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Sample records for accent syndrome fas

  1. The Role of Prosody in a Case of Foreign Accent Syndrome (FAS)

    ERIC Educational Resources Information Center

    Katz, William F.; Garst, Diane M.; Levitt, June

    2008-01-01

    Foreign accent syndrome (FAS) is a rare disorder characterized by the emergence of a perceived foreign accent following brain damage. The symptomotology, functional bases, and neural substrates of this disorder are still being elucidated. In this case study, acoustic analyses were performed on the speech of a 46-year old monolingual female who…

  2. The role of prosody in a case of foreign accent syndrome (FAS).

    PubMed

    Katz, William F; Garst, Diane M; Levitt, June

    2008-07-01

    Foreign accent syndrome (FAS) is a rare disorder characterized by the emergence of a perceived foreign accent following brain damage. The symptomotology, functional bases, and neural substrates of this disorder are still being elucidated. In this case study, acoustic analyses were performed on the speech of a 46-year old monolingual female who presented with FAS of unknown aetiology. The patient had a pseudo-accent frequently described as 'Swedish' or 'Eastern European'. Stop consonant VOT, consonant burst spectra and duration, vowel durations, formant frequencies, and trajectories were analysed, along with prosodic cues for lexical stress assignment and sentence-level intonation. Results indicated VOT values were generally preserved, while there was a strong tendency to realize the English alveolar flap as a full stop, and to produce flaps that had greater-than-normal closure durations. The spectral properties of the patient's vowels resembled those of normal talkers (with the possible exceptions of decreased F1 values for /i/ and slight differences in formant dynamics for /u/, /o/, /i/, and /epsilon/). However, vowel durations were relatively long, contributing to exaggerated tense/lax contrasts. Token-to-token variability in vowel production was slightly higher than normal for duration, but not for formant frequency values. Lexical stress assignment was inaccurate and highly variable (with similar problems noted for non-speech materials), and sentence level intonation showed occasional deviations from typical American English patterns. For this patient, an underlying timing/rhythm difficulty appeared responsible for the range of segmental and suprasegmental changes leading to the impression of a foreign accent. PMID:18568795

  3. Accent Attribution in Speakers with Foreign Accent Syndrome

    ERIC Educational Resources Information Center

    Verhoeven, Jo; De Pauw, Guy; Pettinato, Michele; Hirson, Allen; Van Borsel, John; Marien, Peter

    2013-01-01

    Purpose: The main aim of this experiment was to investigate the perception of Foreign Accent Syndrome in comparison to speakers with an authentic foreign accent. Method: Three groups of listeners attributed accents to conversational speech samples of 5 FAS speakers which were embedded amongst those of 5 speakers with a real foreign accent and 5…

  4. 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…

  5. 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…

  6. 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…

  7. 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…

  8. 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…

  9. 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. PMID:27363254

  10. 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

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

    PubMed

    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

  12. 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

  13. Impaired laryngeal voice production in a patient with foreign accent syndrome.

    PubMed

    Sakurai, Yasuhisa; Itoh, Kenji; Sai, Keiko; Lee, Seitetsu; Abe, Shoko; Terao, Yasuo; Mannen, Toru

    2015-01-01

    We report a Japanese-speaking monolingual woman who developed foreign accent syndrome (FAS) following an infarction in the precentral and premotor cortices (Brodmann Area 6) at and around the inferior frontal sulcus. Her speech sounded Chinese or Korean to our bilingual coauthor who speaks Chinese and Japanese. Quantitative acoustic analyses of words and sentences showed that pitch (fundamental frequency variation) and intensity variances appeared lowered and fully voiced glottal pulses were reduced. These findings suggest laryngeal dysfunction that contributes to the unusual speech production in a case of FAS. This may be caused by damage to a restricted area of the motor and premotor cortices that controls laryngeal function. PMID:24592816

  14. Neural bases of the foreign accent syndrome: a functional magnetic resonance imaging case study.

    PubMed

    Katz, W F; Garst, D M; Briggs, R W; Cheshkov, S; Ringe, W; Gopinath, K S; Goyal, A; Allen, G

    2012-06-01

    Foreign accent syndrome (FAS) is a rare disorder characterized by the emergence of a perceived foreign accent following brain damage. Despite decades of study, little is known about the neural substrates involved in this disorder. In this case study, MRI images of the brain were obtained during a speech task for an American English-speaking monolingual female who presented with FAS of unknown etiology and was thought to sound 'Swedish' or 'Eastern European'. On the basis of MR structural imaging, the patient was noted to have frontal lobe atrophy. An fMRI picture-naming task designed to broadly engage the speech motor network revealed predominantly left-hemisphere involvement, including activation of the (1) left superior temporal and medial frontal structures, (2) bilateral subcortical structures and thalamus, and (3) left cerebellum. The results suggest an instance of substantial brain reorganization for speech motor control. PMID:22011212

  15. 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

  16. 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

  17. Selective alteration of native, but not second language articulation in a patient with foreign accent syndrome.

    PubMed

    Avila, César; González, Julio; Parcet, Maria-Antònia; Belloch, Vicente

    2004-10-01

    The present study deals with a right-handed female polyglot suffering from a Foreign Accent Syndrome (FAS) which affects her native language (L1), but not her other languages learnt since the age of 12. She had a small infarct in the left corona radiata as the result of a carotid occlusion. Her L1 was Spanish, but she also had a good command of French, English and Catalan (L2). Aphasia tests did not reveal any other significant alteration in any language. Analyses of pre-morbid and post-morbid voice recordings revealed that FAS affected Spanish dramatically, but no important changes were observed for French. Results were interpreted as showing that different brain areas control articulation of L1 and L2 learnt after a critical period. PMID:15371747

  18. sFas and sFas ligand and pediatric sepsis-induced multiple organ failure syndrome.

    PubMed

    Doughty, Lesley; Clark, Robert S B; Kaplan, Sandra S; Sasser, Howell; Carcillo, Joseph

    2002-12-01

    The Fas-Fas ligand system is important for apoptosis of activated immune cells. Perturbation of this system occurs in diseases with dysregulated inflammation. Increased soluble Fas (sFas) occurs in systemic inflammatory response syndrome (SIRS) and can block apoptosis. Increased shedding of FasL (sFasL) occurs in viral infection and hepatitis. Although dysregulated inflammation is associated with sepsis-induced multiple organ failure (MOF) in children, a role for Fas has not been established. We hypothesize that 1) sFas will be increased in children with severe and persistent sepsis-induced MOF and will correlate with inflammatory markers suggesting a role for sFas in inflammatory dysregulation in severe sepsis, and 2) sFasL will be increased when viral sepsis or sepsis-induced liver failure-associated MOF is present in children. Plasma sFas, sFasL, IL-6, IL-10, nitrite + nitrates, and organ failure scores were measured on d 1 and d 3 in 92 children with severe sepsis and 12 critically ill control children. sFas levels were increased in severe sepsis, continued to increase in persistent MOF and nonsurvivors, and were correlated with serum inflammatory markers (IL-6, IL-10, nitrite + nitrate levels). In contrast, sFasL was not increased in severe sepsis and did not correlate with inflammation. sFasL was, however, increased in liver failure-associated MOF and in nonsurvivors, and was associated with viral infection. At autopsy, hepatocyte destruction and lymphocyte infiltration were associated with increased sFas and sFasL levels. sFas may interfere with activated immune cell death and contribute to dysregulation of inflammation, worsening outcome from severe sepsis. sFasL may contribute to hepatic injury and the development of liver failure-associated MOF. PMID:12438671

  19. 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

  20. 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

  1. 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

  2. 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)

  3. 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. PMID:27060458

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

    PubMed

    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

  5. 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

  6. Epigenetic control of NF-κB-dependent FAS gene transcription during progression of myelodysplastic syndromes.

    PubMed

    Ettou, Sandrine; Humbrecht, Catherine; Benet, Blandine; Billot, Katy; d'Allard, Diane; Mariot, Virginie; Goodhardt, Michele; Kosmider, Olivier; Mayeux, Patrick; Solary, Eric; Fontenay, Michaela

    2013-07-01

    The death domain containing TNF receptor 6 (CD95/Fas) is a direct target for the NF-κB transcription factor and is repressed in solid tumors such as colon carcinomas. Previously, we reported that the Fas death receptor, while overexpressed in low-risk myelodysplastic syndromes (MDS), becomes undetectable on CD34(+) progenitors when the disease progresses to secondary acute myeloid leukemia (AML). This study determined the interplay between NF-κB and Fas during MDS progression. We first observed that Fas was induced by TNF-α in the HL60 cell line. In these cells, p65 (RELA) was associated with the FAS promoter, and inhibition of the NF-κB pathway by an IKKα inhibitor (BAY11-7082) or lentiviral expression of a nondegradable mutant of IκBα (IκSR) blocked Fas expression. In contrast, TNF-α failed to induce Fas expression in the colon carcinoma cell line SW480, due to hypermethylation of the FAS promoter. Azacitidine rescued p65 binding on FAS promoter in vitro, and subsequently Fas expression in SW480 cells. Furthermore, inhibition of the NF-κB pathway decreased the expression of Fas in MDS CD45(lo)CD34(+) bone marrow cells. However, despite the nuclear expression of p65, Fas was often low on CD45(lo)CD34(+) AML cells. TNF-α failed to stimulate its expression, while azacitidine efficiently rescued p65 binding and Fas reexpression. Overall, these data suggest that DNA methylation at NF-κB sites is responsible for FAS gene silencing. PMID:23604035

  7. Inherited perforin and Fas mutations in a patient with autoimmune lymphoproliferative syndrome and lymphoma.

    PubMed

    Clementi, Rita; Dagna, Lorenzo; Dianzani, Umberto; Dupré, Loïc; Dianzani, Irma; Ponzoni, Maurilio; Cometa, Angela; Chiocchetti, Annalisa; Sabbadini, Maria Grazia; Rugarli, Claudio; Ciceri, Fabio; Maccario, Rita; Locatelli, Franco; Danesino, Cesare; Ferrarini, Marina; Bregni, Marco

    2004-09-30

    A 27-year-old man with the autoimmune lymphoproliferative syndrome and a large-B-cell lymphoma had heterozygous mutations in the Fas and perforin (Prf1) genes. The Fas mutation was inherited from his healthy father and was also carried by his healthy brother, whereas the Prf1 mutation was inherited from his healthy mother. The combined effect of the two mutant genes may have contributed to the development of the autoimmune lymphoproliferative syndrome and lymphoma in this patient. PMID:15459303

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

    PubMed Central

    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

    2015-01-01

    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. PMID:26113417

  9. 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. PMID:24398331

  10. 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

  11. 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…

  12. 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

  13. Fetal Alcohol Syndrome (FAS) in C57BL/6 Mice Detected through Proteomics Screening of the Amniotic Fluid

    PubMed Central

    Datta, Susmita; Turner, Delano; Singh, Reetu; Ruest, L. Bruno; Pierce, William M.; Knudsen, Thomas B.

    2009-01-01

    BACKGROUND Fetal Alcohol Syndrome (FAS), a severe consequence of the Fetal Alcohol Spectrum Disorders, is associated with craniofacial defects, mental retardation, and stunted growth. Previous studies in C57BL/6J and C57BL/6N mice provide evidence that alcohol-induced pathogenesis follows early changes in gene expression within specific molecular pathways in the embryonic headfold. Whereas the former (B6J) pregnancies carry a high-risk for dysmorphogenesis following maternal exposure to 2.9 g/kg alcohol (two injections spaced 4.0 h apart on gestation day 8), the latter (B6N) pregnancies carry a low-risk for malformations. The present study used this murine model to screen amniotic fluid for biomarkers that could potentially discriminate between FAS-positive and FAS-negative pregnancies. METHODS B6J and B6N litters were treated with alcohol (exposed) or saline (control) on day 8 of gestation. Amniotic fluid aspirated on day 17 (n = 6 replicate litters per group) was subjected to trypsin digestion for analysis by matrix-assisted laser desorption–time of flight mass spectrometry with the aid of denoising algorithms, statistical testing, and classification methods. RESULTS We identified several peaks in the proteomics screen that were reduced consistently and specifically in exposed B6J litters. Preliminary characterization by liquid chromatography tandem mass spectrometry and multidimensional protein identification mapped the reduced peaks to alpha fetoprotein (AFP). The predictive strength of AFP deficiency as a biomarker for FAS-positive litters was confirmed by area under the receiver operating characteristic curve. CONCLUSIONS These findings in genetically susceptible mice support clinical observations in maternal serum that implicate a decrease in AFP levels following prenatal alcohol damage. PMID:18240165

  14. 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. PMID:25762779

  15. 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

  16. Disentangling Accent from Comprehensibility

    ERIC Educational Resources Information Center

    Trofimovich, Pavel; Isaacs, Talia

    2012-01-01

    The goal of this study was to determine which linguistic aspects of second language speech are related to accent and which to comprehensibility. To address this goal, 19 different speech measures in the oral productions of 40 native French speakers of English were examined in relation to accent and comprehensibility, as rated by 60 novice raters…

  17. 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. PMID:23645835

  18. Accent-independent adaptation to foreign accented speech

    PubMed Central

    Baese-Berk, Melissa M.; Bradlow, Ann R.; Wright, Beverly A.

    2013-01-01

    Foreign-accented speech can be difficult to understand but listeners can adapt to novel talkers and accents with appropriate experience. Previous studies have demonstrated talker-independent but accent-dependent learning after training on multiple talkers from a single language background. Here, listeners instead were exposed to talkers from five language backgrounds during training. After training, listeners generalized their learning to novel talkers from language backgrounds both included and not included in the training set. These findings suggest that generalization of foreign-accent adaptation is the result of exposure to systematic variability in accented speech that is similar across talkers from multiple language backgrounds. PMID:23464125

  19. 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…

  20. 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

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

    PubMed

    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

  2. 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 ...

  3. 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…

  4. 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. PMID:20964512

  5. 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. PMID:23456266

  6. Roles of Fas and Fas ligand during mammary gland remodeling

    PubMed Central

    Song, Joon; Sapi, Eva; Brown, Wendi; Nilsen, Jon; Tartaro, Karrie; Kacinski, Barry M.; Craft, Joseph; Naftolin, Frederick; Mor, Gil

    2000-01-01

    Mammary involution is associated with degeneration of the alveolar structure and programmed cell death of mammary epithelial cells. In this study, we evaluated the expression of Fas and Fas ligand (FasL) in the mammary gland tissue and their possible role in the induction of apoptosis of mammary cells. FasL-positive cells were observed in normal mammary epithelium from pregnant and lactating mice, but not in nonpregnant/virgin mouse mammary tissue. Fas expression was observed in epithelial and stromal cells in nonpregnant mice but was absent during pregnancy. At day 1 after weaning, high levels of both Fas and FasL proteins and caspase 3 were observed and coincided with the appearance of apoptotic cells in ducts and glands. During the same period, no apoptotic cells were found in the Fas-deficient (MRL/lpr) and FasL-deficient (C3H/gld) mice. Increase in Fas and FasL protein was demonstrated in human (MCF10A) and mouse (HC-11) mammary epithelial cells after incubation in hormone-deprived media, before apoptosis was detected. These results suggest that the Fas-FasL interaction plays an important role in the normal remodeling of mammary tissue. Furthermore, this autocrine induction of apoptosis may prevent accumulation of cells with mutations and subsequent neoplastic development. Failure of the Fas/FasL signal could contribute to tumor development. PMID:11086022

  7. 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…

  8. 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…

  9. The Role of Intonation in Foreign Accent.

    ERIC Educational Resources Information Center

    Van Els, Theo; De Bot, Kees

    1987-01-01

    Investigation of the extent to which recognition of a foreign accent is affected by reducing suprasegmental or segmental information involved the reading of five Dutch sentences by native (N=9) and non-native (N=9) speakers. Results indicated that suprasegmental aspects of speech do play a part in a foreign accent. (CB)

  10. 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…

  11. 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…

  12. Nucleolin inhibits Fas ligand binding and suppresses Fas-mediated apoptosis in vivo via a surface nucleolin-Fas complex.

    PubMed

    Wise, Jillian F; Berkova, Zuzana; Mathur, Rohit; Zhu, Haifeng; Braun, Frank K; Tao, Rong-Hua; Sabichi, Anita L; Ao, Xue; Maeng, Hoyoung; Samaniego, Felipe

    2013-06-01

    Resistance to Fas-mediated apoptosis is associated with poor cancer outcomes and chemoresistance. To elucidate potential mechanisms of defective Fas signaling, we screened primary lymphoma cell extracts for Fas-associated proteins that would have the potential to regulate Fas signaling. An activation-resistant Fas complex selectively included nucleolin. We confirmed the presence of nucleolin-Fas complexes in B-cell lymphoma cells and primary tissues, and the absence of such complexes in B-lymphocytes from healthy donors. RNA-binding domain 4 and the glycine/arginine-rich domain of nucleolin were essential for its association with Fas. Nucleolin colocalized with Fas on the surface of B-cell lymphoma cells. Nucleolin knockdown sensitized BJAB cells to Fas ligand (FasL)-induced and Fas agonistic antibody-induced apoptosis through enhanced binding, suggesting that nucleolin blocks the FasL-Fas interaction. Mice transfected with nucleolin were protected from the lethal effects of agonistic anti-mouse Fas antibody (Jo2) and had lower rates of hepatocyte apoptosis, compared with vector and a non-Fas-binding mutant of nucleolin. Our results show that cell surface nucleolin binds Fas, inhibits ligand binding, and thus prevents induction of Fas-mediated apoptosis in B-cell lymphomas and may serve as a new therapeutic target. PMID:23599269

  13. 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…

  14. 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

  15. 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

  16. Perceived Masculinity, Androgyny, and Accented Speech.

    ERIC Educational Resources Information Center

    Giles, Howard; Marsh, Patricia

    1979-01-01

    An investigation using the matched-guise technique sought to replicate findings that standard accented female speakers were evaluated on tapes as more masculine in attributed sex traits, but more feminine than nonstandard counterparts. (Author/AM)

  17. 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…

  18. [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. PMID:22173965

  19. Fas and Fas ligand expression in fetal and adult human testis with normal or deranged spermatogenesis.

    PubMed

    Francavilla, S; D'Abrizio, P; Rucci, N; Silvano, G; Properzi, G; Straface, E; Cordeschi, G; Necozione, S; Gnessi, L; Arizzi, M; Ulisse, S

    2000-08-01

    In mice, the Fas/Fas ligand (FasL) system has been shown to be involved in germ cell apoptosis. In the present study we evaluated the expression of Fas and Fas ligand (FasL) in fetal and adult human testis. Semiquantitative RT-PCR demonstrated the expression of Fas and FasL messenger ribonucleic acids in adult testis, but not in fetal testis (20-22 weeks gestation). In situ RT-PCR and immunohistochemistry experiments on adult human testis demonstrated the expression of FasL messenger ribonucleic acid and protein in Sertoli and Leydig cells, whereas the expression of Fas was confined to the Leydig cells and sporadic degenerating spermatocytes. The number of Fas-positive germ cells per 100 Sertoli cell nuclei was increased in 10 biopsies with postmeiotic germ cell arrest compared to 10 normal testis biopsies (mean, 3.82 +/- 0.45 vs. 2.02 +/- 0.29; P = 0.0001), but not in 10 biopsies with meiotic germ cell arrest (mean, 1.56 +/- 1.07). Fas and FasL proteins were not expressed in cases of idiopathic hypogonadotropic hypogonadism. Together, these findings may suggest that Fas/FasL expression in the human testis is developmentally regulated and under gonadotropin control. The increased germ cell expression of Fas in patients with postmeiotic germ cell arrest suggests that the Fas/FasL system may be involved in the quality control mechanism of the produced gametes. PMID:10946867

  20. 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.

  1. 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…

  2. 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…

  3. 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…

  4. 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)

  5. 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…

  6. Expression of soluble Fas and soluble FasL in human nucleus pulposus cells.

    PubMed

    Sun, Zhen; Wan, Zhong-Yuan; Liu, Zhi-Heng; Guo, Yun-Shan; Yin, Jun-Bin; Duan, Chun-Guang; Gao, Yang; Li, Tao; Wang, Hai-Qiang; Luo, Zhuo-Jing

    2013-01-01

    The study aimed for addressing the expression of soluble Fas (sFas) and soluble Fas Ligand (sFasL) in human nucleus pulposus (NP) and its attendant relationship with disc degeneration. Human NP samples were collected from patients with disc degeneration and cadavers as degenerate and normal groups, respectively. Subsequently, NP cells were cultured in monolayer. ELISA was performed to identify the expression levels of sFas and sFasL in the supernatant of NP cell cultures in vitro. Quantitative real-time PCR was used to detect the expression of sFas and sFasL in human NP cells in mRNA solution. The study comprised 12 degenerate and 8 normal cadaveric NP samples. The concentration value of sFas in the supernatant was significantly higher from degenerate NP than that from normal NP at each time point. In contrast, sFasL was significantly lower at each time point. Moreover, the expression of sFas and sFasL reached the peak at various early stages of cell cultures and decreased thereafter. Furthermore, the mRNA level of Fas in degenerate NP cells was significantly higher than that in normal cells; whereas FasL showed an opposite pattern. The study is the first addressing the expression of sFas and sFasL in human NP cell cultures. Moreover, the expression of sFas and sFasL varies with culture time in vitro with different levels in degenerate and normal settings. These findings indicate that sFas and sFasL might play a role in intervertebral disc degeneration. PMID:23923075

  7. Where are you from? Preschoolers infer background from accent.

    PubMed

    Weatherhead, Drew; White, Katherine S; Friedman, Ori

    2016-03-01

    For adults, accent is an obvious indicator of a speaker's geographical background. The current study investigated whether preschoolers are sensitive to the relationship between background and accent. Experiment 1 shows that 3- to 5-year-olds believe that two speakers who share the same accent live in the same place but do not share the same personal preferences. Experiment 2 demonstrates that 4- and 5-year-olds believe that two speakers with the same accent share cultural norms associated with a particular place, but that two speakers with different accents have different cultural norms. As in Experiment 1, children did not think that personal preferences were related to accent. These findings show early awareness of the relationship between accent and geographical background. PMID:26614731

  8. 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)

  9. Personality Impressions Elicited by Accented English Speech.

    ERIC Educational Resources Information Center

    Gallois, Cynthia; Callan, Victor J.

