares many components in common with tobacco smoke except for the presence of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the psychotropic compound found only in Cannibis sativa. Delta(9)-THC has been shown to potentiate smoke-induced oxidative stress and necrotic cell death. In the present study, our objective was to determine the effects of Delta(9)-THC on the balance between Fas-induced apoptosis and necrosis in A549 lung tumor cells. We found that Fas-induced activation of caspase-3 was inhibited by whole smoke from both tobacco and marijuana cigarettes. Gas-phase smoke, which generates high levels of intracellular reactive oxygen species, had no effect on caspase-3 activity. However, particulate-phase smoke (tar) was a potent inhibitor of Fas-induced caspase-3 activity, with marijuana tar being more potent than either tobacco or placebo marijuana tar (lacking Delta(9)-THC). Delta(9)-THC also inhibited Fas-induced caspase-3 activity in A549 cells. In contrast, no inhibition was observed when Delta(9)-THC was incubated with activated caspase-3 enzyme, suggesting that Delta(9)-THC acts on the cell pathway(s) leading to caspase-3 activation and not directly on enzyme function. Flow cytometry was used to measure the percentage of cells undergoing apoptosis (staining for annexin V) versus necrosis (staining for propidium iodide) and confirmed that both marijuana tar extract and synthetic Delta(9)-THC inhibit Fas-induced apoptosis while promoting necrosis. These observations suggest that the Delta(9)-THC contained in marijuana smoke disrupts elements of the apoptotic pathway, thereby shifting the balance between apoptotic and necrotic cell death. This shift may affect both the carcinogenic and immunologic consequences of marijuana smoke exposure.

  15. Association between lymphocyte expression of the apoptotic receptor Fas and pain in critically ill patients

    PubMed Central

    Papathanassoglou, Elizabeth DE; Mpouzika, Meropi DA; Giannakopoulou, Margarita; Bozas, Evangelos; Middleton, Nicos; Tsiaousis, George; Karabinis, Andreas

    2017-01-01

    Objective Lymphocyte apoptosis in critical illness is associated with immunosuppression. We explored for the first time the associations between pain ratings and expression of the apoptotic receptor Fas on B and T cells in critically ill patients and the potential mediating effects of adrenocorticotropic hormone (ACTH), cortisol, and substance P (SP). Design This is an exploratory correlational study with repeated measurements (14 days followup) and cross-sectional comparisons. Setting This study was conducted in a state hospital in the metropolitan area of Athens, Greece. Participants The participants were 36 consecutive critically ill patients and 36 matched controls. Outcome measures Pain measured by the self-reported numeric rating scale [NRS], the behavioral pain scale, and the pain assessment scale was the primary outcome measure. Flow cytometry (Fas), electrochemiluminescence (ACTH and cortisol) and enzyme-linked immunosorbent assay (SP) were used. Mixed linear models for repeated measurements and bivariable associations at discrete time points were employed. Results Significant pain at rest was noted. Pain ratings associated with Fas expression on cytotoxic T cells (P=0.041) and B cells (P=0.005), even after adjustment for a number of clinical treatment factors (P=0.006 and P=0.052, respectively). On the day that more patients were able to communicate, Fas on B cells (r=0.897, P=0.029) and cytotoxic T cells (r=0.832; P=0.037) associated with NRS ratings. Associations between pain ratings and ACTH serum levels were noted (P<0.05). When stress neuropeptide levels were added to the model, the statistical significance of the associations between pain ratings and Fas expression was attenuated (P=0.052–0.063), suggesting that stress neuropeptides may partially mediate the association. Conclusion Preliminary evidence for the association between pain and lymphocyte apoptotic susceptibility is provided. The role of pain management in maintaining immunocompetence

  16. Cellular taurine release triggered by stimulation of the Fas(CD95) receptor in Jurkat lymphocytes.

    PubMed

    Lang, F; Madlung, J; Uhlemann, A C; Risler, T; Gulbins, E

    1998-08-01

    One of the hallmarks of apoptosis is cell shrinkage which appears to be important for cell death. The mechanisms mediating cell volume decrease have, however, not been addressed. Mechanisms employed by swollen cells to decrease their cell volume include activation of ion transport pathways, such as ion channels and KCl cotransport, and release of cellular osmolytes, such as taurine, sorbitol, betaine and inositol. The present study has been performed to test for release of taurine. To this end Jurkat human T-lymphocytes were loaded with [3H]taurine and apoptotic cell death induced by triggering the Fas(CD95) receptor with monoclonal crosslinking antibody. Triggering the Fas(CD95) receptor led to a release of 60+/-5% of cellular taurine within 90 min. The release did not occur prior to 45 min. The release coincided with cell shrinkage as evidenced from forward scatter in FACS analysis and preceeded DNA fragmentation according to propidium iodide staining. The delay of taurine release was not influenced by exchange of medium and thus was not due to extracellular accumulation of a stimulator. The Fas(CD95)-induced taurine release, cell shrinkage and DNA fragmentation were blunted by lowering of ambient temperature to 23 degreesC. Following pretreatment of cells with Fas(CD95) antibody at 23 degreesC rewarming led to rapid taurine release, cell shrinkage and DNA fragmentation, indicating that the temperature-sensitive step is distal to the mechanisms accounting for the delay. Osmotic cell swelling led to an immediate release of taurine. In conclusion, Fas(CD95) triggering leads to delayed taurine release through a temperature-sensitive mechanism.

  17. Ursodeoxycholyl Lysophosphatidylethanolamide Protects Against CD95/Fas-Induced Fulminant Hepatitis.

    PubMed

    Utaipan, Tanyarath; Otto, Ann-Christin; Gan-Schreier, Hongying; Chunglok, Warangkana; Pathil, Anita; Stremmel, Wolfgang; Chamulitrat, Walee

    2017-01-04

    Increased activation of CD95/Fas by Fas ligand in viral hepatitis and autoimmunity is involved in pathogenesis of fulminant hepatitis and liver failure. We designed a bile-acid phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE with LPE containing oleate at the sn-1) as a hepatoprotectant that was shown to protect against fulminant hepatitis induced by endotoxin. We herein further assessed the ability of UDCA-LPE to prevent death receptor CD95/Fas-induced fulminant hepatitis. C57BL/6 mice were intravenously administered with CD95/Fas agonistic monoclonal antibody (Jo-2) with or without 1 h pretreatment with 50 mg/kg UDCA-LPE. Jo-2 administration caused massive hepatocyte damage as seen by histology, and this was associated with a significant decrease in hepatic phosphatidylcholine (PC), lysoPC, and lysophosphatidylethanolamine levels. By histology, UDCA-LPE pretreatment improved hepatocyte damage and restored the loss of these phospholipids in part by a mechanism involving an inhibition of cytosolic phospholipaseA2 expression. Accordingly, Jo-2 treatment increased hepatic expression of cleaved caspase 8, caspase 3, and poly (ADP-Ribose) polymerase-1, and on the other hand decreased that of anti-apoptotic cellular FLICE-inhibitory protein. UDCA-LPE pretreatment was able to reverse all these changes. Moreover, UDCA-LPE attenuated inflammatory response by lowering the levels of Jo-2-induced proinflammatory cytokines TNF-α, IL-6, and IL-1β in liver and serum. UDCA-LPE was also able to decrease the levels of stimulated Th1/Th17 cytokines in Jo-2-primed isolated splenocytes. Taken together, UDCA-LPE exhibited potent anti-inflammatory effects against CD95/Fas-induced fulminant hepatitis.

  18. Isolinderalactone inhibits proliferation of A549 human non‑small cell lung cancer cells by arresting the cell cycle at the G0/G1 phase and inducing a Fas receptor and soluble Fas ligand-mediated apoptotic pathway.

    PubMed

    Chang, Wei-An; Lin, En-Shyh; Tsai, Ming-Ju; Huang, Ming-Shyan; Kuo, Po-Lin

    2014-05-01

    Lung cancer is currently the leading cause of cancer-related mortality worldwide. In Taiwan, lung cancer is also the type of malignancy that is the major cause of cancer-mortality. Investigating the mechanism of apoptosis of lung cancer cells is important in the treatment of lung cancer. In the present study, isolinderalactone was demonstrated to exhibit anticancer effects in A549 human non-small cell lung cancer cells. The effect of isolinderalactone on apoptosis, cell cycle distribution p21 levels and the Fas receptor and soluble Fas ligand (sFasL) were assayed in order to determine the mechanism underlying the anticancer effect of isolinderalactone. It was demonstrated that isolinderalactone may induce p21 expression and then cause the cell cycle arrest of A549 cells. The data of the present study also revealed that the Fas/sFasL apoptotic system is significant in the mechanism of isolinderalactone‑induced apoptosis of A549 cells. These novel findings demonstrated that isolinderalactone may cause the cell cycle arrest of A549 cells by induction of p21, and induce apoptosis of A549 human non-small-cell lung carcinoma cells through the Fas/sFasL apoptotic system.

  19. Concerted Action of the FasL/Fas and Perforin/Granzyme A and B Pathways Is Mandatory for the Development of Early Viral Hepatitis but Not for Recovery from Viral Infection

    PubMed Central

    Balkow, Sandra; Kersten, Astrid; Tran, Thi Thanh Thao; Stehle, Thomas; Grosse, Philipp; Museteanu, Crisan; Utermöhlen, Olaf; Pircher, Hanspeter; von Weizsäcker, Fritz; Wallich, Reinhard; Müllbacher, Arno; Simon, Markus M.