    1981-01-01

    Australian born male and female students listened to tapes of accented English speech and were asked to relate their impressions and judgments of the speakers' personalities. Results indicated that the nationality and sex of the speakers were factors which influenced the judgments made about them by the Australian students. (Author/APM)

  10. 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

  11. 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,…

  12. 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)

  13. 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…

  14. Evaluation of the Fas/FasL signaling pathway in diabetic rat testis.

    PubMed

    Bayram, S; Kizilay, G; Topcu-Tarladacalisir, Y

    2016-03-01

    We investigated the role of the Fas/Fas ligand (FasL) signaling pathway in diabetic male infertility. Male rats were divided into two groups: a control group and a streptozotocin induced diabetic group. Thirty days after induction of diabetes, samples of testes were harvested and fixed in 10% formalin for light microscopy. Germ cell apoptosis was determined using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end-labeling (TUNEL) and immunostaining of caspase 8 and active caspase 3. We also investigated the expressions of Fas and FasL using immunohistochemistry. Streptozotocin-induced diabetes caused severe histopathological damage and increased apoptotic tubule and apoptotic cell indices, caspase 8 and caspase 3 expressions, and Fas and FasL-immunopositive cells in the rat testes. We suggest that the Fas/FasL signaling pathway may play a role in male infertility caused by diabetes. PMID:26960002

  15. Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus.

    PubMed

    Bossaller, Lukas; Rathinam, Vijay A K; Bonegio, Ramon; Chiang, Ping-I; Busto, Patricia; Wespiser, Adam R; Caffrey, Daniel R; Li, Quan-Zhen; Mohan, Chandra; Fitzgerald, Katherine A; Latz, Eicke; Marshak-Rothstein, Ann

    2013-09-01

    Loss-of-function mutations in the Fas death receptor or its ligand result in a lymphoproliferative syndrome and exacerbate clinical disease in most lupus-prone strains of mice. One exception is mice injected with 2,6,10,14-tetramethylpentadecane (TMPD), a hydrocarbon oil commonly known as pristane, which induces systemic lupus erythematosus-like disease. Although Fas/Fas ligand (FasL) interactions have been strongly implicated in the activation-induced cell death of both lymphocytes and other APCs, FasL can also trigger the production of proinflammatory cytokines. FasL is a transmembrane protein with a matrix metalloproteinase cleavage site in the ectodomain. Matrix metalloproteinase cleavage inactivates membrane-bound FasL and releases a soluble form reported to have both antagonist and agonist activity. To better understand the impact of FasL cleavage on both the proapoptotic and proinflammatory activity of FasL, its cleavage site was deleted through targeted mutation to produce the deleted cleavage site (ΔCS) mouse line. ΔCS mice express higher levels of membrane-bound FasL than do wild-type mice and fail to release soluble FasL. To determine to what extent FasL promotes inflammation in lupus mice, TMPD-injected FasL-deficient and ΔCS BALB/c mice were compared with control TMPD-injected BALB/c mice. We found that FasL deficiency significantly reduced the early inflammatory exudate induced by TMPD injection. In contrast, ΔCS mice developed a markedly exacerbated disease profile associated with a higher frequency of splenic neutrophils and macrophages, a profound change in anti-nuclear Ab specificity, and markedly increased proteinuria and kidney pathology compared with controls. These results demonstrate that FasL promotes inflammation in TMPD-induced autoimmunity, and its cleavage limits FasL proinflammatory activity. PMID:23918976

  16. Oncolytic poxvirus armed with Fas ligand leads to induction of cellular Fas receptor and selective viral replication in FasR-negative cancer.

    PubMed

    Sathaiah, M; Thirunavukkarasu, P; O'Malley, M E; Kavanagh, M A; Ravindranathan, R; Austin, F; Guo, Z S; Bartlett, D L

    2012-03-01

    Tumor necrosis factor superfamily members, including Fas ligand and TRAIL, have been studied extensively for cancer therapy, including as components of gene therapy. We examined the use of FasL expression to achieve tumor-selective replication of an oncolytic poxvirus (vFasL), and explored its biology and therapeutic efficacy for FasR- and FasR+ cancers. Infection of FasR+ normal and MC38 cancer cells by vFasL led to abortive viral replication owing to acute apoptosis and subsequently showed both reduced pathogenicity in non-tumor-bearing mice and reduced efficacy in FasR+ tumor-bearing mice. Infection of FasR- B16 cancer cells by vFasL led to efficient viral replication, followed by late induction of FasR and subsequent apoptosis. Treatment with vFasL as compared with its parental virus (vJS6) led to increased tumor regression and prolonged survival of mice with FasR- cancer (B16) but not with FasR+ cancer (MC38). The delayed induction of FasR by viral infection in FasR- cells provides for potential increased efficacy beyond the limit of the direct oncolytic effect. FasR induction provides one mechanism for tumor-selective replication of oncolytic poxviruses in FasR- cancers with enhanced safety. The overall result is both a safer and more effective oncolytic virus for FasR- cancer. PMID:22116377

  17. Soluble Fas and Fas ligand and prognosis in children with acute lymphoblastic leukemia.

    PubMed

    Fathi, Mina; Amirghofran, Zahra; Shahriari, Mehdi

    2012-09-01

    The soluble forms of Fas and its ligand (sFas and sFasL) correlate with disease progression in various malignancies. We compared serum levels of sFas and sFasL in children with acute lymphoblastic leukemia and healthy children to determine the prognostic significance of these molecules. Serum levels of sFas and sFasL were measured with an enzyme-linked immunosorbent assay in 48 patients with newly diagnosed childhood acute lymphoblastic leukemia and 38 healthy children. Cut-off values of sFas and sFasL levels were based on their levels in controls. Clinical and laboratory characteristics were recorded on admission. The mean serum concentration of sFas was 243 ± 40 pg/mL in patients and 238 ± 29 pg/mL in controls. Serum levels of sFasL were 4.33 ± 0.25 ng/mL in patients and 4.27 ± 0.11 ng/mL in controls. Neither difference was significant. Based on the cut-off value, 12.5% of the patients were positive for sFas, and 16.6% were positive for sFasL. Survival was significantly longer in sFasL-positive patients (394 ± 69.6 vs. 254 ± 24.3 days) and the duration of complete remission was also longer (380 ± 65.0 vs. 246 ± 26.0 days) than in sFasL-negative patients (P < 0.02), indicating the important role of this molecule in the response to therapy. Higher sFas levels were associated with hepatosplenomegaly (P < 0.047). In conclusion, sFasL positivity was associated with a favorable outcome in ALL patients. PMID:21528407

  18. Accent, intelligibility, and comprehensibility in the perception of foreign-accented Lombard speech

    NASA Astrophysics Data System (ADS)

    Li, Chi-Nin

    2003-10-01

    Speech produced in noise (Lombard speech) has been reported to be more intelligible than speech produced in quiet (normal speech). This study examined the perception of non-native Lombard speech in terms of intelligibility, comprehensibility, and degree of foreign accent. Twelve Cantonese speakers and a comparison group of English speakers read simple true and false English statements in quiet and in 70 dB of masking noise. Lombard and normal utterances were mixed with noise at a constant signal-to-noise ratio, and presented along with noise-free stimuli to eight new English listeners who provided transcription scores, comprehensibility ratings, and accent ratings. Analyses showed that, as expected, utterances presented in noise were less well perceived than were noise-free sentences, and that the Cantonese speakers' productions were more accented, but less intelligible and less comprehensible than those of the English speakers. For both groups of speakers, the Lombard sentences were correctly transcribed more often than their normal utterances in noisy conditions. However, the Cantonese-accented Lombard sentences were not rated as easier to understand than was the normal speech in all conditions. The assigned accent ratings were similar throughout all listening conditions. Implications of these findings will be discussed.

  19. Temporal features of Spanish-accented English

    NASA Astrophysics Data System (ADS)

    Shah, Amee; Strange, Winifred

    2002-05-01

    In this study we attempt to identify the acoustic parameters of Spanish accented English that give it the perception of being accented. Recordings of eight multisyllabic (3, 4, and 5 syllables) words spoken in sentences by 22 Spanish speakers of English and five native speakers of American English (AE) were analyzed for temporal acoustic differences. Segmental durations of Spanish productions, including differences of stressed-unstressed (s/u) vowel duration ratios, Voice Onset Time (VOT) and flap/stop duration, differed from native productions. The sentences and the excised target words were given to native (AE) listeners (N=10) who judged the degree of accentedness on a 9-point scale. The degree of accentedness on target words correlated with perceived ratings on the eight sentences (i.e., global accentedness), rho=+0.82. Spearman rank-order correlations between s/u vowel duration ratios and native listener ratings of accentedness on target words varied from +0.04 to 0.68. The VOT duration of initial voiceless stops correlated positively with accentedness ratings for three of the four words (+0.26 to +0.35). Overall, results suggest that Spanish-accented English is characterized by significant temporal differences from native American English, and that these temporal differences contribute to the perception of accentedness as judged by native American English listeners.

  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. Sequenced subjective accents for brain-computer interfaces

    NASA Astrophysics Data System (ADS)

    Vlek, R. J.; Schaefer, R. S.; Gielen, C. C. A. M.; Farquhar, J. D. R.; Desain, P.

    2011-06-01

    Subjective accenting is a cognitive process in which identical auditory pulses at an isochronous rate turn into the percept of an accenting pattern. This process can be voluntarily controlled, making it a candidate for communication from human user to machine in a brain-computer interface (BCI) system. In this study we investigated whether subjective accenting is a feasible paradigm for BCI and how its time-structured nature can be exploited for optimal decoding from non-invasive EEG data. Ten subjects perceived and imagined different metric patterns (two-, three- and four-beat) superimposed on a steady metronome. With an offline classification paradigm, we classified imagined accented from non-accented beats on a single trial (0.5 s) level with an average accuracy of 60.4% over all subjects. We show that decoding of imagined accents is also possible with a classifier trained on perception data. Cyclic patterns of accents and non-accents were successfully decoded with a sequence classification algorithm. Classification performances were compared by means of bit rate. Performance in the best scenario translates into an average bit rate of 4.4 bits min-1 over subjects, which makes subjective accenting a promising paradigm for an online auditory BCI.

  2. 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. PMID:26950507

  3. 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

  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. PMID:22044081

  5. Microbial Type I Fatty Acid Synthases (FAS): Major Players in a Network of Cellular FAS Systems

    PubMed Central

    Schweizer, Eckhart; Hofmann, Jörg

    2004-01-01

    The present review focuses on microbial type I fatty acid synthases (FASs), demonstrating their structural and functional diversity. Depending on their origin and biochemical function, multifunctional type I FAS proteins form dimers or hexamers with characteristic organization of their catalytic domains. A single polypeptide may contain one or more sets of the eight FAS component functions. Alternatively, these functions may split up into two different and mutually complementing subunits. Targeted inactivation of the individual yeast FAS acylation sites allowed us to define their roles during the overall catalytic process. In particular, their pronounced negative cooperativity is presumed to coordinate the FAS initiation and chain elongation reactions. Expression of the unlinked genes, FAS1 and FAS2, is in part constitutive and in part subject to repression by the phospholipid precursors inositol and choline. The interplay of the involved regulatory proteins, Rap1, Reb1, Abf1, Ino2/Ino4, Opi1, Sin3 and TFIIB, has been elucidated in considerable detail. Balanced levels of subunits α and β are ensured by an autoregulatory effect of FAS1 on FAS2 expression and by posttranslational degradation of excess FAS subunits. The functional specificity of type I FAS multienzymes usually requires the presence of multiple FAS systems within the same cell. De novo synthesis of long-chain fatty acids, mitochondrial fatty acid synthesis, acylation of certain secondary metabolites and coenzymes, fatty acid elongation, and the vast diversity of mycobacterial lipids each result from specific FAS activities. The microcompartmentalization of FAS activities in type I multienzymes may thus allow for both the controlled and concerted action of multiple FAS systems within the same cell. PMID:15353567

  6. Teaching Students with Fetal Alcohol Syndrome/Effects: A Resource Guide for Teachers.

    ERIC Educational Resources Information Center

    Conry, Julie

    This teacher's resource guide from British Columbia provides an overview of the needs of students with fetal alcohol syndrome (FAS). It begins by discussing the definition of FAS and fetal alcohol effects (FAE), characteristics of students with FAS/E, and steps for preparing to teach students with FAS/E (collecting information, making and carrying…

  7. 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…

  8. 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…

  9. 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…

  10. 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…

  11. Toddlers Recognize Words in an Unfamiliar Accent after Brief Exposure

    ERIC Educational Resources Information Center

    Schmale, Rachel; Cristia, Alejandrina; Seidl, Amanda

    2012-01-01

    Both subjective impressions and previous research with monolingual listeners suggest that a foreign accent interferes with word recognition in infants, young children, and adults. However, because being exposed to multiple accents is likely to be an everyday occurrence in many societies, it is unexpected that such non-standard pronunciations would…

  12. 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)

  13. Processing changes when listening to foreign-accented speech.

    PubMed

    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

  14. 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…

  15. 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

  16. Perceptual learning of systematic variation in Spanish-accented speech.

    PubMed

    Sidaras, Sabrina K; Alexander, Jessica E D; Nygaard, Lynne C

    2009-05-01

    Spoken language is characterized by an enormous amount of variability in how linguistic segments are realized. In order to investigate how speech perceptual processes accommodate to multiple sources of variation, adult native speakers of American English were trained with English words or sentences produced by six Spanish-accented talkers. At test, listeners transcribed utterances produced by six familiar or unfamiliar Spanish-accented talkers. With only brief exposure, listeners perceptually adapted to accent-general regularities in spoken language, generalizing to novel accented words and sentences produced by unfamiliar accented speakers. Acoustic properties of vowel production and their relation to identification performance were assessed to determine if the English listeners were sensitive to systematic variation in the realization of accented vowels. Vowels that showed the most improvement after Spanish-accented training were distinct from nearby vowels in terms of their acoustic characteristics. These findings suggest that the speech perceptual system dynamically adjusts to the acoustic consequences of changes in talker's voice and accent. PMID:19425672

  17. 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.

  18. Altered expression of Fas receptor on alveolar macrophages and inflammatory effects of soluble Fas ligand following blunt chest trauma.

    PubMed

    Seitz, Daniel H; Palmer, Annette; Niesler, Ulrike; Braumüller, Sonja T; Bauknecht, Simon; Gebhard, Florian; Knöferl, Markus W

    2011-06-01

    Blunt chest trauma impairs the outcome of multiply-injured patients. Lung contusion induces inflammatory alterations and Fas-dependent apoptosis of alveolar type 2 epithelial (AT2) cells has been described. The Fas/Fas ligand (FasL) system seems to exhibit a proinflammatory potential. We aimed to elucidate the involvement of the Fas/FasL system in the inflammatory response after lung contusion. Chest trauma was induced in male rats by a pressure wave. Soluble FasL concentrations were determined in bronchoalveolar lavage fluids and alveolar macrophage (AMΦ) supernatants. Alveolar macrophages and AT2 cells were isolated to determine the surface expression (FACS) of Fas/FasL, the mRNA expression (reverse transcriptase-polymerase chain reaction) of Fas, FasL, TNF-α, IL-6, and IL-10 and to measure the release of IL-6 and IL-10 after culture with or without stimulation with FasL. After chest trauma, FasL concentration was increased in bronchoalveolar lavage fluid, and AMΦ supernatants and Fas and FasL protein were downregulated on AMΦs and unchanged on AT2 cells. The mRNA expression of Fas was increased in AMΦs and AT2 cells and that of FasL only in AMΦs isolated after lung contusion. Fas ligand stimulation further enhanced IL-6 and suppressed IL-10 release in AMΦs after trauma.The results indicate that the Fas/FasL system is activated after chest trauma, and FasL is associated with the inflammatory response after lung contusion. The proinflammatory response of AMΦs is enhanced by FasL stimulation. Both AMΦs and AT2 cells seem to contribute to the mediator release after lung contusion. These results confirm the importance of the Fas/FasL system in the inflammatory response after chest trauma. PMID:21330946

  19. 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

  20. 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

  1. Association of promoter polymorphisms of Fas -FasL genes with development of Chronic Myeloid Leukemia.

    PubMed

    Edathara, Prajitha Mohandas; Gorre, Manjula; Kagita, Sailaja; Vuree, Sugunakar; Cingeetham, Anuradha; Nanchari, Santhoshi Rani; Meka, Phanni Bhushann; Annamaneni, Sandhya; Digumarthi, Raghunadha Rao; Satti, Vishnupriya

    2016-04-01

    Chronic myeloid leukemia (CML) is a monoclonal myeloproliferative disorder of hematopoietic stem cells (HSCs), characterized by reciprocal translocation, leading to the formation of BCR-ABL oncogene with constitutive tyrosine kinase (TK) activity. This oncogene is known to deregulate different downstream pathways which ultimately lead to cell proliferation, defective DNA repair, and inhibition of apoptosis. Fas (Fas cell surface death receptor) is a member of tumor necrosis factor (TNF) superfamily which interacts with its ligand, FasL, to initiate apoptosis. Promoter polymorphisms in Fas-FasL genes are known to influence the apoptotic signaling. Hence, the present study has been aimed to find out the association of the promoter polymorphisms in Fas and FasL genes with the development and progression of CML. Blood samples from 772 subjects (386 controls and 386 cases) were collected and genotyped for Fas-FasL gene polymorphisms through PCR-RFLP method. The association between SNPs and clinical outcome was analyzed using statistical softwares like SPSS version 20, SNPSTATs, and Haploview 2.1. The study revealed a significant association of Fas -670 G>A and FasL -844 T>C polymorphisms with the development of CML while Fas -670 AG was associated with accelerated phase. Combined risk analysis by taking the risk genotypes in cases and controls revealed a significant increase in CML risk with increase in number of risk genotypes (one risk genotype-OR 1.99 (1.44-2.76), p < 0.0001; two risk genotypes-OR 3.33 (1.91-5.81), p < 0.0001). Kaplan-Meier survival analysis of Fas -670 A>G and FasL -844 T>C showed reduced event-free survival in patients carrying the variant genotypes, Fas -670 GG, 32.363 ± 6.33, and FasL -844 CC, 33.489 ± 5.83, respectively. Our findings revealed a significant association of Fas -670 GG, FasL -844 TC, and CC genotypes with increased risk of CML. PMID:26563376

  2. Stimulation of Fas signaling down-regulates activity of neutrophils from major trauma patients with SIRS.

    PubMed

    Paunel-Görgülü, Adnana; Lögters, Tim; Flohé, Sascha; Cinatl, Jindrich; Altrichter, Jens; Windolf, Joachim; Scholz, Martin

    2011-03-01

    Posttrauma apoptosis resistance of neutrophils (PMN) is related to overshooting immune responses, systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF). Recently, we have shown that the apoptosis resistance in circulating PMN from severely injured patients which is known to be mediated by high serum levels of pro-inflammatory cytokines can be overcome by the activation of Fas death receptor. Here, we aimed to study whether stimulation of surface Fas leads to the inactivation of hyperactivated PMN from critically ill patients with SIRS. PMN from 23 multiple trauma patients (mean injury severity score (ISS) 34±1.9) were isolated at day 1 after admission to the trauma center. PMN from 17 volunteer blood donors served as controls. Neutrophil activity has been determined after ex vivo short (1 h) and long-term (4 h) stimulation of freshly isolated PMN with immobilized agonistic anti-Fas antibodies. We found neutrophil chemotactic migration in response to IL-8, phagocytosis and oxidative burst to be significantly inhibited in control cells already after short-term (1 h) Fas stimulation. In contrast, inactivation of trauma PMN by agonistic anti-Fas antibodies was found to be efficient only after long-term (4 h) incubation of cells with agonistic antibodies. Thus, in trauma PMN down-regulation of neutrophil activity seems to be delayed when compared to cells isolated from healthy controls, suggesting impaired susceptibility for Fas stimulation in these cells. Interestingly, whereas Fas-mediated inhibition of phagocytosis and oxidative burst could be prevented by the broad range caspase inhibitor t-butoxycarbonyl-aspartyl(O-methyl)-fluoromethyl ketone (BocD-fmk), the chemotactic activity in response to IL-8 was unaffected. In conclusion, we demonstrate that stimulation of neutrophil Fas does not only initiate apoptosis but also induces inhibition of neutrophil functions, partially by non-apoptotic signaling. PMID:20832139

  3. 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)

  4. Cytotoxicity Mediated by the Fas Ligand (FasL)-activated Apoptotic Pathway in Stem Cells*

    PubMed Central

    Mazar, Julia; Thomas, Molly; Bezrukov, Ludmila; Chanturia, Alexander; Pekkurnaz, Gulcin; Yin, Shurong; Kuznetsov, Sergei A.; Robey, Pamela G.; Zimmerberg, Joshua

    2009-01-01

    Whereas it is now clear that human bone marrow stromal cells (BMSCs) can be immunosuppressive and escape cytotoxic lymphocytes (CTLs) in vitro and in vivo, the mechanisms of this phenomenon remain controversial. Here, we test the hypothesis that BMSCs suppress immune responses by Fas-mediated apoptosis of activated lymphocytes and find both Fas and FasL expression by primary BMSCs. Jurkat cells or activated lymphocytes were each killed by BMSCs after 72 h of co-incubation. In comparison, the cytotoxic effect of BMSCs on non-activated lymphocytes and on caspase-8(−/−) Jurkat cells was extremely low. Fas/Fc fusion protein strongly inhibited BMSC-induced lymphocyte apoptosis. Although we detected a high level of Fas expression in BMSCs, stimulation of Fas with anti-Fas antibody did not result in the expected BMSC apoptosis, regardless of concentration, suggesting a disruption of the Fas activation pathway. Thus BMSCs may have an endogenous mechanism to evade Fas-mediated apoptosis. Cumulatively, these data provide a parallel between adult stem/progenitor cells and cancer cells, consistent with the idea that stem/progenitor cells can use FasL to prevent lymphocyte attack by inducing lymphocyte apoptosis during the regeneration of injured tissues. PMID:19531476

  5. Association of FAS and FAS Ligand Genes Polymorphism and Risk of Systemic Lupus Erythematosus

    PubMed Central

    Moudi, Bita; Salimi, Saeedeh; Farajian Mashhadi, Farzaneh; Sandoughi, Mahnaz; Zakeri, Zahra

    2013-01-01

    FAS/FASL pathway plays a critical role in maintaining peripheral immune tolerance; therefore, the apoptosis genes, Fas and Fas ligand (FasL), could be suitable candidate genes in human SLE susceptibility. Materials and Methods. In this case-control study, 106 SLE patients and 149 sex, age, and ethnicity matched healthy controls were genotyped for the Fas A-670G and FasLC-844T polymorphisms by polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). Results. The frequency of -670AA genotype was significantly higher in SLE patients than control group and the risk of SLE was 2.1-fold greater in subjects with AA genotype (P = 0.03). The frequency of -670A allele was significantly higher in SLE patients than in controls too (58% versus 49%, P = 0.03). The -844CC genotype frequency was significantly higher in SLE patients than in healthy controls and the risk of SLE was 2.8-fold greater in these subjects (P = 0.01). The C allele frequency was significantly higher in patients than in controls (69% versus 49%, P = 0.001). Increased SLE risk was observed in individuals with combined effect of Fas-670AA and FasL-844CC genotypes (P = 0.001). Conclusion. Fas-670AA and FasL-844CC genotypes were associated with SLE risk, and combined effect of -670AA and -844CC genotypes might increase SLE susceptibility. PMID:24348139

  6. Intestinal expression of Fas and Fas ligand is upregulated by bacterial signaling through TLR4 and TLR5, with activation of Fas modulating intestinal TLR-mediated inflammation.

    PubMed

    Fernandes, Philana; O'Donnell, Charlotte; Lyons, Caitriona; Keane, Jonathan; Regan, Tim; O'Brien, Stephen; Fallon, Padraic; Brint, Elizabeth; Houston, Aileen

    2014-12-15

    TLRs play an important role in mediating intestinal inflammation and homeostasis. Fas is best studied in terms of its function in apoptosis, but recent studies demonstrate that Fas signaling may mediate additional functions such as inflammation. The role of Fas, and the Fas ligand (FasL), in the intestine is poorly understood. The aim of this study was to evaluate potential cross-talk between TLRs and Fas/FasL system in intestinal epithelial cells (IECs). IECs were stimulated with TLR ligands, and expression of Fas and FasL was investigated. Treatment with TLR4 and TLR5 ligands, but not TLR2 and 9 ligands, increased expression of Fas and FasL in IECs in vitro. Consistent with this finding, expression of intestinal Fas and FasL was reduced in vivo in the epithelium of TLR4 knockout (KO), 5KO, and germ-free mice, but not in TLR2KO mice. Modulating Fas signaling using agonistic anti-Fas augmented TLR4- and TLR5-mediated TNF-α and IL-8 production by IECs. In addition, suppression of Fas in IECs reduced the ability of TLR4 and TLR5 ligands and the intestinal pathogens Salmonella typhimurium and Listeria monocytogenes to induce the expression of IL-8. In conclusion, this study demonstrates that extensive cross-talk in IECs occurs between the Fas and TLR signaling pathways, with the FasL/Fas system playing a role in TLR-mediated inflammatory responses in the intestine. PMID:25378591

  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. PMID:27363256

  8. Cognitive predictors of perceptual adaptation to accented speech.

    PubMed

    Banks, Briony; Gowen, Emma; Munro, Kevin J; Adank, Patti

    2015-04-01

    The present study investigated the effects of inhibition, vocabulary knowledge, and working memory on perceptual adaptation to accented speech. One hundred young, normal-hearing adults listened to sentences spoken in a constructed, unfamiliar accent presented in speech-shaped background noise. Speech Reception Thresholds (SRTs) corresponding to 50% speech recognition accuracy provided a measurement of adaptation to the accented speech. Stroop, vocabulary knowledge, and working memory tests were performed to measure cognitive ability. Participants adapted to the unfamiliar accent as revealed by a decrease in SRTs over time. Better inhibition (lower Stroop scores) predicted greater and faster adaptation to the unfamiliar accent. Vocabulary knowledge predicted better recognition of the unfamiliar accent, while working memory had a smaller, indirect effect on speech recognition mediated by vocabulary score. Results support a top-down model for successful adaptation to, and recognition of, accented speech; they add to recent theories that allocate a prominent role for executive function to effective speech comprehension in adverse listening conditions. PMID:25920852

  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. PMID:19128936

  10. Fas/FasL pathway-mediated alveolar macrophage apoptosis involved in human silicosis

    PubMed Central

    Yao, San-qiao; Rojanasakul, Liying Wang; Chen, Zhi-yuan; Xu, Ying-jun; Bai, Yu-ping; Chen, Gang; Zhang, Xi-ying; Zhang, Chun-min; Yu, Yan-qin; Shen, Fu-hai; Yuan, Ju-xiang; Chen, Jie

    2016-01-01

    In vitro and in vivo studies have demonstrated that lung cell apoptosis is associated with lung fibrosis; however the relationship between apoptosis of alveolar macrophages (AMs) and human silicosis has not been addressed. In the present study, AM apoptosis was determined in whole-lung lavage fluid from 48 male silicosis patients, 13 male observers, and 13 male healthy volunteers. The relationships between apoptosis index (AI) and silica exposure history, soluble Fas (sFas)/membrane-bound Fas (mFas), and caspase-3/caspase-8 were analyzed. AI, mFas, and caspase-3 were significantly higher in lung lavage fluids from silicosis patients than those of observers or healthy volunteers, but the level of sFas demonstrated a decreasing trend. AI was related to silica exposure, upregulation of mFas, and activation of caspase-3 and -8, as well as influenced by smoking status after adjusting for confounding factors. These results indicate that AM apoptosis could be used as a potential biomarker for human silicosis, and the Fas/FasL pathway may regulate this process. The present data from human lung lavage samples may help to understand the mechanism of silicosis and in turn lead to strategies for preventing or treating this disease. PMID:21910009

  11. FAS 116 and 117: the implementation process.

    PubMed

    Bigalke, J T

    1993-10-01

    The Financial Accounting Standards Board finalized and issued two new statements in June 1993: "Financial Statements of Not-for-Profit Organizations" (FAS 117) and "Accounting for Contributions Received and Contributions Made" (FAS 116). The statements will become effective for fiscal years beginning after December 15, 1994. Until a revised audit guide is issued, however, several factors will need to be carefully considered when implementing the two standards. PMID:10145884

  12. 21. Detail of brick above Flemish accent band, back side, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    21. Detail of brick above Flemish accent band, back side, between 1st and 2nd windows from the right - Oklahoma State University, Boys Dormitory, Northwest corner of Hester Street & Athletic Avenue, Stillwater, Payne County, OK

  13. What Do ESL Students Say about Their Accents?

    ERIC Educational Resources Information Center

    Derwing, Tracey M.

    2003-01-01

    Examines adult immigrants' perceptions of their own pronunciation problems and the consequences of speaking with a foreign accent. Interviews were conducted with 100 intermediate proficiency English-as-a-Second-Language students. (Author/VWL)

  14. Mining the ACCENT database: a review and update

    PubMed Central

    Renfro, Lindsay A.; Shi, Qian; Sargent, Daniel J.

    2015-01-01

    The database of the Adjuvant Colon Cancer End Points (ACCENT) Group was assembled to address questions in early stage colon cancer that could be best answered by information pooled across many similar trials. Today, the ACCENT database contains individual patient-level data from over 33,000 patients enrolled onto 25 adjuvant colon cancer trials conducted between 1977 and 2008. Since its flagship analysis of 3-year disease-free survival as a surrogate endpoint for 5-year overall survival in 2005, the ACCENT group has produced many noteworthy scientific findings addressing a variety of clinical questions, which we describe here. Additionally, we provide an overview of the history, collaboration, construction, principles, and future of the ACCENT database, as it has set a precedent for multi-trial database creation in other types of cancer. PMID:25841498

  15. Fas/FasL pathway participates in regulation of antiviral and inflammatory response during mousepox infection of lungs.

    PubMed

    Bień, Karolina; Sokołowska, Justyna; Bąska, Piotr; Nowak, Zuzanna; Stankiewicz, Wanda; Krzyzowska, Malgorzata

    2015-01-01

    Fas receptor-Fas ligand (FasL) signalling is involved in apoptosis of immune cells as well as of the virus infected target cells but increasing evidence accumulates on Fas as a mediator of apoptosis-independent processes such as induction of activating and proinflammatory signals. In this study, we examined the role of Fas/FasL pathway in inflammatory and antiviral response in lungs using a mousepox model applied to C57BL6/J, B6. MRL-Faslpr/J, and B6Smn.C3-Faslgld/J mice. Ectromelia virus (ECTV) infection of Fas- and FasL-deficient mice led to increased virus titers in lungs and decreased migration of IFN-γ expressing NK cells, CD4+ T cells, CD8+ T cells, and decreased IL-15 expression. The lungs of ECTV-infected Fas- and FasL-deficient mice showed significant inflammation during later phases of infection accompanied by decreased expression of anti-inflammatory IL-10 and TGF-β1 cytokines and disturbances in CXCL1 and CXCL9 expression. Experiments in vitro demonstrated that ECTV-infected cultures of epithelial cells, but not macrophages, upregulate Fas and FasL and are susceptible to Fas-induced apoptosis. Our study demonstrates that Fas/FasL pathway during ECTV infection of the lungs plays an important role in controlling local inflammatory response and mounting of antiviral response. PMID:25873756

  16. Fas/FasL Pathway Participates in Regulation of Antiviral and Inflammatory Response during Mousepox Infection of Lungs

    PubMed Central

    Bień, Karolina; Sokołowska, Justyna; Bąska, Piotr; Nowak, Zuzanna; Stankiewicz, Wanda; Krzyzowska, Malgorzata

    2015-01-01

    Fas receptor-Fas ligand (FasL) signalling is involved in apoptosis of immune cells as well as of the virus infected target cells but increasing evidence accumulates on Fas as a mediator of apoptosis-independent processes such as induction of activating and proinflammatory signals. In this study, we examined the role of Fas/FasL pathway in inflammatory and antiviral response in lungs using a mousepox model applied to C57BL6/J, B6. MRL-Faslpr/J, and B6Smn.C3-Faslgld/J mice. Ectromelia virus (ECTV) infection of Fas- and FasL-deficient mice led to increased virus titers in lungs and decreased migration of IFN-γ expressing NK cells, CD4+ T cells, CD8+ T cells, and decreased IL-15 expression. The lungs of ECTV-infected Fas- and FasL-deficient mice showed significant inflammation during later phases of infection accompanied by decreased expression of anti-inflammatory IL-10 and TGF-β1 cytokines and disturbances in CXCL1 and CXCL9 expression. Experiments in vitro demonstrated that ECTV-infected cultures of epithelial cells, but not macrophages, upregulate Fas and FasL and are susceptible to Fas-induced apoptosis. Our study demonstrates that Fas/FasL pathway during ECTV infection of the lungs plays an important role in controlling local inflammatory response and mounting of antiviral response. PMID:25873756

  17. 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. PMID:22530648

  18. 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…

  19. Impaired Fas-Fas Ligand Interactions Result in Greater Recurrent Herpetic Stromal Keratitis in Mice

    PubMed Central

    Yin, Xiao-Tang; Keadle, Tammie L.; Hard, Jessicah; Herndon, John; Potter, Chloe A.; Del Rosso, Chelsea R.; Ferguson, Thomas A.; Stuart, Patrick M.

    2015-01-01

    Herpes simplex virus-1 (HSV-1) infection of the cornea leads to a potentially blinding condition termed herpetic stromal keratitis (HSK). Clinical studies have indicated that disease is primarily associated with recurrent HSK following reactivation of a latent viral infection of the trigeminal ganglia. One of the key factors that limit inflammation of the cornea is the expression of Fas ligand (FasL). We demonstrate that infection of the cornea with HSV-1 results in increased functional expression of FasL and that mice expressing mutations in Fas (lpr) and FasL (gld) display increased recurrent HSK following reactivation compared to wild-type mice. Furthermore, both gld and lpr mice took longer to clear their corneas of infectious virus and the reactivation rate for these strains was significantly greater than that seen with wild-type mice. Collectively, these findings indicate that the interaction of Fas with FasL in the cornea restricts the development of recurrent HSK. PMID:26504854

  20. 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. PMID:26869336

  1. 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. PMID:25481649

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

    PubMed Central

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

    2016-01-01

    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. PMID:26869336

  3. Adaptation to novel accents by toddlers

    PubMed Central

    White, Katherine S.; Aslin, Richard N.

    2010-01-01

    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. PMID:21479106

  4. 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. PMID:26780774

  5. Strength of German accent under altered auditory feedback

    PubMed Central

    HOWELL, PETER; DWORZYNSKI, KATHARINA

    2007-01-01

    Borden’s (1979, 1980) hypothesis that speakers with vulnerable speech systems rely more heavily on feedback monitoring than do speakers with less vulnerable systems was investigated. The second language (L2) of a speaker is vulnerable, in comparison with the native language, so alteration to feedback should have a detrimental effect on it, according to this hypothesis. Here, we specifically examined whether altered auditory feedback has an effect on accent strength when speakers speak L2. There were three stages in the experiment. First, 6 German speakers who were fluent in English (their L2) were recorded under six conditions—normal listening, amplified voice level, voice shifted in frequency, delayed auditory feedback, and slowed and accelerated speech rate conditions. Second, judges were trained to rate accent strength. Training was assessed by whether it was successful in separating German speakers speaking English from native English speakers, also speaking English. In the final stage, the judges ranked recordings of each speaker from the first stage as to increasing strength of German accent. The results show that accents were more pronounced under frequency-shifted and delayed auditory feedback conditions than under normal or amplified feedback conditions. Control tests were done to ensure that listeners were judging accent, rather than fluency changes caused by altered auditory feedback. The findings are discussed in terms of Borden’s hypothesis and other accounts about why altered auditory feedback disrupts speech control. PMID:11414137

  6. Strength of German accent under altered auditory feedback.

    PubMed

    Howell, P; Dworzynski, K

    2001-04-01

    Borden's (1979, 1980) hypothesis that speakers with vulnerable speech systems rely more heavily on feedback monitoring than do speakers with less vulnerable systems was investigated. The second language (L2) of a speaker is vulnerable, in comparison with the native language, so alteration to feedback should have a detrimental effect on it, according to this hypothesis. Here, we specifically examined whether altered auditory feedback has an effect on accent strength when speakers speak L2. There were three stages in the experiment. First, 6 German speakers who were fluent in English (their L2) were recorded under six conditions--normal listening, amplified voice level, voice shifted in frequency, delayed auditory feedback, and slowed and accelerated speech rate conditions. Second, judges were trained to rate accent strength. Training was assessed by whether it was successful in separating German speakers speaking English from native English speakers, also speaking English. In the final stage, the judges ranked recordings of each speaker from the first stage as to increasing strength of German accent. The results show that accents were more pronounced under frequency-shifted and delayed auditory feedback conditions than under normal or amplified feedback conditions. Control tests were done to ensure that listeners were judging accent, rather than fluency changes caused by altered auditory feedback. The findings are discussed in terms of Borden's hypothesis and other accounts about why altered auditory feedback disrupts speech control. PMID:11414137

  7. 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. PMID:15918137

  8. 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. PMID:25452578

  9. 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

  10. FAS system deregulation in T-cell lymphoblastic lymphoma

    PubMed Central

    Villa-Morales, M; Cobos, M A; González-Gugel, E; Álvarez-Iglesias, V; Martínez, B; Piris, M A; Carracedo, A; Benítez, J; Fernández-Piqueras, J

    2014-01-01

    The acquisition of resistance towards FAS-mediated apoptosis may be required for tumor formation. Tumors from various histological origins exhibit FAS mutations, the most frequent being hematological malignancies. However, data regarding FAS mutations or FAS signaling alterations are still lacking in precursor T-cell lymphoblastic lymphomas (T-LBLs). The available data on acute lymphoblastic leukemia, of precursor origin as well, indicate a low frequency of FAS mutations but often report a serious reduction in FAS-mediated apoptosis as well as chemoresistance, thus suggesting the occurrence of mechanisms able to deregulate the FAS signaling pathway, different from FAS mutation. Our aim at this study was to determine whether FAS-mediated apoptotic signaling is compromised in human T-LBL samples and the mechanisms involved. This study on 26 T-LBL samples confirms that the FAS system is impaired to a wide extent in these tumors, with 57.7% of the cases presenting any alteration of the pathway. A variety of mechanisms seems to be involved in such alteration, in order of frequency the downregulation of FAS, the deregulation of other members of the pathway and the occurrence of mutations at FAS. Considering these results together, it seems plausible to think of a cumulative effect of several alterations in each T-LBL, which in turn may result in FAS/FASLG system deregulation. Since defective FAS signaling may render the T-LBL tumor cells resistant to apoptotic cell death, the correct prognosis, diagnosis and thus the success of anticancer therapy may require such an in-depth knowledge of the complete scenario of FAS-signaling alterations. PMID:24603338

  11. FAS system deregulation in T-cell lymphoblastic lymphoma.

    PubMed

    Villa-Morales, M; Cobos, M A; González-Gugel, E; Álvarez-Iglesias, V; Martínez, B; Piris, M A; Carracedo, A; Benítez, J; Fernández-Piqueras, J

    2014-01-01

    The acquisition of resistance towards FAS-mediated apoptosis may be required for tumor formation. Tumors from various histological origins exhibit FAS mutations, the most frequent being hematological malignancies. However, data regarding FAS mutations or FAS signaling alterations are still lacking in precursor T-cell lymphoblastic lymphomas (T-LBLs). The available data on acute lymphoblastic leukemia, of precursor origin as well, indicate a low frequency of FAS mutations but often report a serious reduction in FAS-mediated apoptosis as well as chemoresistance, thus suggesting the occurrence of mechanisms able to deregulate the FAS signaling pathway, different from FAS mutation. Our aim at this study was to determine whether FAS-mediated apoptotic signaling is compromised in human T-LBL samples and the mechanisms involved. This study on 26 T-LBL samples confirms that the FAS system is impaired to a wide extent in these tumors, with 57.7% of the cases presenting any alteration of the pathway. A variety of mechanisms seems to be involved in such alteration, in order of frequency the downregulation of FAS, the deregulation of other members of the pathway and the occurrence of mutations at FAS. Considering these results together, it seems plausible to think of a cumulative effect of several alterations in each T-LBL, which in turn may result in FAS/FASLG system deregulation. Since defective FAS signaling may render the T-LBL tumor cells resistant to apoptotic cell death, the correct prognosis, diagnosis and thus the success of anticancer therapy may require such an in-depth knowledge of the complete scenario of FAS-signaling alterations. PMID:24603338

  12. The role of tonal onglides in German nuclear pitch accents.

    PubMed

    Ritter, Simon; Grice, Martine

    2015-03-01

    A perception experiment with native German listeners provided evidence for the relevance of the tonal onglide in nuclear accents--the pitch movement leading towards the target on the accented syllable. Listeners were able to distinguish between two pragmatic meanings of a short phrase (given/non-contrastive and new/contrastive) using the tonal onglide as the sole acoustic cue. On the basis of these findings, we argue that the onglide merits a phonological status in an intonation model of German and should not be regarded as merely phonetic detail. PMID:25935940

  13. Anti-cancer drugs targeting fatty acid synthase (FAS).

    PubMed

    Pandey, Puspa R; Liu, Wen; Xing, Fei; Fukuda, Koji; Watabe, Kounosuke

    2012-05-01

    Fatty acid synthase (FAS) is a key enzyme of the fatty acid biosynthetic pathway which catalyzes de novo lipid synthesis. FAS expression in normal adult tissues is generally very low or undetectable as majority of fatty acids obtained are from dietary sources, whereas it is significantly upregulated in cancer cells despite adequate nutritional lipid supply. Activation of FAS provides rapidly proliferating tumor cells sufficient amount of lipids for membrane biogenesis and confers growth and survival advantage possibly acting as a metabolic oncogene. Importantly, inhibition of FAS in cancer cells using the pharmacological FAS inhibitors results in tumor cell death by apoptosis whereas normal cells are resistant. Due to this differential expression of FAS, the inhibitors of this enzyme are selectively toxic to tumor cells and therefore FAS is considered an attractive therapeutic target for cancer. Several FAS inhibitors are already patented and commercially available; however, the potential toxicity of these FAS inhibitors remains to be tested in clinical trials. In this review, we discuss some of the potent FAS inhibitors along with their patent information, the mechanism of anti-cancer effects and the development of more specific and potent FAS inhibitors with lower side effects that are expected to emerge as anti-cancer treatment in the near future. PMID:22338595

  14. Helicobacter pylori Modulates Lymphoepithelial Cell Interactions Leading to Epithelial Cell Damage through Fas/Fas Ligand Interactions

    PubMed Central

    Wang, Jide; Fan, Xuejun; Lindholm, Catharina; Bennett, Michael; O'Connoll, Joe; Shanahan, Fergus; Brooks, Edward G.; Reyes, Victor E.; Ernst, Peter B.