    2001-01-01

    Cytotoxic T lymphocytes (CTL) play a major role in the recovery from primary viral infections and the accompanying tissue injuries. However, it is unclear to what extent the two main cytolytic pathways, perforin-granzyme A and B exocytosis and Fas ligand (FasL)-Fas interaction, contribute to these processes. Here we have employed mouse strains with either spontaneous mutations or targeted gene defects in one or more components of either of the two cytolytic pathways to analyze the molecular basis of viral clearance and induction of hepatitis during lymphocytic choriomeningitis virus infection. Our results reveal that viral clearance is solely dependent on perforin but that virus-induced liver damage only occurs when both the FasL/Fas and the perforin pathways, including granzymes A and B, are simultaneously activated. The finding that development of hepatitis but not viral clearance is dependent on the concomitant activation of FasL-Fas and perforin-granzymes may be helpful in designing novel strategies to prevent hepatic failures during viral infections. PMID:11507223

  20. Interpretation of contrastive pitch accent in six- to eleven-year-old English-speaking children (and adults).

    PubMed

    Ito, Kiwako; Bibyk, Sarah A; Wagner, Laura; Speer, Shari R

    2014-01-01

    Both off-line and on-line comprehension studies suggest not only toddlers and preschoolers, but also older school-age children have trouble interpreting contrast-marking pitch prominence. To test whether children achieve adult-like proficiency in processing contrast-marking prosody during school years, an eye-tracking experiment examined the effect of accent on referential resolution in six- to eleven-year-old children and adults. In all age groups, a prominent accent facilitated the detection of a target in contrastive discourse sequences (pink cat → green cat), whereas it led to a garden path in non-contrastive sequences (pink rabbit → green monkey: the initial fixations were on rabbits). While the data indicate that children as young as age six immediately interpret contrastive accent, even the oldest child group showed delayed fixations compared to adults. We argue that the children's slower recovery from the garden path reflects the gradual development in cognitive flexibility that matures independently of general oculomotor control.

  1. Endotoxemia contributes to CD27+ memory B-cell apoptosis via enhanced sensitivity to Fas ligation in patients with Cirrhosis

    PubMed Central

    Chang, Li-Yuan; Li, Yonghai; Kaplan, David E.

    2016-01-01

    Peripheral CD27+ memory B-cells become quantitatively reduced and dysfunctional in patients with cirrhosis through poorly characterized mechanisms. We hypothesized that the disappearance of CD27+ memory B-cells results from enhanced sensitivity to apoptosis caused by exposure to gut microbial translocation products. Using isolated naïve and memory B-cells from patients with cirrhosis and age-matched controls, ex vivo and activation-induced sensitivity to Fas-mediated apoptosis was assessed under relevant experimental conditions. We observed differential expression of CD95(Fas) in CD27+ B-cells from cirrhotic patients that was inversely correlated with peripheral CD27+ B-cell frequency. While memory B-cells from cirrhotic patients were resistant to Fas-mediated apoptosis ex vivo, Toll-like receptor 4(TLR4)-ligation restored Fas-sensitivity. Sensitivity to Fas-mediated apoptosis could be transferred to healthy donor memory B-cells by co-culturing these cells with plasma from cirrhotic patients, a sensitivity partially mediated by Fas and TLR4 signaling, and partially rescued via B-cell receptor crosslinking. We conclude that peripheral CD27+ memory B-cells in cirrhosis exhibit increased sensitivity to Fas-induced apoptosis in an activation-dependent manner to which endotoxin contributes, associated with reduced frequency of circulating memory B-cells. Destruction of this critical cell subset may contribute to the cirrhotic immunodeficiency state and heightened risk of systemic infections in advanced liver disease. PMID:27857173

  2. Leafy gall formation is controlled by fasR, an AraC-type regulatory gene in Rhodococcus fascians.

    PubMed

    Temmerman, W; Vereecke, D; Dreesen, R; Van Montagu, M; Holsters, M; Goethals, K

    2000-10-01

    Rhodococcus fascians can interact with many plant species and induce the formation of either leafy galls or fasciations. To provoke symptoms, R. fascians strain D188 requires pathogenicity genes that are located on a linear plasmid, pFiD188. The fas genes are essential for virulence and constitute an operon that encodes, among other functions, a cytokinin synthase gene. Expression of the fas genes is induced by extracts of infected plant tissue only. We have isolated an AraC-type regulatory gene, fasR, located on pFiD188, which is indispensable for pathogenesis and for fas gene expression. The combined results of our experiments show that in vitro expression of the fas genes in a defined medium is strictly regulated and that several environmental factors (pH, carbon and nitrogen sources, phosphate and oxygen content, and cell density) and regulatory proteins are involved. We further show that expression of the fas genes is controlled at both the transcriptional and the translational levels. The complex expression pattern probably reflects the necessity of integrating a multitude of signals and underlines the importance of the fas operon in the pathogenicity of R. fascians.