    2000-01-01

    Helicobacter pylori causes a common chronic infection of humans that leads to epithelial cell damage. Studies have shown that apoptosis of the gastric epithelium is increased during infection and this response is associated with an expansion of gastric T-helper type 1 (Th1) cells. We report that gastric T cells contribute to apoptosis of the epithelium by a Fas/Fas ligand (FasL) interaction. Fas receptor expression was detected on freshly isolated gastric epithelial cells by flow cytometry and immunohistochemistry, and this level of expression was increased during infection with H. pylori. The expression of Fas receptor on three gastric epithelial cell lines was increased by H. pylori, either alone or in combination with gamma interferon or tumor necrosis factor alpha. The role of Fas in apoptosis of gastric epithelial cell lines was evidenced by DNA fragmentation after cross-linking of Fas with specific antibodies. FasL expression was detected by immunohistochemistry on mononuclear cells in gastric biopsy specimens of infected but not uninfected subjects. Gastric T-cell lines were also shown to express FasL, as evidenced by reverse transcription-PCR and killing of target cells expressing Fas receptor. Moreover, these T-cell lines were capable of killing cultured gastric epithelial target cells and antibodies that block the interaction between Fas receptor and FasL inhibited this cytotoxic activity. These observations demonstrate that local Th1 cells may contribute to the pathogenesis of gastric disease during H. pylori infection by increasing the expression of Fas on gastric epithelial cells and inducing apoptosis through Fas/FasL interactions. PMID:10858249

  15. 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. PMID:26677641

  16. How to Speak English without a Foreign Accent. Oriental Edition.

    ERIC Educational Resources Information Center

    Catran, Jack

    This transcript and guide of a two-cassette course is designed to assist immigrants from the Asian-Pacific areas of China, Japan, Taiwan, Korea, and Vietnam eliminate their foreign accents. The course is appropriate for both individual and group study. The guide includes narrative and taped demonstrations of American English that pinpoint typical…

  17. The contribution of prosody to the perception of foreign accent.

    PubMed

    Boula de Mareüil, Philippe; Vieru-Dimulescu, Bianca

    2006-01-01

    The general goal of this study was to expand our understanding of what is meant by 'foreign accent'. More specifically, it deals with the role of prosody (timing and melody), which has rarely been examined. New technologies, including diphone speech synthesis (experiment 1) and speech manipulation (experiment 2), are used to study the relative importance of prosody in what is perceived as a foreign accent. The methodology we propose, based on the prosody transplantation paradigm, can be applied to different languages or language varieties. Here, it is applied to Spanish and Italian. We built up a dozen sentences which are spoken in almost the same way in both languages (e.g. ha visto la casa del presidente americano 'you/(s)he saw the American president's house'). Spanish/Italian monolinguals and bilinguals were recorded. We then studied what is perceived when the segmental specification of an utterance is combined with suprasegmental features belonging to a different language. Under these conditions, results obtained with Spanish and Italian listeners suggest that prosody is important in identifying Spanish-accented Italian and Italian-accented Spanish. PMID:17293645

  18. 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)

  19. 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…

  20. Factors affecting the perception of Korean-accented American English

    NASA Astrophysics Data System (ADS)

    Cho, Kwansun; Harris, John G.; Shrivastav, Rahul

    2005-09-01

    This experiment examines the relative contribution of two factors, intonation and articulation errors, on the perception of foreign accent in Korean-accented American English. Ten native speakers of Korean and ten native speakers of American English were asked to read ten English sentences. These sentences were then modified using high-quality speech resynthesis techniques [STRAIGHT Kawahara et al., Speech Commun. 27, 187-207 (1999)] to generate four sets of stimuli. In the first two sets of stimuli, the intonation patterns of the Korean speakers and American speakers were switched with one another. The articulatory errors for each speaker were not modified. In the final two sets, the sentences from the Korean and American speakers were resynthesized without any modifications. Fifteen listeners were asked to rate all the stimuli for the degree of foreign accent. Preliminary results show that, for native speakers of American English, articulation errors may play a greater role in the perception of foreign accent than errors in intonation patterns. [Work supported by KAIM.

  1. 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…

  2. 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…

  3. 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. PMID:19673825

  4. 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…

  5. 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. PMID:25381758

  6. 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…

  7. 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…

  8. Fas/Fas ligand-mediated apoptosis in different cell lineages and functional compartments of human lymph nodes.

    PubMed

    Kokkonen, Tuomo S; Karttunen, Tuomo J

    2010-02-01

    We have optimized an immunohistochemical double-staining method combining immunohistochemical lymphocyte lineage marker detection and apoptosis detection with terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling. The method was used to trace Fas-mediated apoptosis in human reactive lymph nodes according to cell lineage and anatomical location. In addition to Fas, we also studied the expression of Fas ligand (FasL), CD3, CD20, CD19, CD23, and CD68 of apoptotic cells. The presence of simultaneous Fas and FasL positivity indicated involvement of activation-induced death in the induction of paracortical apoptosis. FasL expression in the high endothelial venules might be an inductor of apoptosis of Fas-positive lymphoid cells. In addition to B-lymphocyte apoptosis in the germinal centers, there was often a high apoptosis rate of CD23-expressing follicular dendritic cells. In summary, our double-staining method provides valuable new information about the occurrence and mechanisms of apoptosis of different immune cell types in the lymph node compartments. Among other things, we present support for the importance of Fas/FasL-mediated apoptosis in lymph node homeostasis. PMID:19826071

  9. 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…

  10. 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.

  11. 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.…

  12. Pitch accent type affects the N400 during referential processing.

    PubMed

    Schumacher, Petra B; Baumann, Stefan

    2010-06-23

    Discourse processing depends on semantic memory as well as maintaining and updating of a mental model. Using event-related potentials, we investigated how a referent's information status (new, accessible, given) is processed in combination with three different prosodic realizations (an appropriate accent and two inappropriate accents). The data reveal a biphasic N400-late positivity pattern, indicating that prosodic information affects an early discourse linking stage, during which prominence information reflecting a referent's accessibility is computed (N400), and a later discourse updating stage, during which conflicts between prosodic information and a referent's actual information status are detected (late positivity). Crucially, the data show that the N400 is not only sensitive to lexico-semantic relations but also to discourse accessibility induced by prosodic cues. PMID:20489672

  13. Drifting without an anchor: how pitch accents withstand vowel loss.

    PubMed

    Baltazani, Mary; Kainada, Evia

    2015-03-01

    We offer an analysis of the influence exerted by segmental rules on the suprasegmental structure in the dialect of Ipiros Greek (IG). In particular we investigated how vowel deletion (VD) affects the phonetic realization of the L*+H pitch accent. Our data empirically establish that the H tone aligns much earlier when VD applies than when it does not. Furthermore, we show that there is a phonological contrast between the nuclear L+H* and the prenuclear L*+H which hinges on early versus late H alignment respectively. We demonstrate that the contrast between the L*+H and the L+H* pitch accents is not compromised by the earlier alignment caused by VD. In other words, intonational contrasts are not endangered by fine phonetic alignment variability within the same category. PMID:25935939

  14. A lighting metric for quantitative evaluation of accent lighting systems

    NASA Astrophysics Data System (ADS)

    Acholo, Cyril O.; Connor, Kenneth A.; Radke, Richard J.

    2014-09-01

    Accent lighting is critical for artwork and sculpture lighting in museums, and subject lighting for stage, Film and television. The research problem of designing effective lighting in such settings has been revived recently with the rise of light-emitting-diode-based solid state lighting. In this work, we propose an easy-to-apply quantitative measure of the scene's visual quality as perceived by human viewers. We consider a well-accent-lit scene as one which maximizes the information about the scene (in an information-theoretic sense) available to the user. We propose a metric based on the entropy of the distribution of colors, which are extracted from an image of the scene from the viewer's perspective. We demonstrate that optimizing the metric as a function of illumination configuration (i.e., position, orientation, and spectral composition) results in natural, pleasing accent lighting. We use a photorealistic simulation tool to validate the functionality of our proposed approach, showing its successful application to two- and three-dimensional scenes.

  15. Effects of age and hearing loss on recognition of unaccented and accented multisyllabic words

    PubMed Central

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

    2015-01-01

    The effects of age and hearing loss on recognition of unaccented and accented words of varying syllable length were investigated. It was hypothesized that with increments in length of syllables, there would be atypical alterations in syllable stress in accented compared to native English, and that these altered stress patterns would be sensitive to auditory temporal processing deficits with aging. Sets of one-, two-, three-, and four-syllable words with the same initial syllable were recorded by one native English and two Spanish-accented talkers. Lists of these words were presented in isolation and in sentence contexts to younger and older normal-hearing listeners and to older hearing-impaired listeners. Hearing loss effects were apparent for unaccented and accented monosyllabic words, whereas age effects were observed for recognition of accented multisyllabic words, consistent with the notion that altered syllable stress patterns with accent are sensitive for revealing effects of age. Older listeners also exhibited lower recognition scores for moderately accented words in sentence contexts than in isolation, suggesting that the added demands on working memory for words in sentence contexts impact recognition of accented speech. The general pattern of results suggests that hearing loss, age, and cognitive factors limit the ability to recognize Spanish-accented speech. PMID:25698021

  16. The influence of neighborhood density on the recognition of Spanish-accented words.

    PubMed

    Chan, Kit Ying; Vitevitch, Michael S

    2015-02-01

    Foreign-accented speech is more difficult to recognize than the same words produced by a native speaker because the accented speech may activate many additional competitors, or it may strongly activate a single, but incorrect, word during lexical retrieval. Experiments 1 and 2 examined the recognition of native-produced and foreign-accented words varying in neighborhood density with auditory lexical decision and perceptual identification tasks, respectively. Experiment 1 found increased reaction times (RTs), especially for accented dense words. Analysis of misperceptions from Experiment 2 found that the mean number of phonologically distinct misperception tokens was higher for native than accented stimuli, suggesting that accented speech does not tend to activate more lexical candidates. Furthermore, a higher proportion of misperceptions in the accented condition (71%) compared with the native condition (58%) was accounted for by the most frequently reported misperception token, suggesting that accented speech instead tends to strongly activate 1 particular neighbor of the target word during lexical competition. Moreover, systematic phonemic substitutions in the misperceptions suggest that lawful acoustic-phonetic variations introduced by the accented speaker's L1 (native language) play a crucial role in determining which neighbor is activated as a strong competitor. PMID:25485666

  17. Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-xL

    PubMed Central

    Huang, David C. S.; Hahne, Michael; Schroeter, Michael; Frei, Karl; Fontana, Adriano; Villunger, Andreas; Newton, Kim; Tschopp, Juerg; Strasser, Andreas

    1999-01-01

    Fas activation triggers apoptosis in many cell types. Studies with anti-Fas antibodies have produced conflicting results on Fas signaling, particularly the role of the Bcl-2 family in this process. Comparison between physiological ligand and anti-Fas antibodies revealed that only extensive Fas aggregation, by membrane bound FasL or aggregated soluble FasL consistently triggered apoptosis, whereas antibodies could act as death agonists or antagonists. Studies on Fas signaling in cell lines and primary cells from transgenic mice revealed that FADD/MORT1 and caspase-8 were required for apoptosis. In contrast, Bcl-2 or Bcl-xL did not block FasL-induced apoptosis in lymphocytes or hepatocytes, demonstrating that signaling for cell death induced by Fas and the pathways to apoptosis regulated by the Bcl-2 family are distinct. PMID:10611305

  18. Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function.

    PubMed

    Clementi, Rita; Chiocchetti, Annalisa; Cappellano, Giuseppe; Cerutti, Elisa; Ferretti, Massimo; Orilieri, Elisabetta; Dianzani, Irma; Ferrarini, Marina; Bregni, Marco; Danesino, Cesare; Bozzi, Valeria; Putti, Maria Caterina; Cerutti, Franco; Cometa, Angela; Locatelli, Franco; Maccario, Rita; Ramenghi, Ugo; Dianzani, Umberto

    2006-11-01

    Mutations decreasing function of the Fas death receptor cause the autoimmune lymphoproliferative syndrome (ALPS) with autoimmune manifestations, spleen/lymph node enlargement, and expansion of CD4/CD8-negative T cells. Dianzani Autoimmune Lymphoproliferative Disease (DALD) is a variant lacking this expansion. Perforin is involved in cell-mediated cytotoxicity and its biallelic mutations cause familial hemophagocytic lymphohistiocytosis (HLH). We previously described an ALPS patient carrying heterozygous mutations of the Fas and perforin genes and suggested that they concurred in ALPS. This work extends the analysis to 14 ALPS, 28 DALD, and 816 controls, and detects an N252S amino acid substitution in 2 ALPS, and an A91V amino acid substitution in 6 DALD. N252S conferred an OR = 62.7 (P = .0016) for ALPS and A91V conferred an OR = 3 (P = .016) for DALD. Copresence of A91V and variations of the osteopontin gene previously associated with DALD conferred an OR = 17 (P = .0007) for DALD. In one N252S patient, NK activity was strikingly defective in early childhood, but became normal in late childhood. A91V patients displayed lower NK activity than controls. These data suggest that perforin variations are a susceptibility factor for ALPS/DALD development in subjects with defective Fas function and may influence disease expression. PMID:16720836

  19. Long noncoding RNA Saf and splicing factor 45 increase soluble Fas and resistance to apoptosis

    PubMed Central

    Riberdy, Janice M.; Persons, Derek A.; Wilber, Andrew

    2016-01-01

    In multicellular organisms, cell growth and differentiation is controlled in part by programmed cell death or apoptosis. One major apoptotic pathway is triggered by Fas receptor (Fas)-Fas ligand (FasL) interaction. Neoplastic cells are frequently resistant to Fas-mediated apoptosis, evade Fas signals through down regulation of Fas and produce soluble Fas proteins that bind FasL thereby blocking apoptosis. Soluble Fas (sFas) is an alternative splice product of Fas pre-mRNA, commonly created by exclusion of transmembrane spanning sequences encoded within exon 6 (FasΔEx6). Long non-coding RNAs (lncRNAs) interact with other RNAs, DNA, and proteins to regulate gene expression. One lncRNA, Fas-antisense or Saf, was shown to participate in alternative splicing of Fas pre-mRNA through unknown mechanisms. We show that Saf is localized in the nucleus where it interacts with Fas receptor pre-mRNA and human splicing factor 45 (SPF45) to facilitate alternative splicing and exclusion of exon 6. The product is a soluble Fas protein that protects cells against FasL-induced apoptosis. Collectively, these studies reveal a novel mechanism to modulate this critical cell death program by an lncRNA and its protein partner. PMID:26885613

  20. Long noncoding RNA Saf and splicing factor 45 increase soluble Fas and resistance to apoptosis.

    PubMed

    Villamizar, Olga; Chambers, Christopher B; Riberdy, Janice M; Persons, Derek A; Wilber, Andrew

    2016-03-22

    In multicellular organisms, cell growth and differentiation is controlled in part by programmed cell death or apoptosis. One major apoptotic pathway is triggered by Fas receptor (Fas)-Fas ligand (FasL) interaction. Neoplastic cells are frequently resistant to Fas-mediated apoptosis, evade Fas signals through down regulation of Fas and produce soluble Fas proteins that bind FasL thereby blocking apoptosis. Soluble Fas (sFas) is an alternative splice product of Fas pre-mRNA, commonly created by exclusion of transmembrane spanning sequences encoded within exon 6 (FasΔEx6). Long non-coding RNAs (lncRNAs) interact with other RNAs, DNA, and proteins to regulate gene expression. One lncRNA, Fas-antisense or Saf, was shown to participate in alternative splicing of Fas pre-mRNA through unknown mechanisms. We show that Saf is localized in the nucleus where it interacts with Fas receptor pre-mRNA and human splicing factor 45 (SPF45) to facilitate alternative splicing and exclusion of exon 6. The product is a soluble Fas protein that protects cells against FasL-induced apoptosis. Collectively, these studies reveal a novel mechanism to modulate this critical cell death program by an lncRNA and its protein partner. PMID:26885613

  1. Platelets induce apoptosis via membrane-bound FasL

    PubMed Central

    Schleicher, Rebecca I.; Reichenbach, Frank; Kraft, Peter; Kumar, Anil; Lescan, Mario; Todt, Franziska; Göbel, Kerstin; Hilgendorf, Ingo; Geisler, Tobias; Bauer, Axel; Olbrich, Marcus; Schaller, Martin; Wesselborg, Sebastian; O’Reilly, Lorraine; Meuth, Sven G.; Schulze-Osthoff, Klaus; Gawaz, Meinrad; Li, Xuri; Kleinschnitz, Christoph; Edlich, Frank

    2015-01-01

    After tissue injury, both wound sealing and apoptosis contribute to restoration of tissue integrity and functionality. Although the role of platelets (PLTs) for wound closure and induction of regenerative processes is well established, the knowledge about their contribution to apoptosis is incomplete. Here, we show that PLTs present the death receptor Fas ligand (FasL) on their surface after activation. Activated PLTs as well as the isolated membrane fraction of activated PLTs but not of resting PLTs induced apoptosis in a dose-dependent manner in primary murine neuronal cells, human neuroblastoma cells, and mouse embryonic fibroblasts. Membrane protein from PLTs lacking membrane-bound FasL (FasL△m/△m) failed to induce apoptosis. Bax/Bak-mediated mitochondrial apoptosis signaling in target cells was not required for PLT-induced cell death, but increased the apoptotic response to PLT-induced Fas signaling. In vivo, PLT depletion significantly reduced apoptosis in a stroke model and an inflammation-independent model of N-methyl-d-aspartic acid-induced retinal apoptosis. Furthermore, experiments using PLT-specific PF4Cre+ FasLfl/fl mice demonstrated a role of PLT-derived FasL for tissue apoptosis. Because apoptosis secondary to injury prevents inflammation, our findings describe a novel mechanism on how PLTs contribute to tissue homeostasis. PMID:26232171

  2. A survey of Italian and Spanish neonatologists and paediatricians regarding awareness of the diagnosis of FAS and FASD and maternal ethanol use during pregnancy

    PubMed Central

    2011-01-01

    Background Ethanol is the most widely used drug in the world and a human teratogen whose consumption among women of childbearing age has been steadily increasing. There are no Italian or Spanish statistics on ethanol consumption during pregnancy nor any information regarding prevalence of fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorders (FASD). There is also a reasonable suspicion that these two diseases are underdiagnosed by professionals from the above-reported countries. The objectives of this study were: 1) to evaluate the experience, knowledge and confidence of Italian and Spanish neonatologists and paediatricians with respect to the diagnosis of FAS and FASD, and 2) to evaluate professionals awareness of maternal drinking patterns during pregnancy. Methods A multiple-choice anonymous questionnaire was e-mailed to Italian neonatologists registered in the mailing list of the corresponding Society and administered to Italian and Spanish paediatricians during their National Congress. Results The response rate was 16% (63/400) for the Italian neonatologists of the National Society while a total of 152 Spanish and 41 Italian paediatricians agreed to complete the questionnaire during National Congress. Over 90% of the surveyed physicians declared that FAS is an identifiable syndrome and over 60% of them identified at least one of the most important features of FAS. Although over 60% Italian responders and around 80% Spanish responders were aware that ethanol use in pregnancy is dangerous, approximately 50% Italian responders and 40% Spanish ones allowed women to drink sometimes a glass of wine or beer during pregnancy. Neonatologists and paediatricians rated confidence in the ability to diagnosis FAS and FASD as low, with over 50% responders feeling they needed more information regarding FAS and FASD identification in newborn and child. Conclusions Italian and Spanish neonatologists and paediatricians do not feel confident about diagnosing FAS and

  3. You Sound Attractive! Perceptions of Accented English in a Multilingual Environment

    ERIC Educational Resources Information Center

    Eisenchlas, Susana A.; Tsurutani, Chiharu

    2011-01-01

    Sociolinguistic research on attitudes towards language has revealed that native speakers of English are drawn towards those who share their native accent and respond cautiously, perhaps negatively, towards those speaking in "accented" English (Lambert, Hodgson, Gardner & Fillenbaum, 1960; Rubin, 1992). These perceptions greatly disadvantage…

  4. 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…

  5. Listening with an Accent: Speech Perception in a Second Language by Late Bilinguals

    ERIC Educational Resources Information Center

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

    2009-01-01

    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…

  6. 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…

  7. The Speakers' Accent Shapes the Listeners' Phonological Predictions during Speech Perception

    ERIC Educational Resources Information Center

    Brunelliere, Angele; Soto-Faraco, Salvador

    2013-01-01

    This study investigates the specificity of predictive coding in spoken word comprehension using event-related potentials (ERPs). We measured word-evoked ERPs in Catalan speakers listening to semantically constraining sentences produced in their native regional accent (Experiment 1) or in a non-native accent (Experiment 2). Semantically anomalous…

  8. 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…

  9. 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…

  10. 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…

  11. 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…

  12. 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…

  13. 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…

  14. 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…

  15. 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.…

  16. 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 contrastive accent on…

  17. The Development of Language Constancy: Attention to Native versus Nonnative Accents

    ERIC Educational Resources Information Center

    Kitamura, Christine; Panneton, Robin; Best, Catherine T.