  3. FasL Gene -844T/C Mutation of Esophageal Cancer in South China and Its Clinical Significance

    PubMed Central

    Zhao, Hongguang; Zheng, Linfeng; Li, Xinru; Wang, Lifang

    2014-01-01

    In this study, we investigated the association between the FasL -844T/C polymorphism and the risk of developing esophageal squamous cell carcinoma (ESCC) in South China. For the investigation, we randomly selected 248 patients suffering from ESCC from Southern China along with 297 healthy individuals as the control group. The relationship between the FasL gene -844T/C SNP and ESCC was studied using PCR-RFLP and immunohistochemistry. The Fas -1377G/A SNP was also selected for investigation to detect whether it interferes with the functional effect of the FasL -844C/T polymorphism in ESCC development. A significant difference in the FasL -844T/C genotypes between the patients and the control group was observed (P<0.05), with those expressing the C allele having a significantly reduced risk of developing ESCC, however younger patients (<60 years) exhibited a more malignant pathological T grade if they were homozygous for the C allele. FasL -844 CC combined with the Fas -1377 G allele is a protective factor against ESCC. Having said this, even though the C allele has a protective effect prior to development of ESCC, once the host does develop the condition the tumour will develop faster and have a higher degree of malignancy than T carriers. PMID:24473454

  4. Engineering of bone marrow cells with fas-ligand protein-enhances donor-specific tolerance to solid organs.

    PubMed

    Askenasy, E M; Shushlav, Y; Sun, Z; Shirwan, H; Yolcu, E S; Askenasy, N

    2011-11-01

    Effective immunomodulation to induce tolerance to tissue/organ allografts is attained by infusion of donor lymphocytes endowed with killing capacity through ectopic expression of a short-lived Fas-ligand (FasL) protein. The same approach has proven effective in improving hematopoietic stem and progenitor cell engraftment. This study evaluates the possibility of substitution of immune cells for bone marrow cells (BMC) to induce FasL-mediated tolerance to solid organ grafts. Expression of FasL protein on BMC increased the survival of simultaneously grafted vascularized heterotopic cardiac grafts to 90%, as compared to 30% in recipients of naïve BMC. Similar results were obtained for skin allografts implanted into radiation chimeras at 1 week after bone marrow transplantation. Further reduction of preparative conditioning to busulfan resulted in acceptance of donor skin implanted at 2 weeks after transplantation of naïve and FasL-coated BMC, whereas third-party grafts were acutely rejected. The levels of donor chimerism were in the range of 0.7% to 12% at the time of skin grafting, with higher levels in recipients of FasL-coated BMC. It is concluded that FasL-mediated abrogation of alloimmune responses can be effectively attained with BMC. There is no threshold of donor chimerism, but tolerance to solid organs evolves during the process of donor-host mutual acceptance.

  5. Induction of tolerance to cardiac allografts using donor splenocytes engineered to display on their surface an exogenous fas ligand protein.

    PubMed

    Yolcu, Esma S; Gu, Xiao; Lacelle, Chantale; Zhao, Hong; Bandura-Morgan, Laura; Askenasy, Nadir; Shirwan, Haval

    2008-07-15

    The critical role played by Fas ligand (FasL) in immune homeostasis renders this molecule an attractive target for immunomodulation to achieve tolerance to auto- and transplantation Ags. Immunomodulation with genetically modified cells expressing FasL was shown to induce tolerance to alloantigens. However, genetic modification of primary cells in a rapid, efficient, and clinically applicable manner proved challenging. Therefore, we tested the efficacy of donor splenocytes rapidly and efficiently engineered to display on their surface a chimeric form of FasL protein (SA-FasL) for tolerance induction to cardiac allografts. The i.p. injection of ACI rats with Wistar-Furth rat splenocytes displaying SA-FasL on their surface resulted in tolerance to donor, but not F344 third-party cardiac allografts. Tolerance was associated with apoptosis of donor reactive T effector cells and induction/expansion of CD4(+)CD25(+)FoxP3(+) T regulatory (Treg) cells. Treg cells played a critical role in the observed tolerance as adoptive transfer of sorted Treg cells from long-term graft recipients into naive unmanipulated ACI rats resulted in indefinite survival of secondary Wistar-Furth grafts. Immunomodulation with allogeneic cells rapidly and efficiently engineered to display on their surface SA-FasL protein provides an effective and clinically applicable means of cell-based therapy with potential application to regenerative medicine, transplantation, and autoimmunity.