    2013-01-01

    The time frame for infants' acquisition of language constancy was probed, using the phonetic variation in a rarely heard accent (South African English) or a frequently heard accent (American English). A total of 156 Australian infants were tested. Six-month-olds looked longer to Australian English than less commonly heard South African…

  18. Acentos, Tildes, Casas, Cosas, Casos, Cosos? (Accents, Tildes, [Punctuation, and Spelling Accuracy]).

    ERIC Educational Resources Information Center

    Fabri Diaz, Victor

    1972-01-01

    Correct spelling, punctuation marks, and spelling accents must be taught in the beginning Spanish course. Accent marks make a difference in the interpretation of the written word. Rules govern the placing of exclamation and question marks and make up an integral part of written Spanish. Teachers have a duty and a responsibility to teach these…

  19. 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…

  20. 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…

  1. 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…

  2. 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:…

  3. 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. PMID:26905515

  4. 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 writing of the final disposition of its application. FAS will send a program agreement,...

  5. 7 CFR 1484.30 - How does FAS formalize its working relationship with approved Cooperators?

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 10 2011-01-01 2011-01-01 false How does FAS formalize its working relationship with... FAS formalize its working relationship with approved Cooperators? FAS will notify each applicant in writing of the final disposition of its application. FAS will send a program agreement,...

  6. Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity.

    PubMed

    Daburon, Sophie; Devaud, Christel; Costet, Pierre; Morello, Aurore; Garrigue-Antar, Laure; Maillasson, Mike; Hargous, Nathalie; Lapaillerie, Delphine; Bonneu, Marc; Dechanet-Merville, Julie; Legembre, Patrick; Capone, Myriam; Moreau, Jean-François; Taupin, Jean-Luc

    2013-01-01

    Binding of ligand FasL to its receptor Fas triggers apoptosis via the caspase cascade. FasL itself is homotrimeric, and a productive apoptotic signal requires that FasL be oligomerized beyond the homotrimeric state. We generated a series of FasL chimeras by fusing FasL to domains of the Leukemia Inhibitory Factor receptor gp190 which confer homotypic oligomerization, and analyzed the capacity of these soluble chimeras to trigger cell death. We observed that the most efficient FasL chimera, called pFasL, was also the most polymeric, as it reached the size of a dodecamer. Using a cellular model, we investigated the structure-function relationships of the FasL/Fas interactions for our chimeras, and we demonstrated that the Fas-mediated apoptotic signal did not solely rely on ligand-mediated receptor aggregation, but also required a conformational adaptation of the Fas receptor. When injected into mice, pFasL did not trigger liver injury at a dose which displayed anti-tumor activity in a model of human tumor transplanted to immunodeficient animals, suggesting a potential therapeutic use. Therefore, the optimization of the FasL conformation has to be considered for the development of efficient FasL-derived anti-cancer drugs targeting Fas. PMID:23326557

  7. 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. PMID:27177077

  8. Quantitative assessment of the association between Fas/FasL gene polymorphism and susceptibility to esophageal carcinoma in a north Chinese population.

    PubMed

    Zhang, Meijuan; Wu, Cuiping; Li, Baohuan; Du, Wenjun; Zhang, Chuanzhen; Chen, Ziping

    2016-04-01

    The case-control study aims to investigate the association of Fas and FasL genetic polymorphisms (Fas-670A/G (rs1800682), Fas-1377G/A (rs2234767) and FasL-844T/C (rs763110)) with esophageal carcinoma susceptibility in a north Chinese population. A total of 204 patients with esophageal carcinoma and 248 healthy controls were enrolled from Henan, China and genotyped by the polymerase chain reaction and restriction fragment length polymorphism method. There were no significant differences in distributions of their genotypes frequencies between patients and controls in Fas-670A/G, Fas-1377G/A and FasL-844T/C polymorphisms (P > 0.05). Stratified analysis showed that no significant association was found between esophageal carcinoma and gene polymorphisms of Fas-670 A/G, Fas-1377G/A, and FasL-844T/C (P > 0.05). Genetic polymorphisms in the death pathway genes Fas and FasL were not associated with risk of developing esophageal carcinoma in a north Chinese population. PMID:26819081

  9. 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…

  10. 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,…

  11. 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.…

  12. 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…

  13. 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…

  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. PMID:25111665

  15. 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

  16. Advanced glycation end-product (AGE) induces apoptosis in human retinal ARPE-19 cells via promoting mitochondrial dysfunction and activating the Fas-FasL signaling.

    PubMed

    Wang, Pu; Xing, Yiqiao; Chen, Changzheng; Chen, Zhen; Qian, Zhimin

    2016-01-01

    Advanced glycation end-products (AGEs) are extremely accumulated in the retinal vascular and epithelial cells of diabetes mellitus (DM) patients, particularly with diabetic retinopathy (DR). To elucidate the pathogenesis of the AGE-induced toxicity to retinal epithelial cells, we investigated the role of Fas-Fas ligand (FasL) signaling and mitochondrial dysfunction in the AGE-induced apoptosis. Results demonstrated that the AGE-BSA- induced apoptosis of retinal ARPE-19 cells. And the AGE-BSA treatment caused mitochondrial dysfunction, via deregulating the B-cell lymphoma 2 (Bcl-2) signaling. Moreover, the Fas/FasL and its downstreamer Caspase 8 were promoted by the AGE-BSA treatment, and the exogenous α-Fas exacerbated the activation of Caspase 3/8. On the other side, the siRNA-mediated knockdown of Fas/FasL inhibited the AGE-BSA-induced apoptosis. Taken together, we confirmed the activation of Fas-FasL signaling and of mitochondrial dysfunction in the AGE-BSA-promoted apoptosis in retinal ARPE-19 cells, implying the important role of Fas-FasL signaling in the DR in DM. PMID:26479732

  17. Autoimmune lymphoproliferative syndrome presenting with glomerulonephritis.

    PubMed

    Kanegane, Hirokazu; Vilela, Maria Marluce dos Santos; Wang, Yue; Futatani, Takeshi; Matsukura, Hiroyoshi; Miyawaki, Toshio

    2003-05-01

    Autoimmune lymphoproliferative syndrome (ALPS) is characterized clinically by chronic non-malignant lymphoproliferation and autoimmunity and is caused by a genetic defect in programmed cell death (apoptosis). Most patients with ALPS have heterozygous mutations in the Fas gene. We describe an 11-year-old Brazilian boy with hepatosplenomegaly, lymphadenopathy, hemolytic anemia, and hypergammaglobulinemia since early infancy. T cell lines from the patient were defective in Fas-mediated apoptosis. He was diagnosed as having ALPS and found to have a novel Fas gene mutation (IVS4+1G>A). In addition, he presented with glomerulonephritis in infancy. An aunt and uncle who had the same Fas mutations also had histories of glomerulonephritis. Although glomerulonephritis is common in Fas-deficient mice, it is infrequent in human ALPS. Corticosteroid therapy ameliorated the glomerulonephritis in our patient, as well as his lymphoproliferation, anemia, and hypergammaglobulinemia. This study suggests that glomerulonephritis is one of the characteristic features of ALPS. PMID:12736807

  18. Dialectal differences in hemispheric specialization for Japanese lexical pitch accent.

    PubMed

    Sato, Yutaka; Utsugi, Akira; Yamane, Naoto; Koizumi, Masatoshi; Mazuka, Reiko

    2013-12-01

    Language experience can alter perceptual abilities and the neural specialization for phonological contrasts. Here we investigated whether dialectal differences in the lexical use of pitch information lead to differences in functional lateralization for pitch processing. We measured cortical hemodynamic responses to pitch pattern changes in native speakers of Standard (Tokyo) Japanese, which has a lexical pitch accent system, and native speakers of 'accentless' dialects, which do not have any lexical tonal phenomena. While the Standard Japanese speakers showed left-dominant responses in temporal regions to pitch pattern changes within words, the accentless dialects speakers did not show such left-dominance. Pitch pattern changes within harmonic-complex tones also elicited different brain activation patterns between the two groups. These results indicate that the neural processing of pitch information differs depending on the listener's native dialect, and that listeners' linguistic experiences may further affect the processing of pitch changes even for non-linguistic sounds. PMID:24139706

  19. 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.

  20. 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.

  1. Sp3 regulates fas expression in lung epithelial cells.

    PubMed Central

    Pang, H; Miranda, K; Fine, A

    1998-01-01

    By transducing an apoptotic signal in immune effector cells, Fas has been directly implicated in the control of immunological activity. Expression and functional results, however, have also suggested a role for Fas in regulating cell turnover in specific epithelial populations. To characterize factors responsible for Fas expression in epithelial cells, approximately 3 kb of the 5' flanking region of the mouse Fas gene was isolated. By rapid amplification of cDNA ends and primer extension, transcriptional start sites were identified within 50 bp upstream of the translation start site. Transient transfection of promoter-luciferase constructs in a mouse lung epithelial cell line, MLE-15, localized promoter activity to the first 77 bp of upstream sequence. By using a 60 bp DNA probe (-18 to -77) in electrophoretic mobility-shift assays, three shifted complexes were found. Incubation with excess cold Sp1 oligonucleotide or an anti-Sp3 antibody inhibited complex formation. Site-directed mutagenesis of the Sp1 site resulted in 60-70% loss of promoter activity. In Drosophila SL-2 cells, promoter activity was markedly increased by co-transfection of an Sp3 expression construct. These results show that the Sp3 protein is involved in regulating Fas gene expression in lung epithelial cells. PMID:9639581

  2. 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)

  3. Learning about Atmospheric Composition Change within a Network of Excellence: a Synthesis of ACCENT "Training & Education

    NASA Astrophysics Data System (ADS)

    Schuepbach, E.; Uherek, E.; Ladstaetter-Weissenmayer, A.

    2009-04-01

    The fast move towards a knowledge-based society poses sweeping challenges to science education worldwide. Being a new instrument under EU funding mode, the Network of Excellence in Atmospheric Composition Change (ACCENT; www.accent-network.org) seeks to meet these challenges, and to explore novel ways for learning and teaching. The Task Training and Education (T&E) in ACCENT has developed an «Integrated Learning Environment» (ILE) aimed at serving the learner's needs (beginners, advanced learners). It focuses on interactivity and problem-based learning, and incorporates multifaceted learning opportunities like debates with stakeholders. A virtual knowledge train connects knowledge on atmospheric composition change across the world. Evolving good practice in ACCENT T&E are compiled in a Handbook.

  4. Ex vivo pediatric brain tumors express Fas (CD95) and FasL (CD95L) and are resistant to apoptosis induction.

    PubMed Central

    Riffkin, C. D.; Gray, A. Z.; Hawkins, C. J.; Chow, C. W.; Ashley, D. M.

    2001-01-01

    Fas (APO-1/CD95/TNFRSF6) is a member of the tumor necrosis/nerve growth factor receptor family that signals apoptotic cell death in sensitive cells.Expression of Fas and its agonistic ligand (FasL/TNFSF6) was investigated in ex vivo pediatric brain tumor specimens of various histologic types. Fas expression was identified in all of the 18 tumors analyzed by flow cytometry and immunohistochemistry. FasL expression was identified in most of the 13 tumors analyzed by both Western analysis and immunohistochemistry. Nine of these tumor specimens were treated with either the agonistic anti-Fas antibody (APO-1) in combination with protein A or FasL in short-term cytotoxicity assays. Sensitivity to apoptosis induced by the topoisomerase II inhibitor, etoposide, was also assessed. Despite the presence of Fas, all the specimens analyzed demonstrated a high degree of resistance to Fas-mediated apoptosis. These 9 specimens also showed a high degree of resistance to etoposide. Only 2 of the 9 specimens were susceptible to etoposide-induced cell death, whereas only 3 were sensitive to Fas-mediated apoptosis. One brain tumor was sensitive to both Fas ligation and etoposide treatment. This contrasted with the high degree of susceptibility to both etoposide- and Fas-induced apoptosis observed in the reference Jurkat cell line. The results suggest that Fas expression may be a general feature of tumors of the CNS and that a significant degree of resistance to Fas-mediated apoptosis may exist in ex vivo pediatric brain tumor specimens. PMID:11584892

  5. Audiovisual cues benefit recognition of accented speech in noise but not perceptual adaptation.

    PubMed

    Banks, Briony; Gowen, Emma; Munro, Kevin J; Adank, Patti

    2015-01-01

    Perceptual adaptation allows humans to recognize different varieties of accented speech. We investigated whether perceptual adaptation to accented speech is facilitated if listeners can see a speaker's facial and mouth movements. In Study 1, participants listened to sentences in a novel accent and underwent a period of training with audiovisual or audio-only speech cues, presented in quiet or in background noise. A control group also underwent training with visual-only (speech-reading) cues. We observed no significant difference in perceptual adaptation between any of the groups. To address a number of remaining questions, we carried out a second study using a different accent, speaker and experimental design, in which participants listened to sentences in a non-native (Japanese) accent with audiovisual or audio-only cues, without separate training. Participants' eye gaze was recorded to verify that they looked at the speaker's face during audiovisual trials. Recognition accuracy was significantly better for audiovisual than for audio-only stimuli; however, no statistical difference in perceptual adaptation was observed between the two modalities. Furthermore, Bayesian analysis suggested that the data supported the null hypothesis. Our results suggest that although the availability of visual speech cues may be immediately beneficial for recognition of unfamiliar accented speech in noise, it does not improve perceptual adaptation. PMID:26283946

  6. 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

  7. Audiovisual cues benefit recognition of accented speech in noise but not perceptual adaptation

    PubMed Central

    Banks, Briony; Gowen, Emma; Munro, Kevin J.; Adank, Patti

    2015-01-01

    Perceptual adaptation allows humans to recognize different varieties of accented speech. We investigated whether perceptual adaptation to accented speech is facilitated if listeners can see a speaker’s facial and mouth movements. In Study 1, participants listened to sentences in a novel accent and underwent a period of training with audiovisual or audio-only speech cues, presented in quiet or in background noise. A control group also underwent training with visual-only (speech-reading) cues. We observed no significant difference in perceptual adaptation between any of the groups. To address a number of remaining questions, we carried out a second study using a different accent, speaker and experimental design, in which participants listened to sentences in a non-native (Japanese) accent with audiovisual or audio-only cues, without separate training. Participants’ eye gaze was recorded to verify that they looked at the speaker’s face during audiovisual trials. Recognition accuracy was significantly better for audiovisual than for audio-only stimuli; however, no statistical difference in perceptual adaptation was observed between the two modalities. Furthermore, Bayesian analysis suggested that the data supported the null hypothesis. Our results suggest that although the availability of visual speech cues may be immediately beneficial for recognition of unfamiliar accented speech in noise, it does not improve perceptual adaptation. PMID:26283946

  8. 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

  9. Role of the Fas/FasL system in a model of RSV infection in mechanically ventilated mice

    PubMed Central

    van den Berg, Elske; van Woensel, Job B. M.; Bos, Albert P.; Bem, Reinout A.; Altemeier, William A.; Gill, Sean E.; Martin, Thomas R.

    2011-01-01

    Infection with respiratory syncytial virus (RSV) in children can progress to respiratory distress and acute lung injury necessitating mechanical ventilation (MV). MV enhances apoptosis and inflammation in mice infected with pneumonia virus of mice (PVM), a mouse pneumovirus that has been used as a model for severe RSV infection in mice. We hypothesized that the Fas/Fas ligand (FasL) system, a dual proapoptotic/proinflammatory system involved in other forms of lung injury, is required for enhanced lung injury in mechanically ventilated mice infected with PVM. C57BL/6 mice and Fas-deficient (“lpr”) mice were inoculated intratracheally with PVM. Seven or eight days after PVM inoculation, the mice were subjected to 4 h of MV (tidal volume 10 ml/kg, fraction of inspired O2 = 0.21, and positive end-expiratory pressure = 3 cm H2O). Seven days after PVM inoculation, exposure to MV resulted in less severe injury in lpr mice than in C57BL/6 mice, as evidenced by decreased numbers of polymorphonuclear neutrophils in the bronchoalveolar lavage (BAL), and lower concentrations of the proinflammatory chemokines KC, macrophage inflammatory protein (MIP)-1α, and MIP-2 in the lungs. However, when PVM infection was allowed to progress one additional day, all of the lpr mice (7/7) died unexpectedly between 0.5 and 3.5 h after the onset of ventilation compared with three of the seven ventilated C57BL/6 mice. Parameters of lung injury were similar in nonventilated mice, as was the viral content in the lungs and other organs. Thus, the Fas/FasL system was partly required for the lung inflammatory response in ventilated mice infected with PVM, but attenuation of lung inflammation did not prevent subsequent mortality. PMID:21743025

  10. Intervention of selenium on apoptosis and Fas/FasL expressions in the liver of fluoride-exposed rats.

    PubMed

    Miao, Keke; Zhang, Lei; Yang, Shuying; Qian, Wei; Zhang, Zigui

    2013-11-01

    Fluorosis is a major public health problem in numerous areas around the world, including China. To alleviate this problem, selenium has been used. In this study, we aimed to investigate the influence of selenium on apoptosis in fluorosis-affected rat livers and determine the optimal selenium concentration in drinking water to fight fluorosis. The protein levels of Fas in NaF and NaF+Se (0.375 and 0.75 mg/L) groups as well as FasL in NaF, Se (0.75 and 1.5 mg/L), and NaF+Se (0.375 mg/L) groups were significantly increased compared with those in the control group. The mRNA levels of Fas in NaF and Se (1.5 mg/L) groups as well as FasL in NaF and NaF+Se (0.375 mg/L) groups were significantly increased. The protein levels of Fas in NaF+Se (1.5 mg/L) group and FasL in three NaF+Se groups were significantly decreased compared with those in the NaF group. The mRNA levels of Fas in the three NaF+Se groups and FasL in NaF+Se (0.75 and 1.5 mg/L) groups were significantly decreased. Compared with the control group, activity of GSH-Px, and SOD in the NaF group decreased obviously and MDA content increased obviously; activity of SOD in 1.5 mg/L Se group decreased obviously. Compared with the NaF group, activity of GSH-Px in NaF+Se (1.5 mg/L) group significantly increased, and MDA content decreased obviously. Thus, fluoride induced apoptosis in the liver, thereby causing liver damage in the rats. Selenium could alleviate fluorosis-induced liver injury. In particular, selenium at 1.5 mg/L is considered the optimum concentration against fluorosis. PMID:24008008

  11. Plasma content of soluble fas antigen in patients with adrenal tumors and tumor-like pathologies.

    PubMed

    Kushlinskii, N E; Britvin, T A; Polyakova, G A; Abbasova, S G; Baronini, A A; Tishenina, R S; Molchanova, G S; Sel'chuk, V Yu; Pirogov, D A; Bogatyrev, O P; Lipkin, V M; Kalinin, A P

    2002-08-01

    We compared plasma content of soluble Fas antigen (sFas) in 59 patients with tumors and tumor-like pathologies of the adrenal cortex and medulla and 60 healthy donors (control). The incidence and content of sFas in the plasma from patients with adrenal tumors was significantly higher than in healthy donors. A direct correlation was found between sFas content and patient's age. The maximum sFas concentrations were found in patients with pheochromocytoma and aldosterone-producing adenoma. In patients with adrenocortical cancer plasma content of sFas was lower than in patients with tumors of other morphological types. Plasma sFas content in patients with adrenocortical cancer directly correlated with the size of tumors. Our results suggest that sFas plays a role in the pathogenesis of primary adrenal tumors. PMID:12459844

  12. Characterization of Calmodulin–Fas Death Domain Interaction: An Integrated Experimental and Computational Study

    PubMed Central

    2015-01-01

    The Fas death receptor-activated death-inducing signaling complex (DISC) regulates apoptosis in many normal and cancer cells. Qualitative biochemical experiments demonstrate that calmodulin (CaM) binds to the death domain of Fas. The interaction between CaM and Fas regulates Fas-mediated DISC formation. A quantitative understanding of the interaction between CaM and Fas is important for the optimal design of antagonists for CaM or Fas to regulate the CaM–Fas interaction, thus modulating Fas-mediated DISC formation and apoptosis. The V254N mutation of the Fas death domain (Fas DD) is analogous to an identified mutant allele of Fas in lpr-cg mice that have a deficiency in Fas-mediated apoptosis. In this study, the interactions of CaM with the Fas DD wild type (Fas DD WT) and with the Fas DD V254N mutant were characterized using isothermal titration calorimetry (ITC), circular dichroism spectroscopy (CD), and molecular dynamics (MD) simulations. ITC results reveal an endothermic binding characteristic and an entropy-driven interaction of CaM with Fas DD WT or with Fas DD V254N. The Fas DD V254N mutation decreased the association constant (Ka) for CaM–Fas DD binding from (1.79 ± 0.20) × 106 to (0.88 ± 0.14) × 106 M–1 and slightly increased a standard state Gibbs free energy (ΔG°) for CaM–Fas DD binding from −8.87 ± 0.07 to −8.43 ± 0.10 kcal/mol. CD secondary structure analysis and MD simulation results did not show significant secondary structural changes of the Fas DD caused by the V254N mutation. The conformational and dynamical motion analyses, the analyses of hydrogen bond formation within the CaM binding region, the contact numbers of each residue, and the electrostatic potential for the CaM binding region based on MD simulations demonstrated changes caused by the Fas DD V254N mutation. These changes caused by the Fas DD V254N mutation could affect the van der Waals interactions and electrostatic interactions between CaM and Fas DD, thereby

  13. FETAL ALCOHOL SYNDROME SURVEILLANCE NETWORK (FASSNET)

    EPA Science Inventory

    CDC, in collaboration with four states, has developed the first state-based program specifically designed to monitor trends in the occurrence of fetal alcohol syndrome (FAS). The program, Fetal Alcohol Syndrome Surveillance Network (FASSNet), reports that many children continue t...