  6. Soluble Fas ligand released by colon adenocarcinoma cells induces host lymphocyte apoptosis: an active mode of immune evasion in colon cancer

    PubMed Central

    Song, E; Chen, J; Ouyang, N; Su, F; Wang, M; Heemann, U

    2001-01-01

    Expression of membrane-bound Fas ligand (mFasL) on colon cancer cells serves as a potential mechanism to inhibit host immune function by inducing apoptosis of host lymphocytes. Membrane-bound FasL can be cleaved and released as a soluble mediator (sFasL), which may spread the apoptosis induction effect. Our study examined whether colon adenocarcinoma cells release sFasL, and induce apoptosis of host lymphocytes without direct cell–cell contact. In 12 consecutive patients with colon adenocarcinoma mFasL was identified in the tumours, sFasL was measured in the sera and apoptosis identified in tumour-infiltrating and peripheral blood lymphocytes. To analyse the function of sFasL, colon cancer cells were primarily cultured; sFasL was isolated from supernatants, measured, incubated with Fas-bearing Jurkat cells, and the resulting apoptosis was analysed. Serum levels of sFasL were significantly elevated in all colon cancer patients with mFasL expression in tumour tissues (n = 8). In these patients, the number of apoptotic lymphocytes was significantly increased within tumour and peripheral blood. Furthermore, sFasL was present in the corresponding supernatants and induced apoptosis of Jurkat cells in a dose-dependent manner. These findings suggest that mFasL-positive colon cancer cells release sFasL, and thus may induce apoptosis of host lymphocytes as a potential mechanism for immune evasion. © 2001 Cancer Research Campaignhttp://www.bjcancer.com PMID:11592778

  7. Advances in autoimmune lymphoproliferative syndromes.

    PubMed

    Madkaikar, Manisha; Mhatre, Snehal; Gupta, Maya; Ghosh, Kanjaksha

    2011-07-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis. It is characterized by non-malignant lymphoproliferation autoimmunity mostly directed toward blood cells and increased risk of lymphoma. Majority of patients with ALPS harbor heterozygous germline mutations in the gene for the TNF receptor-family member Fas (CD 95, Apo-1) which are inherited in an autosomal dominant fashion. Somatic Fas mutations are the second most common genetic etiology of ALPS. Additionally mutations in the genes encoding Fas-ligand (FASLG), caspase 10 (CASP10) and caspase 8 (CASP8), NRAS and KRAS have been identified in a small number of patients with ALPS and related disorders. Approximately one-third of patients with ALPS have yet unidentified defect. ALPS was initially thought to be a very rare disease, but recent studies have shown that it may be more common than previously thought. Testing for ALPS should therefore be considered in patients with unexplained lymphadenopathy, cytopenias, and hepatosplenomegaly. There have been significant advances in the understanding of the pathophysiology of ALPS in last few years which has resulted in the development of new diagnostic criteria and a number of targeted therapies. This review describes the clinical and laboratory manifestations found in patients with ALPS, as well as the molecular basis for the disease and new advances in treatment.

  8. Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study.

    PubMed

    Seif, Alix E; Manno, Catherine S; Sheen, Cecilia; Grupp, Stephan A; Teachey, David T

    2010-03-18

    Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by dysregulation of the Fas apoptotic pathway. Clinical manifestations of ALPS include autoimmune cytopenias, organomegaly, and lymphadenopathy. These findings overlap with Evans syndrome (ES), defined by presence of at least 2 autoimmune cytopenias. We hypothesized a subset of patients with ES have ALPS and tested 45 children at 22 institutions, measuring peripheral blood double-negative T cells (DNTs) and Fas-mediated apoptosis. ALPS was diagnosed in 47% of patients tested. Markedly elevated DNTs (> or = 5%) were a strong predictor of ALPS (positive predictive value = 94%), whereas no patients with DNTs less than 2.5% had ALPS on apoptosis testing. Severity of cytopenias and elevated immunoglobulin levels also predicted ALPS. This is the largest published series describing children with ES and documents a high rate of ALPS among pediatric ES patients. These data suggest that children with ES should be screened for ALPS with DNTs.

  9. Beals syndrome (congenital contractural arachnodactyly): prenatal ultrasound findings and molecular analysis.

    PubMed

    Inbar-Feigenberg, M; Meirowitz, N; Nanda, D; Toi, A; Okun, N; Chitayat, D

    2014-10-01

    We report the prenatal findings in two cases of Beals syndrome. Both pregnancies presented with clinical features of arthrogryposis multiplex congenita/fetal akinesia syndrome (AMC/FAS), including clenched fists and multiple joint contractures on repeat prenatal ultrasound examinations. The first case was diagnosed as having Beals syndrome on physical examination shortly after birth and the diagnosis was confirmed by DNA analysis, shown as a point mutation in the fibrillin 2 (FBN2) gene. The second case was diagnosed with Beals syndrome following microarray analysis on amniocytes, which showed a deletion of the FBN2 gene. Although most cases with AMC/FAS carry a poor prognosis, Beals syndrome is consistent with normal cognitive development and a better prognosis. Thus, making the correct diagnosis is crucial, both pre- and postnatally, for accurate counseling and management.