  14. 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

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

    PubMed

    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

  16. 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. PMID:23614175

  17. 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

    2016-05-01

    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. PMID:26907631

  18. Regulation of hippocampal Fas receptor and death-inducing signaling complex after kainic acid treatment in mice.

    PubMed

    Keller, Benjamin; García-Sevilla, Jesús A

    2015-12-01

    Kainic acid (KA)-induced brain neuronal cell death (especially in the hippocampus) was shown to be mainly mediated by the intrinsic (mitochondrial) apoptotic pathway. This study investigated the regulation of the extrinsic apoptotic pathway mediated by Fas ligand/Fas receptor and components of the indispensable death-inducing signaling complex (DISC) in the hippocampus (marked changes) and cerebral cortex (modest changes) of KA-treated mice. KA (45mg/kg) induced a severe behavioral syndrome with recurrent motor seizures (scores; maximal at 60-90min; minimal at 72h) with activation of hippocampal pro-apoptotic JNK (+2.5 fold) and increased GFAP (+57%) and nuclear PARP-1 fragmentation (+114%) 72h post-treatment (delayed neurotoxicity). In the extrinsic apoptotic pathway (hippocampus), KA (72h) reduced Fas ligand (-92%) and Fas receptor aggregates (-24%). KA (72h) also altered the contents of major DISC components: decreased FADD adaptor (-44%), reduced activation of initiator caspase-8 (-47%) and increased survival FLIP-S (+220%). Notably, KA (72h) upregulated the content of anti-apoptotic p-Ser191 FADD (+41%) and consequently the expression of p-FADD/FADD ratio (+1.9-fold), a neuroplastic index. Moreover, the p-FADD dependent transcription factor NF-κB was also increased (+61%) in the hippocampus after KA (72h). The convergent adaptation of the extrinsic apoptotic machinery 72h after KA in mice (with otherwise normal gross behavior) is a novel finding which suggests the induction of survival mechanisms to partly counteract the delayed neuronal death in the hippocampus. PMID:26044520

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

    PubMed

    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

  20. 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

  1. Uncouplers of Oxidative Phosphorylation Can Enhance a Fas Death Signal

    PubMed Central

    Linsinger, Georg; Wilhelm, Sabine; Wagner, Hermann; Häcker, Georg

    1999-01-01

    Recent work suggests a participation of mitochondria in apoptotic cell death. This role includes the release of apoptogenic molecules into the cytosol preceding or after a loss of mitochondrial membrane potential ΔΨm. The two uncouplers of oxidative phosphorylation carbonyl cyanide m-chlorophenylhydrazone (CCCP) and 2,4-dinitrophenol (DNP) reduce ΔΨm by direct attack of the proton gradient across the inner mitochondrial membrane. Here we show that both compounds enhance the apoptosis-inducing capacity of Fas/APO-1/CD95 signaling in Jurkat and CEM cells without causing apoptotic changes on their own account. This amplification occurred upstream or at the level of caspases and was not inhibited by Bcl-2. The effect could be blocked by the cowpox protein CrmA and is thus likely to require caspase 8 activity. Apoptosis induction by staurosporine in Jurkat cells as well as by Fas in SKW6 cells was unaffected by CCCP and DNP. The role of cytochrome c during Fas-DNP signaling was investigated. No early cytochrome c release from mitochondria was detected by Western blotting. Functional assays with cytoplasmic preparations from Fas-DNP-treated cells also indicated that there was no major contribution by cytochrome c or caspase 9 to the activation of effector caspases. Furthermore, an increase of rhodamine-123 uptake into intact cells, which has been explained by mitochondrial swelling, occurred considerably later than the caspase activation and was blocked by Z-VAD-fmk. These data show that uncouplers of oxidative phosphorylation can presensitize some but not all cells for a Fas death signal and provide information about the existence of separate pathways in the induction of apoptosis. PMID:10207055

  2. Uncouplers of oxidative phosphorylation can enhance a Fas death signal.

    PubMed

    Linsinger, G; Wilhelm, S; Wagner, H; Häcker, G

    1999-05-01

    Recent work suggests a participation of mitochondria in apoptotic cell death. This role includes the release of apoptogenic molecules into the cytosol preceding or after a loss of mitochondrial membrane potential DeltaPsim. The two uncouplers of oxidative phosphorylation carbonyl cyanide m-chlorophenylhydrazone (CCCP) and 2, 4-dinitrophenol (DNP) reduce DeltaPsim by direct attack of the proton gradient across the inner mitochondrial membrane. Here we show that both compounds enhance the apoptosis-inducing capacity of Fas/APO-1/CD95 signaling in Jurkat and CEM cells without causing apoptotic changes on their own account. This amplification occurred upstream or at the level of caspases and was not inhibited by Bcl-2. The effect could be blocked by the cowpox protein CrmA and is thus likely to require caspase 8 activity. Apoptosis induction by staurosporine in Jurkat cells as well as by Fas in SKW6 cells was unaffected by CCCP and DNP. The role of cytochrome c during Fas-DNP signaling was investigated. No early cytochrome c release from mitochondria was detected by Western blotting. Functional assays with cytoplasmic preparations from Fas-DNP-treated cells also indicated that there was no major contribution by cytochrome c or caspase 9 to the activation of effector caspases. Furthermore, an increase of rhodamine-123 uptake into intact cells, which has been explained by mitochondrial swelling, occurred considerably later than the caspase activation and was blocked by Z-VAD-fmk. These data show that uncouplers of oxidative phosphorylation can presensitize some but not all cells for a Fas death signal and provide information about the existence of separate pathways in the induction of apoptosis. PMID:10207055

  3. Ontogenesis and cell specific localization of Fas ligand expression in the rat testis.

    PubMed

    D'Abrizio, Piera; Baldini, Enke; Russo, Paola F; Biordi, Leda; Graziano, Filomena M; Rucci, Nadia; Properzi, Giuliana; Francavilla, Sandro; Ulisse, Salvatore

    2004-10-01

    Over the past few years, a number of experimental evidences suggested the involvement of Fas Ligand (FasL) expressing Sertoli cells to induce apoptosis of Fas bearing germ cells. However, the FasL expression during testicular development and its cell specific localization within the testis is still a matter of debate. In the present study, we have monitored FasL expression during rat testis development by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and evaluated cell specific localization of FasL expression, by in situ RT-PCR and immunohistochemistry, on adult rat testis. RT-PCR analysis, performed on total RNA from rat testes obtained from 1 day up to 1-year-old animals, demonstrated the presence of FasL transcripts at all developmental stages examined. In situ RT-PCR analysis clearly indicated the presence of FasL mRNA in Sertoli cells of adult testis, while we could never detect FasL transcripts in germ cells. Immunohistochemistry experiments showed a strong immunostaining for FasL in Sertoli cells of adult testis and again, no immunopositivity was observed in germ cells. In conclusion, our data suggest that FasL expression in rat testis is present from the early postnatal days up to the adult, and the Sertoli cells is the main FasL expressing cell within the seminiferous tubule. PMID:15379972

  4. 48 CFR 47.303-8 - F.a.s. vessel, port of shipment.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false F.a.s. vessel, port of... CONTRACT MANAGEMENT TRANSPORTATION Transportation in Supply Contracts 47.303-8 F.a.s. vessel, port of shipment. (a) Explanation of delivery term. F.a.s. vessel, port of shipment means free of expense to...

  5. 48 CFR 52.247-36 - F.a.s. Vessel, Port of Shipment.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Shipment. 52.247-36 Section 52.247-36 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION....247-36 F.a.s. Vessel, Port of Shipment. As prescribed in 47.303-8(c), insert the following clause in solicitations and contracts when the delivery term is f.a.s. vessel, port of shipment: F.a.s. Vessel, Port...

  6. Measurement of ClO and CO2 for ACCENT

    NASA Technical Reports Server (NTRS)

    Toohey, Darin

    2000-01-01

    Observations have shown that ozone in largely removed in rocket plumes within an hour of launch [M.N. Ross, et al., Nature 390, 62-64, 1997]. Large abundances of chlorine oxide (ClO) were first detected in the fresh plume of a Delta rocket in May of 1998 from the NASA WB-57 during the Air Force RISO campaign by the CORE instrument developed at UC Irvine. Similar abundances were detected a month later in the plume of an ATLAS II rocket. Although the maximum ClO observed in these plumes was twenty-five times larger than the highest values ever observed in the perturbed polar vortices, in a new study, [M.N. Ross, et al., Geophys. Res. Lett., 2000, in press] could not account for observed ozone losses based on known chlorine photochemistry. New measurements were obtained in plumes of Delta, Atlas, and Athena rockets in 1999 during ACCENT with the CORE instrument augmented with a modified LiCor non-dispersed infrared detector for fast-response measurements of carbon-dioxide (CO2). The absolute abundance of this specie constrains the rocket emission stoichiometry, and its relative abundance serves as a tracer of dilution. The combination of ClO and CO2 will provide important new insights into the temporal and spatial evolution of reactive chlorine partitioning and its dependence on rocket motor type.

  7. Identification of the Calmodulin-Binding Domains of Fas Death Receptor.

    PubMed

    Chang, Bliss J; Samal, Alexandra B; Vlach, Jiri; Fernandez, Timothy F; Brooke, Dewey; Prevelige, Peter E; Saad, Jamil S

    2016-01-01

    The extrinsic apoptotic pathway is initiated by binding of a Fas ligand to the ectodomain of the surface death receptor Fas protein. Subsequently, the intracellular death domain of Fas (FasDD) and that of the Fas-associated protein (FADD) interact to form the core of the death-inducing signaling complex (DISC), a crucial step for activation of caspases that induce cell death. Previous studies have shown that calmodulin (CaM) is recruited into the DISC in cholangiocarcinoma cells and specifically interacts with FasDD to regulate the apoptotic/survival signaling pathway. Inhibition of CaM activity in DISC stimulates apoptosis significantly. We have recently shown that CaM forms a ternary complex with FasDD (2:1 CaM:FasDD). However, the molecular mechanism by which CaM binds to two distinct FasDD motifs is not fully understood. Here, we employed mass spectrometry, nuclear magnetic resonance (NMR), biophysical, and biochemical methods to identify the binding regions of FasDD and provide a molecular basis for the role of CaM in Fas-mediated apoptosis. Proteolytic digestion and mass spectrometry data revealed that peptides spanning residues 209-239 (Fas-Pep1) and 251-288 (Fas-Pep2) constitute the two CaM-binding regions of FasDD. To determine the molecular mechanism of interaction, we have characterized the binding of recombinant/synthetic Fas-Pep1 and Fas-Pep2 peptides with CaM. Our data show that both peptides engage the N- and C-terminal lobes of CaM simultaneously. Binding of Fas-Pep1 to CaM is entropically driven while that of Fas-Pep2 to CaM is enthalpically driven, indicating that a combination of electrostatic and hydrophobic forces contribute to the stabilization of the FasDD-CaM complex. Our data suggest that because Fas-Pep1 and Fas-Pep2 are involved in extensive intermolecular contacts with the death domain of FADD, binding of CaM to these regions may hinder its ability to bind to FADD, thus greatly inhibiting the initiation of apoptotic signaling pathway

  8. 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…

  9. Fetal Alcohol Syndrome: The Impact on Children's Ability To Learn. Occasional Paper #10.

    ERIC Educational Resources Information Center

    Troccoli, Karen B.

    This paper provides information on the incidence and prevalence of alcohol-related birth defects, the human and economic costs of fetal alcohol syndrome (FAS) and fetal alcohol effects (FAE), and examples of prevention and intervention strategies that can help reduce the occurrence of and ameliorate the consequences of FAS/FAE. It discusses the…

  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. 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)

  12. 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)

  13. 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.…

  14. FasL-triggered death of Jurkat cells requires caspase 8-induced, ATP-dependent cross-talk between Fas and the purinergic receptor P2X(7).

    PubMed

    Aguirre, Adam; Shoji, Kenji F; Sáez, Juan C; Henríquez, Mauricio; Quest, Andrew F G

    2013-02-01

    Fas ligation via the ligand FasL activates the caspase-8/caspase-3-dependent extrinsic death pathway. In so-called type II cells, an additional mechanism involving tBid-mediated caspase-9 activation is required to efficiently trigger cell death. Other pathways linking FasL-Fas interaction to activation of the intrinsic cell death pathway remain unknown. However, ATP release and subsequent activation of purinergic P2X(7) receptors (P2X(7)Rs) favors cell death in some cells. Here, we evaluated the possibility that ATP release downstream of caspase-8 via pannexin1 hemichannels (Panx1 HCs) and subsequent activation of P2X(7)Rs participate in FasL-stimulated cell death. Indeed, upon FasL stimulation, ATP was released from Jurkat cells in a time- and caspase-8-dependent manner. Fas and Panx1 HCs colocalized and inhibition of the latter, but not connexin hemichannels, reduced FasL-induced ATP release. Extracellular apyrase, which hydrolyzes ATP, reduced FasL-induced death. Also, oxidized-ATP or Brilliant Blue G, two P2X(7)R blockers, reduced FasL-induced caspase-9 activation and cell death. These results represent the first evidence indicating that the two death receptors, Fas and P2X(7)R connect functionally via caspase-8 and Panx1 HC-mediated ATP release to promote caspase-9/caspase-3-dependent cell death in lymphoid cells. Thus, a hitherto unsuspected route was uncovered connecting the extrinsic to the intrinsic pathway to amplify death signals emanating from the Fas receptor in type II cells. PMID:22806078

  15. Effects of Shenqi Fuzheng injection on Fas/FasL protein expression levels in the cardiomyocytes of a mouse model of viral myocarditis

    PubMed Central

    WU, TIANMIN; CHEN, JINSHUI; FAN, LIUFANG; XIE, WENYAN; XU, CHANGSHENG; WANG, HUAJUN

    2016-01-01

    The aim of the present study was to examine the effects of Shenqi Fuzheng injection (SFI) on Fas and FasL protein expression levels in the cardiomyocytes of mice with viral myocarditis (VMC) and to explore the underlying anti-apoptotic mechanisms. A total of 120 male BALB/c mice were randomly divided into five groups as follows: Blank control group, model group, ribavirin group, low-dose SFI group and high-dose SFI group. The VMC model was established by the injection of coxsackievirus group B type 3 and saline, ribavirin or SFI was administered 30 min later. Cardiac samples were harvested from mice in each group on days 3, 10 and 30. Apoptosis of cardiac cells was examined using terminal deoxynucleotidyl transferase dUTP nick-end labeling, and Fas and FasL protein expression levels were detected using immunohistochemistry. Myocardial apoptosis and Fas/FasL protein expression levels were significantly increased in the model group, as compared with the blank group (P<0.01), whereas the apoptotic index (AI) and Fas/FasL protein expression levels of cardiac cells in the high-dose SFI group were significantly decreased compared with those in the model group on day 10 (acute phase; P<0.01). The AI and Fas/FasL protein expression levels of cardiac cells in the low- and high-dose SFI groups were also significantly decreased on day 30 (chronic phase; P<0.01); however, no differences between the high- and low-dose groups were detected. In conclusion, SFI relieves VMC via the downregulation of Fas and FasL protein expression and the inhibition of cell apoptosis. PMID:27168814

  16. 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…

  17. 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. PMID:21988389

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

    PubMed

    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

  19. Recognition of accented and unaccented speech in different maskers by younger and older listeners

    PubMed Central

    Gordon-Salant, Sandra; Yeni-Komshian, Grace H.; Fitzgibbons, Peter J.; Cohen, Julie I.; Waldroup, Christopher

    2013-01-01

    This investigation examined the effect of accent of target talkers and background speech maskers on listeners' ability to use cues to separate speech from noise. Differences in accent may create a disparity in the relative timing between signal and background, and such timing cues may be used to separate the target talker from the background speech masker. However, the use of this cue could be reduced for older listeners with temporal processing deficits, especially those with hearing loss. Participants were younger and older listeners with normal hearing and older listeners with hearing loss. Stimuli were IEEE sentences recorded in English by male native speakers of English and Spanish. These sentences were presented in different maskers that included speech-modulated noise and background babbles varying in talker gender and accent. Signal-to-noise ratios corresponding to 50% correct performance were measured. Results indicate that a pronounced Spanish accent limits a listener's ability to take advantage of cues to speech segregation and that a difference in accentedness between the target talker and background masker may be a useful cue for speech segregation. Older hearing-impaired listeners performed poorly in all conditions with the accented talkers. PMID:23862836

  20. Education and training in ACCENT - the European Network of Excellence in Atmospheric Composition Change

    NASA Astrophysics Data System (ADS)

    Schuepbach, E.

    2004-12-01

    This contribution focuses on opportunities for education and training activities in the new Network of Excellence (NoE) in Atmospheric Composition Change (ACCENT) of the European Union FP6 (2004-2008). ACCENT (see www.accent-network.org) aims at promoting a common European strategy for research on atmospheric composition sustainability, to develop and maintain durable means of communication and collaboration within the European scientific community, to facilitate this research and to optimise the interactions with policy-makers and the general public. These overall goals of ACCENT will be pursued through specific objectives which can be classified as (i) joint research programmes, (ii) tasks for integration and (iii) outreach tasks. Here, the strategies for education and training in ACCENT are outlined, and specific objectives and activities of the Task Education and Training for the first 18 months are presented. The aim of this contribution is to exchange and seek possibilities for international co-operation on education and training in atmospheric composition change.

  1. High glucose induces mitochondrial dysfunction and apoptosis in human retinal pigment epithelium cells via promoting SOCS1 and Fas/FasL signaling.

    PubMed

    Chen, Min; Wang, Wei; Ma, Jian; Ye, Panpan; Wang, Kaijun

    2016-02-01

    Diabetic retinopathy (DR) is one of the most serious complications of diabetes mellitus (DM), however, the contribution of high glucose (HG) or hyperglycemia to DR is far from fully understanding. In the present study, we examined the expression of Fas/FasL signaling and suppressors of cytokine signaling (SOCS)1 and 3 in HG-induced human retinal pigment epithelium cells (ARPE-19 cells). And then we investigated the regulatory role of both Fas and SOCS1 in HG-induced mitochondrial dysfunction and apoptosis. Results demonstrated that HG with more than 40mM induced mitochondrial dysfunction via reducing mitochondrial membrane potential (MMP) and via inhibiting the Bcl-2 level, which is the upstream signaling of mitochondria in ARPE-19 cells. HG also upreuglated the Fas signaling and SOCS levels probably via promoting JAK/STAT signaling in ARPE-19 cells. Moreover, the exogenous Fas or entogenous overexpressed SOCS1 accentuated the HG-induced mitochondrial dysfunction and apoptosis, whereas the knockdown of either Fas or SOCS1 reduced the HG-induced mitochondria dysfunction and apoptosis. Thus, the present study confirmed that both Fas/FasL signaling and SOCS1 promoted the HG-induced mitochondrial dysfunction and apoptosis. These results implies the key regulatory role of Fas signaling and SOCS in DR. PMID:26700587

  2. Identification of the Calmodulin-Binding Domains of Fas Death Receptor

    PubMed Central

    Chang, Bliss J.; Samal, Alexandra B.; Vlach, Jiri; Fernandez, Timothy F.; Brooke, Dewey; Prevelige, Peter E.; Saad, Jamil S.

    2016-01-01

    The extrinsic apoptotic pathway is initiated by binding of a Fas ligand to the ectodomain of the surface death receptor Fas protein. Subsequently, the intracellular death domain of Fas (FasDD) and that of the Fas-associated protein (FADD) interact to form the core of the death-inducing signaling complex (DISC), a crucial step for activation of caspases that induce cell death. Previous studies have shown that calmodulin (CaM) is recruited into the DISC in cholangiocarcinoma cells and specifically interacts with FasDD to regulate the apoptotic/survival signaling pathway. Inhibition of CaM activity in DISC stimulates apoptosis significantly. We have recently shown that CaM forms a ternary complex with FasDD (2:1 CaM:FasDD). However, the molecular mechanism by which CaM binds to two distinct FasDD motifs is not fully understood. Here, we employed mass spectrometry, nuclear magnetic resonance (NMR), biophysical, and biochemical methods to identify the binding regions of FasDD and provide a molecular basis for the role of CaM in Fas–mediated apoptosis. Proteolytic digestion and mass spectrometry data revealed that peptides spanning residues 209–239 (Fas-Pep1) and 251–288 (Fas-Pep2) constitute the two CaM-binding regions of FasDD. To determine the molecular mechanism of interaction, we have characterized the binding of recombinant/synthetic Fas-Pep1 and Fas-Pep2 peptides with CaM. Our data show that both peptides engage the N- and C-terminal lobes of CaM simultaneously. Binding of Fas-Pep1 to CaM is entropically driven while that of Fas-Pep2 to CaM is enthalpically driven, indicating that a combination of electrostatic and hydrophobic forces contribute to the stabilization of the FasDD–CaM complex. Our data suggest that because Fas-Pep1 and Fas-Pep2 are involved in extensive intermolecular contacts with the death domain of FADD, binding of CaM to these regions may hinder its ability to bind to FADD, thus greatly inhibiting the initiation of apoptotic signaling

  3. 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.

  4. Possible association of FAS and FASLG polymorphisms with the risk of idiopathic azoospermia in southeast Turkey.

    PubMed

    Balkan, Mahmut; Atar, Murat; Erdal, Mehmet Emin; Rustemoğlu, Aydin; Yildiz, Ismail; Gunesacar, Ramazan; Hatipoğlu, Namık Kemal; Bodakçi, Mehmet Nuri; Ay, Ozlem Izci; Çevik, Kenan

    2014-06-01

    To investigate the association of the genetic variants of FAS/FASLG cell death pathway genes in male infertility, we genotyped the FAS -670A/G, -1377G/A, and FASLG -124A/G single-nucleotide polymorphisms (SNPs) by real-time polymerase chain reaction in 108 infertile men with idiopathic azoospermia and in 125 proven fertile controls. The distribution of genotypes and alleles for SNPs at FAS -1377G/A and FASLG -124A/G loci were determined not to be statistically different between the case and control groups. However, the genotype frequencies of SNPs, FAS -670AA and FAS -670AG, were found to be significantly different between the case and control groups. Whereas the FAS -670AA genotype might be regarded as a higher predisposition for idiopathic azoospermia, FAS -670AG could be interpreted to mean that this genotype provides protection against idiopathic azoospermia. The study of combined genotype and haplotype frequencies has found statistically significant differences between case and control subjects for some combinations. The AA-GG binary genotype for the FAS670 and FAS1377 loci couple, in particular, may have a high degree of predisposition to idiopathic azoospermia. Our results suggest that FAS -670A/G SNP may be a genetic predisposing factor of idiopathic azoospermia among southeastern Anatolian men. Larger studies are needed to verify these findings. Furthermore, our data indicated a possible linkage between the FAS and FASLG genes and idiopathic azoospermia. PMID:24665877

  5. Effects of Noise and Speech Intelligibility on Listener Comprehension and Processing Time of Korean-Accented English

    ERIC Educational Resources Information Center

    Wilson, Erin O'Brien; Spaulding, Tammie J.

    2010-01-01

    Purpose: This study evaluated the effects of noise and speech intelligibility on the processing of speech produced from native English; high-intelligibility, Korean-accented English; and moderate-intelligibility, Korean-accented English speakers. Method: Both listener comprehension, determined by accuracy judgment on true/false sentences, and…

  6. 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…

  7. 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…

  8. Mechanisms underlying accent accommodation in early word learning: evidence for general expansion.

    PubMed

    Schmale, Rachel; Seidl, Amanda; Cristia, Alejandrina

    2015-07-01

    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, we assess whether toddlers might additionally use a general expansion strategy, whereby they simply accept non-standard pronunciations when variability is expected. We exposed a group of 24-month-old English-learning toddlers to variability in indexical cues (very diverse voices from native English talkers), and another to variability in social cues (very diverse-looking silent actors); neither group was familiarized with the target novel accent. At test, both groups succeeded in recognizing a novel word when spoken in the novel accent. Thus, even when no lexical cues are available, variability can prepare young children for non-standard pronunciations. PMID:25443808

  9. 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

  10. Integrating science and soft skills in training courses for early-career scientists in ACCENT

    NASA Astrophysics Data System (ADS)

    Schuepbach, E.

    2006-12-01

    Scientists receive little training in communicating to non-scientists. Yet, both stakeholders and politicians increasingly see scientists as an important part of their world. Scientists feel, however, often uncomfortable with a socio-political role, especially, as discussion frequently moves away from the area of their expertise. The European Network of Excellence in Atmospheric Composition Change (ACCENT; www.accent- network.org) has thus started to integrate both science (disciplinary, interdisciplinary approaches) and soft skills (e.g., communicating to non-scientists) in training courses for early-career scientists. In doing so, the Training and Education Task in ACCENT attempts to respond to a need expressed by many early-career scientists in Europe. There are different ways how scientific material can be brought into the public and political arenas. This contribution will share experiences in integrated training for early-career scientists, incorporating both science and outreach to the general public and politicians.

  11. Misleading Bias-Driven Expectations in Referential Processing and the Facilitative Role of Contrastive Accent.

    PubMed

    Itzhak, Inbal; Baum, Shari R

    2015-10-01

    Probabilistic preferences are often facilitative in language processing and may assist in discourse prediction. However, occasionally these sources of information may lead to inaccurate expectations. The current study investigated a test case of this scenario. An eye-tracking experiment examined the interpretation of ambiguous personal pronouns in the context of implicit causality biases. We tested whether reference resolution may be facilitated online by contrastive accent in cases of a bias-inconsistent referent. Implicit causality biases directed looks to the biased noun phrase; however, when the name of the bias-inconsistent antecedent was accented (e.g., JOHN envied Bill because he ...), this tendency was modulated. Contrastive accent seems to dampen the occasionally confusing prediction of implicit causality biases in referential processing. This demonstrates one way in which the spoken language comprehension system copes with occasional misguidance of otherwise helpful probabilistic information. PMID:25015025

  12. 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. PMID:16803934

  13. The effects of age on the strategic use of pitch accents in memory for discourse: A processing-resource account

    PubMed Central

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

    2011-01-01

    In two experiments, we investigated age-related changes in how prosodic pitch accents affect memory. Participants listened to recorded discourses that contained two contrasts between pairs of items (e.g. one story contrasted British scientists with French scientists and Malaysia with Indonesia). The end of each discourse referred to one item from each pair; these references received a pitch accent that either denoted contrast (L+H* in the ToBI system) or did not (H*). A contrastive accent on a particular pair improved later recognition memory equally for young and older adults. However, older adults showed decreased memory if the other pair received a contrastive accent (Experiment 1). Young adults with low working memory performance also showed this penalty (Experiment 2). These results suggest that pitch accents guide processing resources to important information for both older and younger adults, but diminish memory for less important information in groups with reduced resources, including older adults. PMID:21639646

  14. 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

  15. Fas-mediated apoptosis of melanoma cells and infiltrating lymphocytes in human malignant melanomas.

    PubMed

    Shukuwa, Tetsuo; Katayama, Ichiro; Koji, Takehiko

    2002-04-01

    In a rodent system, melanoma cells expressing Fas ligand (FasL) could kill Fas-positive lymphocytes, suggesting that FasL expression was an essential factor for melanoma cell survival in vivo. These findings led us to investigate apoptosis, and to histochemically analyze involvement of Fas and FasL in the induction of apoptosis, in human malignant melanoma tissues. The percentages of terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end-labeling (TUNEL)-positive melanoma cells and of proliferating cell nuclear antigen (PCNA)-positive melanoma cells in melanoma tissues (n = 22) were greater than those in melanocytes in uninvolved skin (n = 6) and nevus cells in nevi tissues (n = 9). The infiltrating lymphocytes around melanomas were also TUNEL positive. Immunohistochemistry revealed expression of Fas and FasL in melanoma cells and lymphocytes, whereas no Fas or FasL expression was detected in normal skin melanocytes and nevus cells. There was significant correlation between Fas-positive indices and TUNEL indices in melanoma tissues. Moreover, TUNEL-, Fas-, and FasL-positive indices of melanoma cells from patients with Stage 3 melanomas were significantly lower than those with Stage 2 melanomas. The PCNA index of Stage 1 melanoma was significantly lower than that of the other stages, although the difference of PCNA index was insignificant among Stages 2 to 4. Among Stages 1 to 4, there was no difference in the PCNA, TUNEL-, and Fas-positive indices of lymphocytes, although the FasL-positive index of lymphocytes from Stage 3 melanomas was significantly lower than in that from Stage 2. These data reveal that melanoma cells and infiltrating lymphocytes have the potential to induce their own apoptosis regulated by Fas and FasL in an autocrine and/or paracrine fashion and that the decline of Fas-mediated apoptosis of melanoma cells, rather than the apoptosis of infiltrating lymphocytes, may affect the prognosis of melanoma patients, possibly through the

  16. Effect of insoluble extracellular matrix molecules on Fas expression in epithelial cells.

    PubMed

    Fine, A; Miranda, K; Farmer, S R; Anderson, N L

    1998-03-01

    Fas, which functions to initiate a signal causing apoptosis, is expressed in epithelia, thus, suggesting a role in controlling cell number during states of cell and matrix turnover. In view of this, we hypothesized that cell-matrix interactions may be an important determinant of Fas expression in epithelial cells. To investigate this, we examined the effect of insoluble extracellular matrix molecules on Fas expression in murine lung epithelial (MLE) cells, a transformed mouse lung epithelial cell line. We report that 1) insoluble extracellular matrices increased Fas mRNA in a time and concentration-dependent manner; 2) induced increases in Fas mRNA were associated with concomitantly increased Fas protein; and 3) nonspecific adherence to a polylysine substrate did not induce Fas mRNA. Consistent with these findings, Fas-induced apoptosis was significantly enhanced in cultures plated on type IV collagen. Employing rat hepatocytes, we confirmed that the insoluble extracellular matrix also increases Fas expression in primary epithelial cells. By amplifying Fas-mediated apoptosis, these data suggest a mechanism whereby the extracellular matrix regulates the fate of specific epithelial cell populations. PMID:9462690

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

    PubMed

    Kokkonen, Tuomo S; Karttunen, Tuomo J

    2015-12-01

    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

  18. 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…

  19. 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. PMID:26869716

  20. Splenectomy promotes indirect elimination of intraocular tumors by CD8+ T cells that is associated with IFNγ- and Fas/FasL-dependent activation of intratumoral macrophages.

    PubMed

    Miller, Maxine R; Mandell, Jonathan B; Beatty, Kelly M; Harvey, Stephen A K; Rizzo, Michael J; Previte, Dana M; Thorne, Stephen H; McKenna, Kyle C

    2014-12-01

    Ocular immune privilege (IP) limits the immune surveillance of intraocular tumors as certain immunogenic tumor cell lines (P815, E.G7-OVA) that are rejected when transplanted in the skin grow progressively when placed in the anterior chamber of the eye. As splenectomy (SPLNX) is known to terminate ocular IP, we characterized the immune mechanisms responsible for rejection of intraocular tumors in SPLNX mice as a first step toward identifying how to restore tumoricidal activity within the eye. CD8(+) T cells, IFNγ, and FasL, but not perforin, or TNFα were required for the elimination of intraocular E.G7-OVA tumors that culminated in destruction of the eye (ocular phthisis). IFNγ and FasL did not target tumor cells directly as the majority of SPLNX IFNγR1(-/-) mice and Fas-defective lpr mice failed to eliminate intraocular E.G7-OVA tumors that expressed Fas and IFNγR1. Bone marrow chimeras revealed that IFNγR1 and Fas expression on immune cells was most critical for rejection, and SPLNX increased the frequency of activated macrophages (Mϕ) within intraocular tumors in an IFNγ- and Fas/FasL-dependent manner, suggesting an immune cell target of IFNγ and Fas. As depletion of Mϕs limited CD8 T cell-mediated rejection of intraocular tumors in SPLNX mice, our data support a model in which IFNγ- and Fas/FasL-dependent activation of intratumoral Mϕs by CD8(+) T cells promotes severe intraocular inflammation that indirectly eliminates intraocular tumors by inducing phthisis, and suggests that immunosuppressive mechanisms that maintain ocular IP interfere with the interaction between CD8(+) T cells and Mϕs to limit the immunosurveillance of intraocular tumors. PMID:25248763

  1. Piperlongumine alleviates lupus nephritis in MRL-Fas(lpr) mice by regulating the frequency of Th17 and regulatory T cells.

    PubMed

    Yao, Lan; Chen, Hai-ping; Ma, Qing

    2014-09-01

    Recent data have shown that piperlongumine (PL), an important component of Piper longum fruits, is known to possess anti-inflammatory and vascular-protective activities. This study aimed to examine the therapeutic effects and underlying mechanisms of PL on lupus-prone MRL-Fas(lpr) mice. Female MRL-Fas(lpr) mice were intraperitoneally treated with PL (2.4 mg kg(-1) d(-1)) for 10 weeks, and the proteinuria level was biweekly monitored. After the mice were euthanized, serum biochemical parameters and renal damage were determined. Splenocytes of MRL-Fas(lpr) mice were isolated for in vitro study. Treatment of the mice with PL significantly attenuated the progression of proteinuria and glomerulonephritis. The improvement was accompanied by decreased serum levels of nephritogenic anti-dsDNA antibodies, IL-6, IL-17, IL-23 and TNF-α. Treatment of the mice with PL suppressed the frequency of Th17 cells and increased the regulatory T cells (Tregs). In vitro, the levels of IL-6, IL-17, IL-23 and TNF-α were significantly decreased in the cultures of splenocytes from PL-treated mice compared with those from vehicle-treated mice. In addition, PL treatment impeded activation of the JAK/STAT3 signaling in splenocytes. Of great important, the survival of MRL-Fas(lpr) mice were improved by PL treatment. In summary, PL effectively ameliorates lupus syndrome in MRL-Fas(lpr) mice by suppressing the pathogenic Th17 cells and increasing the Tregs as well as inhibiting activation of the JAK/STAT3 signaling pathway. This study sheds new light on the immune-modulatory role of PL. PMID:24837470

  2. 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…

  3. Age Matters, and so May Raters: Rater Differences in the Assessment of Foreign Accents

    ERIC Educational Resources Information Center

    Huang, Becky H.; Jun, Sun-Ah

    2015-01-01

    Research on the age of learning effect on second language learners' foreign accents utilizes human judgments to determine speech production outcomes. Inferences drawn from analyses of these ratings are then used to inform theories. The present study focuses on rater differences in the age of learning effect research. Three groups of raters who…

  4. 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…

  5. The Processing of the Right-Sided Accent Mark in Left Neglect Dyslexia

    ERIC Educational Resources Information Center

    Cubelli, Roberto; Beschin, Nicoletta

    2005-01-01

    Italian polysyllabic words with stress falling on the last syllable are written with a diacritic sign on the last vowel. It allows discrimination between two words with the same orthographic segments (e.g., papa [pope], papa [dad]). The effect of the accent mark in left neglect dyslexia has never been investigated. In the current study, six…

  6. 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,…

  7. 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…

  8. 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).…

  9. 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…

  10. Comprehension of Familiar and Unfamiliar Native Accents under Adverse Listening Conditions

    ERIC Educational Resources Information Center

    Adank, Patti; Evans, Bronwen G.; Stuart-Smith, Jane; Scott, Sophie K.

    2009-01-01

    This study aimed to determine the relative processing cost associated with comprehension of an unfamiliar native accent under adverse listening conditions. Two sentence verification experiments were conducted in which listeners heard sentences at various signal-to-noise ratios. In Experiment 1, these sentences were spoken in a familiar or an…

  11. 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…

  12. 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,…

  13. 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…

  14. 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…

  15. Learning to contend with accents in infancy: benefits of brief speaker exposure.

    PubMed

    van Heugten, Marieke; Johnson, Elizabeth K

    2014-02-01

    Although adults rapidly adjust to accented speakers' pronunciation of words, young children appear to struggle when confronted with unfamiliar variants of their native language (e.g., American English-learning 15-month-olds cannot recognize familiar words spoken in Jamaican English; Best et al., 2009). It is currently unclear, however, why this is the case, or how infants overcome this apparent inability. Here, we begin to address these crucial questions. Experiments 1 and 2 confirm with a new population that infants are initially unable to recognize familiar words produced in unfamiliar accents. That is, Canadian English-learning infants cannot recognize familiar words spoken in Australian English until they near their second birthday. However, Experiments 3 and 4 show that this early inability to recognize accented words can readily be overcome when infants are exposed to a story read in the unfamiliar accent prior to test. Importantly, this adaptation only occurs when the story is highly familiar, consistent with the idea that top-down lexical feedback may enable the adaptation process. We conclude that infants, like adults, have the cognitive capacity to rapidly deduce the mapping between their own and an unfamiliar variant of their native language. Thus, the essential machinery underlying spoken language communication is in place much earlier than previous studies have suggested. PMID:23506084

  16. 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…

  17. 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…

  18. 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…

  19. 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

  20. 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. PMID:25618072

  1. The Sound of German: Descriptions of Accent by Native and Non-Native Listeners

    ERIC Educational Resources Information Center

    Wilkerson, Miranda E.

    2013-01-01

    This paper presents a study of factors affecting judgments of native and non-native accent in German. The data suggest that listener status (native or non-native speakers) and degree of experience with German play a role in the aspects of speech which raters cite as salient. Interestingly, the same descriptive terms used by raters were shown to…

  2. 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…

  3. 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…

  4. 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…

  5. Plasticity in speech production and perception: A study of accent change in young adults

    NASA Astrophysics Data System (ADS)

    Evans, Bronwen G.; Iverson, Paul

    2005-04-01

    This study investigated plasticity in speech production and perception among university students, as individuals change their accent from regional to educated norms. Subjects were tested before beginning university, 3 months later and on completion of their first year of study. At each stage they were recorded reading a set of test words and a short passage. They also completed two perceptual tasks; they found best exemplar locations for vowels embedded in carrier sentences and identified words in noise. The results demonstrated that subjects changed their spoken accent after attending university. The changes were linked to sociolinguistic factors; subjects who were highly motivated to fit in with their university community changed their accent more. There was some evidence for a link between production and perception; between-subject differences in production and perception were correlated. However, this relationship was weaker for within-subject changes in accent over time. The results suggest that there were limitations in the ability of these subjects to acquire new phonological rules.

  6. 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. PMID:27036250

  7. Abnormal structural luteolysis in ovaries of the senescence accelerated mouse (SAM): expression of Fas ligand/Fas-mediated apoptosis signaling molecules in luteal cells.

    PubMed

    Kiso, Minako; Manabe, Noboru; Komatsu, Kohji; Shimabe, Munetake; Miyamoto, Hajime

    2003-12-01

    Senescence accelerated mouse-prone (SAMP) mice with a shortened life span show accelerated changes in many of the signs of aging and a shorter reproductive life span than SAM-resistant (SAMR) controls. We previously showed that functional regression (progesterone dissimilation) occurs in abnormally accumulated luteal bodies (aaLBs) of SAMP mice, but structural regression of luteal cells in aaLB is inhibited. A deficiency of luteal cell apoptosis causes the abnormal accumulation of LBs in SAMP ovaries. In the present study, to show the abnormality of Fas ligand (FasL)/Fas-mediated apoptosis signal transducing factors in the aaLBs of the SAMP ovaries, we assessed the changes in the expression of FasL, Fas, caspase-8 and caspase-3 mRNAs by reverse transcription-polymerase chain reaction, and in the expression and localization of FasL, Fas and activated caspase-3 proteins by Western blotting and immunohistochemistry, respectively, during the estrus cycle/luteolysis. These mRNAs and proteins were expressed in normal LBs of both SAMP and SAMR ovaries, but not at all or only in trace amounts in aaLBs of SAMP, indicating that structural regression is inhibited by blockage of the expression of these transducing factors in luteal cells of aaLBs in SAMP mice. PMID:14967896

  8. 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... quantifiable product or country or region goals. These performance indicators are part of FAS'...

  9. Therapeutic Use of Soluble Fas Ligand Ameliorates Acute and Recurrent Herpetic Stromal Keratitis in Mice

    PubMed Central

    Rogge, Megan; Yin, Xiao-Tang; Godfrey, Lisa; Lakireddy, Priya; Potter, Chloe A.; Del Rosso, Chelsea R.; Stuart, Patrick M.

    2015-01-01

    Purpose The present study was designed to test the therapeutic value of soluble FasL (sFasL) in an acute model of herpetic stromal keratitis (HSK) and, more importantly, a recurrent model of HSK using BALB/c, BALB-lpr, and National Institutes of Health (NIH) mice. Methods Mice were infected either acutely with the KOS strain of herpes simplex virus 1 (HSV-1) or latently with the McKrae strain of HSV-1. Acutely infected mice as well as ultraviolet-B (UV-B) reactivated mice (recurrent infection) were treated with sFasL, or soluble TNF-related apoptosis inducing ligand (sTRAIL), or BSA daily or 3 times/wk by using either a combination of subconjunctival injection and topical ointment, or with topical ointment alone. These mice then were evaluated for corneal opacity and neovascularization for 6 weeks. Results Following acute and recurrent HSV-1 infection, wild-type BALB/c mice treated with sFasL displayed significantly reduced incidence of corneal opacity and neovascularization compared to the control animals. However, BALB-lpr mice, which are deficient in Fas+ inflammatory cells, displayed no such differences in ocular disease, as expected. Latently infected NIH mice treated with sFasL displayed similar results. Flow cytometric analysis revealed that the corneal inflammatory infiltrate in those treated with sFasL was significantly less than in sTRAIL- or BSA-treated mice. Furthermore, corneas from sFasL-treated mice displayed relatively more cells undergoing apoptosis. Conclusions This study provides evidence that sFasL treatment has potential therapeutic benefit in reducing inflammatory infiltrate and neovascularization in primary and recurrent forms of HSK, and that it does so by augmenting the restriction of Fas+ inflammatory cells mediated by membrane FasL. PMID:26444718

  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. Expression of Fas ligand by human gastric adenocarcinomas: a potential mechanism of immune escape in stomach cancer

    PubMed Central

    Bennett, M; O'Connell, J; O'Sullivan, G; Roche, D; Brady, C; Kelly, J; Collins, J; Shanahan, F

    1999-01-01

    Background—Despite being immunogenic, gastric cancers overcome antitumour immune responses by mechanisms that have yet to be fully elucidated. Fas ligand (FasL) is a molecule that induces Fas receptor mediated apoptosis of activated immunocytes, thereby mediating normal immune downregulatory roles including immune response termination, tolerance acquisition, and immune privilege. Colon cancer cell lines have previously been shown to express FasL and kill lymphoid cells by Fas mediated apoptosis in vitro. Many diverse tumours have since been found to express FasL suggesting that a "Fas counterattack" against antitumour immune effector cells may contribute to tumour immune escape. 
Aim—To ascertain if human gastric tumours express FasL in vivo, as a potential mediator of immune escape in stomach cancer. 
Specimens—Thirty paraffin wax embedded human gastric adenocarcinomas. 
Methods—FasL protein was detected in gastric tumours using immunohistochemistry; FasL mRNA was detected in the tumours using in situ hybridisation. Cell death was detected in situ in tumour infiltrating lymphocytes using terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL). 
Results—Prevalent expression of FasL was detected in all 30 resected gastric adenocarcinomas examined. In the tumours, FasL protein and mRNA were co-localised to neoplastic gastric epithelial cells, confirming expression by the tumour cells. FasL expression was independent of tumour stage, suggesting that it may be expressed throughout gastric cancer progression. TUNEL staining disclosed a high level of cell death among lymphocytes infiltrating FasL positive areas of tumour. 
Conclusions—Human gastric adenocarcinomas express the immune downregulatory molecule, FasL. The results suggest that FasL is a prevalent mediator of immune privilege in stomach cancer. 