  10. Fas ligand based immunotherapy: A potent and effective neoadjuvant with checkpoint inhibitor properties, or a systemically toxic promoter of tumor growth?

    PubMed

    Modiano, Jaime F; Bellgrau, Donald

    2016-02-01

    Fas ligand (FasL, CD95L) is a 40-kDa type II transmembrane protein that binds to Fas (CD95) receptors and promotes programmed cell death. Fas receptors are expressed at higher levels in many tumors than in normal cells; however, systemic administration of FasL or agonistic anti-Fas antibodies to mice with tumors caused lethal hepatitis. Somewhat paradoxically, elimination of Fas or FasL from tumors also leads to death induced by CD95 receptor/ligand elimination (DICE). At face value, this suggests that Fas signaling not only kills normal cells, but that it also is essential for tumor cell survival. Targeting this pathway may not only fail to kill tumors, but instead may even enhance their growth, leading some to report the demise of Fas ligand in cancer immunotherapy. But, to paraphrase Mark Twain, is this death an exaggeration? Here, we provide a careful examination of the literature exploring the merits of FasL as a novel form of cancer immunotherapy. With local administration using delivery vectors that achieve high levels of expression in the tumor environment, our results indicate that the potential for systemic toxicity is eliminated in higher mammals, and that a systemic anti-tumor response ensues, which delays or prevents progression and simultaneously attacks distant metastases.

  11. Imatinib sensitizes T-cell lymphocytes from chronic myeloid leukemia patients to FasL-induced cell death: a brief communication.

    PubMed

    Legros, Laurence; Ebran, Nathalie; Stebe, Emmanuelle; Rousselot, Philippe; Rea, Delphine; Cassuto, Jill Patrice; Mahon, Francois-Xavier; Hueber, Anne-Odile

    2012-01-01

    There is now substantial evidence that imatinib may affect immune responses, especially those mediated by T lymphocytes. Fas (CD95/Apo-1), a cell death receptor, is a key regulator of the immune system. We have explored the consequences of treatment on the Fas system in chronic myeloid leukemia patients treated with imatinib. In comparison with healthy controls, we found not only a mild blood lymphopenia but also impairment of phytohemagglutinin activation in CD4Fas and CD8Fas lymphocytes of imatinib-treated patients. Moreover, these lymphocyte populations were more sensitive to FasL-induced cell death in relation to an increase in Fas expression at the cell surface. Taken together, these results reveal the role of Fas receptor in the lymphopenia observed in patients treated with imatinib, with potential deleterious consequences on antileukemic responses against this immunogenic hematological malignancy.

  12. A Mozart is not a Pavarotti: singers outperform instrumentalists on foreign accent imitation

    PubMed Central

    Christiner, Markus; Reiterer, Susanne Maria

    2015-01-01

    Recent findings have shown that people with higher musical aptitude were also better in oral language imitation tasks. However, whether singing capacity and instrument playing contribute differently to the imitation of speech has been ignored so far. Research has just recently started to understand that instrumentalists develop quite distinct skills when compared to vocalists. In the same vein the role of the vocal motor system in language acquisition processes has poorly been investigated as most investigations (neurobiological and behavioral) favor to examine speech perception. We set out to test whether the vocal motor system can influence an ability to learn, produce and perceive new languages by contrasting instrumentalists and vocalists. Therefore, we investigated 96 participants, 27 instrumentalists, 33 vocalists and 36 non-musicians/non-singers. They were tested for their abilities to imitate foreign speech: unknown language (Hindi), second language (English) and their musical aptitude. Results revealed that both instrumentalists and vocalists have a higher ability to imitate unintelligible speech and foreign accents than non-musicians/non-singers. Within the musician group, vocalists outperformed instrumentalists significantly. Conclusion: First, adaptive plasticity for speech imitation is not reliant on audition alone but also on vocal-motor induced processes. Second, vocal flexibility of singers goes together with higher speech imitation aptitude. Third, vocal motor training, as of singers, may speed up foreign language acquisition processes. PMID:26379537

  13. Effective Acoustic Modeling for Pronunciation Quality Scoring of Strongly Accented Mandarin Speech

    NASA Astrophysics Data System (ADS)

    Ge, Fengpei; Liu, Changliang; Shao, Jian; Pan, Fuping; Dong, Bin; Yan, Yonghong

    In this paper we present our investigation into improving the performance of our computer-assisted language learning (CALL) system through exploiting the acoustic model and features within the speech recognition framework. First, to alleviate channel distortion, speaker-dependent cepstrum mean normalization (CMN) is adopted and the average correlation coefficient (average CC) between machine and expert scores is improved from 78.00% to 84.14%. Second, heteroscedastic linear discriminant analysis (HLDA) is adopted to enhance the discriminability of the acoustic model, which successfully increases the average CC from 84.14% to 84.62%. Additionally, HLDA causes the scoring accuracy to be more stable at various pronunciation proficiency levels, and thus leads to an increase in the speaker correct-rank rate from 85.59% to 90.99%. Finally, we use maximum a posteriori (MAP) estimation to tune the acoustic model to fit strongly accented test speech. As a result, the average CC is improved from 84.62% to 86.57%. These three novel techniques improve the accuracy of evaluating pronunciation quality.

  14. Political skill: explaining the effects of nonnative accent on managerial hiring and entrepreneurial investment decisions.

    PubMed

    Huang, Laura; Frideger, Marcia; Pearce, Jone L

    2013-11-01

    We propose and test a new theory explaining glass-ceiling bias against nonnative speakers as driven by perceptions that nonnative speakers have weak political skill. Although nonnative accent is a complex signal, its effects on assessments of the speakers' political skill are something that speakers can actively mitigate; this makes it an important bias to understand. In Study 1, White and Asian nonnative speakers using the same scripted responses as native speakers were found to be significantly less likely to be recommended for a middle-management position, and this bias was fully mediated by assessments of their political skill. The alternative explanations of race, communication skill, and collaborative skill were nonsignificant. In Study 2, entrepreneurial start-up pitches from national high-technology, new-venture funding competitions were shown to experienced executive MBA students. Nonnative speakers were found to have a significantly lower likelihood of receiving new-venture funding, and this was fully mediated by the coders' assessments of their political skill. The entrepreneurs' race, communication skill, and collaborative skill had no effect. We discuss the value of empirically testing various posited reasons for glass-ceiling biases, how the importance and ambiguity of political skill for executive success serve as an ostensibly meritocratic cover for nonnative speaker bias, and other theoretical and practical implications of this work.

  15. Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines.

    PubMed Central

    Weller, M; Frei, K; Groscurth, P; Krammer, P H; Yonekawa, Y; Fontana, A

    1994-01-01

    Fas/APO-1 is a transmembrane protein of the nerve growth factor/TNF alpha receptor family which signals apoptotic cell death in susceptible target cells. We have investigated the susceptibility of seven human malignant glioma cell lines to Fas/APO-1-dependent apoptosis. Sensitivity to Fas/APO-1 antibody-mediated cell killing correlated with cell surface expression of Fas/APO-1. Expression of Fas/APO-1 as well as Fas/APO-1-dependent cytotoxicity were augmented by preexposure of human malignant glioma cells to IFN gamma and TNF alpha. Further, pretreatment with TGF beta 2, IL1 and IL8 enhanced Fas/APO-1 antibody-induced glioma cell apoptosis whereas other cytokines including TNF beta, IL6, macrophage colony-stimulating factor, IL10 and IL13 had no such effect. None of the human malignant glioma cell lines was susceptible to TNF alpha-induced cytotoxicity. Fas/APO-1 antibody-sensitive glioma cell lines (n = 5), but not Fas/APO-1 antibody-resistant glioma cell lines (n = 2), became sensitive to TNF alpha when co-treated with inhibitors of RNA and protein synthesis. Resistance of human glioma cells to Fas/APO-1 antibody-mediated apoptosis was mainly related to low level expression of Fas/APO-1 and appeared not to be linked to overexpression of the anti-apoptotic protooncogene, bcl-2. Given the resistance of human malignant glioma to surgery, irradiation, chemotherapy and immunotherapy, we propose that Fas/APO-1 may be a promising target for a novel locoregionary approach to human malignant glioma. This strategy gains support from the demonstration of Fas/APO-1 expression in ex vivo human malignant glioma specimens and from the absence of Fas/APO-1 in normal human brain parenchyma. Images PMID:7521890

  16. An Update on Fetal Alcohol Syndrome-Pathogenesis, Risks, and Treatment.

    PubMed

    Gupta, Keshav K; Gupta, Vinay K; Shirasaka, Tomohiro

    2016-08-01

    Alcohol is a well-established teratogen that can cause variable physical and behavioral effects on the fetus. The most severe condition in this spectrum of diseases is known as fetal alcohol syndrome (FAS). The differences in maternal and fetal enzymes, in terms of abundance and efficiency, in addition to reduced elimination, allow for alcohol to have a prolonged effect on the fetus. This can act as a teratogen through numerous methods including reactive oxygen species (generated as by products of CYP2E1), decreased endogenous antioxidant levels, mitochondrial damage, lipid peroxidation, disrupted neuronal cell-cell adhesion, placental vasoconstriction, and inhibition of cofactors required for fetal growth and development. More recently, alcohol has also been shown to have epigenetic effects. Increased fetal exposure to alcohol and sustained alcohol intake during any trimester of pregnancy is associated with an increased risk of FAS. Other risk factors include genetic influences, maternal characteristics, for example, lower socioeconomic statuses and smoking, and paternal chronic alcohol use. The treatment options for FAS have recently started to be explored although none are currently approved clinically. These include prenatal antioxidant administration food supplements, folic acid, choline, neuroactive peptides, and neurotrophic growth factors. Tackling the wider impacts of FAS, such as comorbidities, and the family system have been shown to improve the quality of life of FAS patients. This review aimed to focus on the pathogenesis, especially mechanisms of alcohol teratogenicity, and risks of developing FAS. Recent developments in potential management strategies, including prenatal interventions, are discussed.

  17. Immunohistochemical Localization of Fas-associated phosphatase-1 (FAP-1) in Alzheimer disease hippocampus.

    PubMed

    Savaskan, Egemen; Ravid, Rivka; Meier, Fides; Müller-Spahn, Franz; Jockers, Ralf

    2005-06-01

    Fas-associated phosphatase-1 (FAP-1) is a regulatory peptide inhibiting apoptotic signal transduction via the death receptor Fas. Because apoptosis is a common mechanism leading to neuronal death in neurodegenerative disorders, the authors investigated the immunohistochemical distribution of FAP-1 in the hippocampus of elderly control subjects and Alzheimer disease (AD) patients. The current study provides the first evidence that FAP-1 is localized in the human hippocampus in pyramidal neurons of the hippocampal subfields CA1-4 and in granular cells. Cellular and extracellular FAP-1 intensity was increased in some control subjects and AD patients, but was not related to the stage of the illness. Rather, these data may indicate a general role for FAP-1 in neuronal death both in adult CNS and during the course of neurodegenerative disorders.

  18. 41 CFR 102-38.360 - What must an executive agency do to implement the eFAS program?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... impracticable or inefficient. Waiver approval will be coordinated with GSA's Office of Travel, Transportation..., the agency must still (1) post asset information on the eFAS Web site and (2) provide post-sales...

  19. 41 CFR 102-38.360 - What must an executive agency do to implement the eFAS program?

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... impracticable or inefficient. Waiver approval will be coordinated with GSA's Office of Travel, Transportation..., the agency must still (1) post asset information on the eFAS Web site and (2) provide post-sales...

  20. Decoy receptor 3 suppresses FasL-induced apoptosis via ERK1/2 activation in pancreatic cancer cells

    SciTech Connect

    Zhang, Yi; Li, Dechun; Zhao, Xin; Song, Shiduo; Zhang, Lifeng; Zhu, Dongming; Wang, Zhenxin; Chen, Xiaochen; Zhou, Jian

    2015-08-07

    Resistance to Fas Ligand (FasL) mediated apoptosis plays an important role in tumorigenesis. Decoy receptor 3 (DcR3) is reported to interact with FasL and is overexpressed in some malignant tumors. We sought to investigate the role of DcR3 in resistance to FasL in pancreatic cancer. We compared expression of apoptosis related genes between FasL-resistant SW1990 and FasL-sensitive Patu8988 pancreatic cell lines by microarray analysis. We explored the impact of siRNA knockdown of, or exogenous supplementation with, DcR3 on FasL-induced cell growth inhibition in pancreatic cancer cell lines and expression of proteins involved in apoptotic signaling. We assessed the level of DcR3 protein and ERK1/2 phosphorylation in tumor and non-tumor tissue samples of 66 patients with pancreatic carcinoma. RNAi knockdown of DcR3 expression in SW1990 cells reduced resistance to FasL-induced apoptosis, and supplementation of Patu8988 with rDcR3 had the opposite effect. RNAi knockdown of DcR3 in SW1990 cells elevated expression of caspase 3, 8 and 9, and reduced ERK1/2 phosphorylation (P < 0.05), but did not alter phosphorylated-Akt expression. 47 tumor tissue specimens, but only 15 matched non-tumor specimens stained for DcR3 (χ{sup 2} = 31.1447, P < 0.001). The proliferation index of DcR3 positive specimens (14.26  ±  2.67%) was significantly higher than that of DcR3 negative specimens (43.58  ±  7.88%, P < 0.01). DcR3 expression positively correlated with p-ERK1/2 expression in pancreatic cancer tissues (r = 0.607, P < 0.001). DcR3 enhances ERK1/2 phosphorylation and opposes FasL signaling in pancreatic cancer cells. - Highlights: • We investigated the role of DcR3 in FasL resistance in pancreatic cancer. • Knockdown of DcR3 in SW1990 cells reduced resistance to FasL-induced apoptosis. • DcR3 knockdown also elevated caspase expression, and reduced ERK1/2 phosphorylation. • Tumor and non-tumor tissues were collected from 66 pancreatic carcinoma patients