 Keywords: Fas ligand; gastric cancer; immune escape; apoptosis; tumour; mRNA PMID:9895372

  12. 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…

  13. 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)

  14. Silencing of fas, fas-associated via death domain, or caspase 3 differentially affects lung inflammation, apoptosis, and development of trauma-induced septic acute lung injury.

    PubMed

    Messer, Mirko Philipp; Kellermann, Philipp; Weber, Sascha Jörn; Hohmann, Christoph; Denk, Stephanie; Klohs, Bettina; Schultze, Anke; Braumüller, Sonja; Huber-Lang, Markus Stefan; Perl, Mario

    2013-01-01

    Activation of Fas signaling is a potentially important pathophysiological mechanism in the development of septic acute lung injury (ALI). However, so far the optimal targets within this signaling cascade remain elusive. Thus, we tested the hypothesis that in vivo gene silencing of Fas, Fas-associated via death domain (FADD), or caspase 3 by intratracheal administration of small interfering RNA would ameliorate ALI in a clinically relevant double-hit mouse model of trauma induced septic lung injury. Male C57Bl/6 mice received small interfering (Fas, FADD, caspase 3) or control RNA 24 h before and 12 h after blunt chest trauma or sham procedures. Polymicrobial sepsis was induced by cecal ligation and puncture 24 h after chest trauma. Twelve or 24 h later, lung tissue, plasma, and bronchoalveolar lavage fluid were harvested. During ALI, lung apoptosis (active caspase 3 Western blotting, TUNEL staining) was substantially increased when compared with sham. Silencing of caspase 3 or FADD both markedly reduced pulmonary apoptosis. Fas- and FADD-small interfering RNA administration substantially decreased lung cytokine concentration, whereas caspase 3 silencing did not reduce lung inflammation. In addition, Fas silencing markedly decreased lung neutrophil infiltration. Interestingly, only in response to caspase 3 silencing, ALI-induced lung epithelial barrier dysfunction was substantially improved, and histological appearance was beneficially affected. Taken together, downstream inhibition of lung apoptosis via caspase 3 silencing proved to be superior in mitigating ALI when compared with upstream inhibition of apoptosis via Fas or FADD silencing, even in the presence of additional anti-inflammatory effects. This indicates a major pathophysiological role of lung apoptosis and suggests the importance of other than Fas-driven apoptotic pathways in trauma-induced septic ALI. PMID:23247118

  15. Depletion of resident alveolar macrophages does not prevent Fas-mediated lung injury in mice.

    PubMed

    Bem, R A; Farnand, A W; Wong, V; Koski, A; Rosenfeld, M E; van Rooijen, N; Frevert, C W; Martin, T R; Matute-Bello, G

    2008-08-01

    Activation of the Fas/Fas ligand (FasL) system in the lungs results in a form of injury characterized by alveolar epithelial apoptosis and neutrophilic inflammation. Studies in vitro show that Fas activation induces apoptosis in alveolar epithelial cells and cytokine production in alveolar macrophages. The main goal of this study was to determine the contribution of alveolar macrophages to Fas-induced lung inflammation in mice, by depleting alveolar macrophages using clodronate-containing liposomes. Liposomes containing clodronate or PBS were instilled by intratracheal instillation. After 24 h, the mice received intratracheal instillations of the Fas-activating monoclonal antibody Jo2 or an isotype control antibody and were studied 18 h later. The Jo2 MAb induced increases in bronchoalveolar lavage fluid (BALF) total neutrophils, lung caspase-3 activity, and BALF total protein and worsened histological lung injury in the macrophage-depleted mice. Studies in vitro showed that Fas activation induced the release of the cytokine KC in a mouse lung epithelial cell line, MLE-12. These results suggest that the lung inflammatory response to Fas activation is not primarily dependent on resident alveolar macrophages and may instead depend on cytokine release by alveolar epithelial cells. PMID:18556802

  16. 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

  17. 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.

  18. Fas signaling promotes chemoresistance in gastrointestinal cancer by up-regulating P-glycoprotein

    PubMed Central

    Wang, Yadong; Lin, Shiyong; Chen, Jinmin; Wang, Jing; Wang, Zhiqing; Jiang, Bo

    2014-01-01

    Fas signaling promotes metastasis of gastrointestinal (GI) cancer cells by inducing epithelial-mesenchymal transition (EMT), and EMT acquisition has been found to cause cancer chemoresistance. Here, we demonstrated that the response to chemotherapy of GI cancer patients with higher expression of FasL was significantly worse than patients with lower expression. Fas-induced activation of the ERK1/2-MAPK pathway decreased the sensitivity of GI cancer cells to chemotherapeutic agents and promoted the expression of P-glycoprotein (P-gp). FasL promoted chemoresistance of GI cancer cell via upregulation of P-gp by increasing β-catenin and decreasing miR-145. β-catenin promoted P-gp gene transcription by binding with P-gp promoter while miR-145 suppressed P-gp expression by interacting with the mRNA 3′UTR of P-gp. Immunostaining and qRT-PCR analysis of human GI cancer samples revealed a positive association among FasL, β-catenin, and P-gp, but a negative correlation between miR-145 and FasL or P-gp. Altogether, our results showed Fas signaling could promote chemoresistance in GI cancer through modulation of P-gp expression by β-catenin and miR-145. Our findings suggest that Fas signaling-based cancer therapies should be administered cautiously, as activation of this pathway may not only lead to apoptosis but also induce chemoresistance. PMID:25333257

  19. Activated T cell exosomes promote tumor invasion via Fas signaling pathway.

    PubMed

    Cai, Zhijian; Yang, Fei; Yu, Lei; Yu, Zhou; Jiang, Lingling; Wang, Qingqing; Yang, Yunshan; Wang, Lie; Cao, Xuetao; Wang, Jianli

    2012-06-15

    Activated T cells release bioactive Fas ligand (FasL) in exosomes, which subsequently induce self-apoptosis of T cells. However, their potential effects on cell apoptosis in tumors are still unknown. In this study, we purified exosomes expressing FasL from activated CD8(+) T cell from OT-I mice and found that activated T cell exosomes had little effect on apoptosis and proliferation of tumor cells but promoted the invasion of B16 and 3LL cancer cells in vitro via the Fas/FasL pathway. Activated T cell exosomes increased the amount of cellular FLICE inhibitory proteins and subsequently activated the ERK and NF-κB pathways, which subsequently increased MMP9 expression in the B16 murine melanoma cells. In a tumor-invasive model in vivo, we observed that the activated T cell exosomes promoted the migration of B16 tumor cells to lung. Interestingly, pretreatment with FasL mAb significantly reduced the migration of B16 tumor cells to lung. Furthermore, CD8 and FasL double-positive exosomes from tumor mice, but not normal mice, also increased the expression of MMP9 and promoted the invasive ability of B16 murine melanoma and 3LL lung cancer cells. In conclusion, our results indicate that activated T cell exosomes promote melanoma and lung cancer cell metastasis by increasing the expression of MMP9 via Fas signaling, revealing a new mechanism of tumor immune escape. PMID:22573809

  20. A Fail-safe Mechanism for Negative Selection of Isotype-switched B Cell Precursors Is Regulated by the Fas/FasL Pathway

    PubMed Central

    Seagal, Jane; Edry, Efrat; Keren, Zohar; Leider, Nira; Benny, Ofra; Machluf, Marcelle; Melamed, Doron

    2003-01-01

    In B lymphocytes, immunoglobulin (Ig)M receptors drive development and construction of naive repertoire, whereas IgG receptors promote formation of the memory B cell compartment. This isotype switching process requires appropriate B cell activation and T cell help. In the absence of T cell help, activated B cells undergo Fas-mediated apoptosis, a peripheral mechanism contributing to the establishment of self-tolerance. Using Igμ-deficient μMT mouse model, where B cell development is blocked at pro-B stage, here we show an alternative developmental pathway used by isotype-switched B cell precursors. We find that isotype switching occurs normally in B cell precursors and is T independent. Ongoing isotype switching was found in both normal and μMT B cell development as reflected by detection of IgG1 germline and postswitch transcripts as well as activation-induced cytidine deaminase expression, resulting in the generation of IgG-expressing cells. These isotype-switched B cells are negatively selected by Fas pathway, as blocking the Fas/FasL interaction rescues the development of isotype-switched B cells in vivo and in vitro. Similar to memory B cells, isotype-switched B cells have a marginal zone phenotype. We suggest a novel developmental pathway used by isotype-switched B cell precursors that effectively circumvents peripheral tolerance requirements. This developmental pathway, however, is strictly controlled by Fas/FasL interaction to prevent B cell autoimmunity. PMID:14623914

  1. Distribution of apoptosis-mediating Fas antigen in human skin and effects of anti-Fas monoclonal antibody on human epidermal keratinocyte and squamous cell carcinoma cell lines.

    PubMed

    Oishi, M; Maeda, K; Sugiyama, S

    1994-01-01

    Fast antigen is a cell surface protein that mediates apoptosis. Using immunohistological, flow cytometry and electron microscopic analyses, we investigated the expression of Fas antigen on various skin tissues, and on cultured SV40-transformed human epidermal keratinocyte cell line KJD and human skin squamous cell carcinoma cell line HSC. The Fas antigen was widely distributed in skin components such as the keratinocytes in the lower portion of the epidermis, epidermal dendritic cells, endothelial cells, fibroblasts, apocrine glands, eccrine sweat glands, sebaceous glands, some normal melanocytes and infiltrating lymphoid cells. It was also strongly expressed on the keratinocytes of lichenoid eruptions seen in lupus erythematosus and lichen planus, and on the spongiotic or acanthotic epidermis seen in chronic eczema, adult T-cell leukaemia/lymphoma (ATLL) and atopic dermatitis. Its expression was closely correlated with lymphoid infiltrating cells and it was strongly expressed in lymphoid neoplastic cells, particularly ATLL cells, and fibroblasts seen in dermatofibroma. However, the antigen was not detected on basal cell epithelioma cells, some malignant melanomas or any junctional naevi. The cell lines KJD and HSC strongly expressed the Fas antigen, and crosslinking of the Fas antigen by an anti-Fas monoclonal antibody induced apoptosis of these cell lines. These results indicate that the apoptosis-mediating Fas antigen may play an important role in normal skin turnover and cell differentiation, in immune regulation of skin tumours, and in the pathogenesis of various skin diseases. PMID:7529480

  2. Cryo-EM structure of fatty acid synthase (FAS) from Rhodosporidium toruloides provides insights into the evolutionary development of fungal FAS

    PubMed Central

    Fischer, Manuel; Rhinow, Daniel; Zhu, Zhiwei; Mills, Deryck J; Zhao, Zongbao K; Vonck, Janet; Grininger, Martin

    2015-01-01

    Fungal fatty acid synthases Type I (FAS I) are up to 2.7 MDa large molecular machines composed of large multifunctional polypeptides. Half of the amino acids in fungal FAS I are involved in structural elements that are responsible for scaffolding the elaborate barrel-shaped architecture and turning fungal FAS I into highly efficient de novo producers of fatty acids. Rhodosporidium toruloides is an oleaginous fungal species and renowned for its robust conversion of carbohydrates into lipids to over 70% of its dry cell weight. Here, we use cryo-EM to determine a 7.8-Å reconstruction of its FAS I that reveals unexpected features; its novel form of splitting the multifunctional polypeptide chain into the two subunits α and β, and its duplicated ACP domains. We show that the specific distribution into α and β occurs by splitting at one of many possible sites that can be accepted by fungal FAS I. While, therefore, the specific distribution in α and β chains in R. toruloides FAS I is not correlated to increased protein activities, we also show that the duplication of ACP is an evolutionary late event and argue that duplication is beneficial for the lipid overproduction phenotype. PMID:25761671

  3. 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

    2015-01-01

    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

  4. 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

  5. Perception of acoustic cues to Tokyo Japanese pitch-accent contrasts in native Japanese and naive English listeners.

    PubMed

    Shport, Irina A

    2015-07-01

    This study examines how native language shapes the perception of a prosodic contrast. In Tokyo Japanese, a high-low pitch accent is a lexical property of a word, and the F0 fall after the peak associated with the accented syllable is the fundamental cue to accent perception. In English, pitch accents do not create lexically contrastive F0 patterns. A hypothesis that English listeners naive to Japanese use the F0 fall cue less than Japanese listeners was tested in two experiments. The alignment of F0 peak, the presence and magnitude of F0 fall were manipulated in a trisyllabic nonword to resynthesize Japanese 1st-syllable accented, 2nd-syllable accented, and unaccented patterns. In an AX-discrimination experiment, both listener groups showed sensitivity to the presence of F0 fall at every peak location. In a categorization experiment, the English group did not use the F0 fall cue in decisions about whether the 1st or the 2nd syllable sounded more prominent. The Japanese group relied on the F0 fall information, some listeners much heavily than others. These findings suggest that one's native language constrains how much attention the prosodic dimension of F0 change receives and that individual listeners may have qualitatively different perceptual strategies. PMID:26233031

  6. Zinc Induces Apoptosis of Human Melanoma Cells, Increasing Reactive Oxygen Species, p53 and FAS Ligand.

    PubMed

    Provinciali, Mauro; Pierpaoli, Elisa; Bartozzi, Beatrice; Bernardini, Giovanni

    2015-10-01

    The aim of this study was to examine the in vitro effect of zinc on the apoptosis of human melanoma cells, by studying the zinc-dependent modulation of intracellular levels of reactive oxygen species (ROS) and of p53 and FAS ligand proteins. We showed that zinc concentrations ranging from 33.7 μM to 75 μM Zn(2+) induced apoptosis in the human melanoma cell line WM 266-4. This apoptosis was associated with an increased production of intracellular ROS, and of p53 and FAS ligand protein. Treatment of tumor cells with the antioxidant N-acetylcysteine was able to prevent Zn(2+)-induced apoptosis, as well as the increase of p53 and FAS ligand protein induced by zinc. Zinc induces apoptosis in melanoma cells by increasing ROS and this effect may be mediated by the ROS-dependent induction of p53 and FAS/FAS ligand. PMID:26408691

  7. Vowel normalization for accent: An investigation of perceptual plasticity in young adults

    NASA Astrophysics Data System (ADS)

    Evans, Bronwen G.; Iverson, Paul

    2001-05-01

    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.

  8. Life Expectancy of People with Fetal Alcohol Syndrome.

    PubMed

    Thanh, Nguyen Xuan; Jonsson, Egon

    2016-01-01

    ObjectivesTo estimate the life expectancy and specify the causes of death among people with fetal alcohol syndrome (FAS). MethodsIncluded were all patients recorded in Alberta provincial databases of inpatients, outpatients, or practitioner claims from 2003 to 2012. People with FAS were identified by ICD-9 code 760.71 and ICD-10 codes Q86.0 and P04.3, and were linked to the Vital Statistics Death Registry to get information about mortality. Life expectancy was estimated by using the life table template developed in the United Kingdom, which is recommended for estimating life expectancy in small areas or populations. ResultsThe life expectancy at birth of people with FAS was 34 years (95% confidence interval: 31 to 37 years), which was about 42% of that of the general population. The leading causes of death for people with FAS were "external causes" (44%), which include suicide (15%), accidents (14%), poisoning by illegal drugs or alcohol (7%), and other external causes (7%). Other common causes of death were diseases of the nervous and respiratory systems (8% each), diseases of the digestive system (7%), congenital malformations (7%), mental and behavioural disorders (4%), and diseases of the circulatory system (4%). ConclusionThe life expectancy of people with FAS is considerably lower than that of the general population. As the cause of FAS is known and preventable, more attention devoted to the prevention of FAS is urgently needed. PMID:26962962

  9. Expression of apoptotic regulatory molecules in renal cell carcinoma: elevated expression of Fas ligand.

    PubMed

    Olive, C; Cheung, C; Nicol, D; Falk, M C

    1999-02-01

    Renal cell carcinoma (RCC) is the most common renal neoplasm. Despite being infiltrated by tumour infiltrating lymphocytes (TIL), these TIL are unable to control tumour growth in vivo, suggesting that the cytotoxic capacity of TIL against RCC is impaired, or that the tumour cells are resistant to killing and therefore escape detection by the immune system. It is postulated that the expression of apoptotic regulatory molecules in RCC favours tumour cell survival. The present study has therefore determined the expression of Fas (APO-1/CD95), Fas ligand (Fas L) and bcl-2 in these tumours. The expression of Fas, Fas L and bcl-2 mRNA transcripts was determined in RCC, normal kidney and peripheral blood by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), following RNA extraction and cDNA synthesis from tissues and cell samples. Transcript levels were measured by densitometry after Southern blot hybridization of PCR products with internal radio-labelled oligonucleotide probes; a densitometry score was assigned to each hybridizing DNA band and expressed as a ratio of the glyceraldehyde-3-phosphate dehydrogenase content. In peripheral blood, the expression of Fas L and bcl-2 transcripts was similar between patients and normal healthy individuals; however, Fas transcript expression was significantly down-regulated in the patients' versus normal peripheral blood (P = 0.026). Most interestingly, significantly up-regulated Fas L expression was observed in RCC compared to normal kidney (P = 0.041). In contrast, bcl-2 transcripts were well represented in normal kidney but markedly decreased in RCC (P = 0.021). The expression of Fas transcripts in normal kidney and RCC was variable. These data demonstrate elevated expression of Fas L transcripts in RCC, but the functional relevance of this remains to be investigated. PMID:10101681

  10. Circulating and Hepatic Fas Expression in HCV-Induced Chronic Liver Disease and Hepatocellular Carcinoma

    PubMed Central

    El Bassiouny, Azza E. I.; El-Bassiouni, Nora E. I.; Nosseir, Mona M. F.; Zoheiry, Mona M.K.; El-Ahwany, Eman G.; Salah, Faten; Omran, Zeinab S.O.; Ibrahim, Raafat A.

    2008-01-01

    Apoptosis is central for control and elimination of viral infections. In chronic hepatitis C virus (HCV) infection, enhanced hepatocyte apoptosis and upregulation of the death-inducing ligands CD95/Fas occur. This study aimed to study the role of serum soluble Fas and hepatic Fas expression as early predictors of advancement of chronic hepatitis C disease. The current study included 50 cases of chronic hepatitis C (CHC) (and negative hepatitis B virus infection), 30 cases of liver cirrhosis (LC) and HCV, and 20 cases of hepatocellular carcinoma (HCC) and HCV admitted to Theodor Bilharz Research Institute, Giza, Egypt. Fifteen wedge liver biopsies, taken during laparoscopic cholecystectomy, were included in the study as normal controls. Assessment of serum soluble Fas level (sFas) and other laboratory investigations, including liver function tests, serologic markers for viral hepatitis, and serum alpha-fetoprotein level (alpha-FP), were determined for all cases. Histopathologic study and immunohistochemistry using monoclonal antibody for CD95 were also done. The sFas was significantly increased in CHC, LC, and HCC cases compared with normal controls (P < .01). The increase of sFas in HCC was also significantly higher than that of CHC (P < .01). However, positive hepatic expression of Fas antigen was higher in CHC than LC with no significant difference; meanwhile, it was significantly lower in HCC (P < .01) compared with CHC. In conclusion, circulating and hepatic Fas expression in chronic hepatitis C infection illustrate the mechanism of liver injury caused by death receptors throughout the multistep process of fibrosis/carcinogenesis. Not only the higher degree of hepatic fibrosis, but also the lower expression of Fas protein, are correlated with the increased incidence of HCC. PMID:18679533

  11. Systemic FasL and TRAIL neutralisation reduce leishmaniasis induced skin ulceration.

    PubMed

    Tasew, Geremew; Nylén, Susanne; Lieke, Thorsten; Lemu, Befekadu; Meless, Hailu; Ruffin, Nicolas; Wolday, Dawit; Asseffa, Abraham; Yagita, Hideo; Britton, Sven; Akuffo, Hannah; Chiodi, Francesca; Eidsmo, Liv

    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

  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. PMID:26730801

  13. Correlation of insulin resistance, beta cell function and insulin sensitivity with serum sFas and sFasL in newly diagnosed type 2 diabetes.

    PubMed

    Kumar, Hemant; Mishra, Manish; Bajpai, Surabhi; Pokhria, Deepa; Arya, Awadhesh Kumar; Singh, Rakesh Kumar; Tripathi, Kamlakar

    2013-08-01

    Pancreatic beta cell dysfunction and reduced insulin sensitivity are fundamental factors associated with glucotoxicity, lipotoxicity and oxidative stress in type 2 diabetic patients (T2DM). Diabetic milieu can induce apoptosis in several types of cells. The aim of present study was to compare circulating soluble apoptotic markers (sFas and sFas-L) with HOMA-IR, HOMA-%S, HOMA-%B in the serum of newly diagnosed T2DM and healthy subjects. For this study, 94 T2DM and 60 healthy subjects were enroled and evaluated for various parameters. Biochemical quantifications were performed with Syncron CX5 auto-analyzer. The levels of serum sFas-L, TNF-α and IL-6 were estimated by flowcytometry. The fasting serum insulin and sFas quantified by ELISA. HOMA-IR, HOMA-%S and HOMA-%B were calculated with HOMA calculator v2.2.2. The levels of TC, TG, LDL-C, VLDL-C were augmented and HDL declined significantly (P < 0.001) in diabetics. The levels of serum insulin, TNF-α, IL-6, sFas, HOMA-IR were raised (P < 0.001) and sFas-L, HOMA-%S and HOMA-%B were decreased significantly (P < 0.001) in T2DM subjects than healthy. In diabetics, serum sFas was positively correlated with HOMA-IR (r = 0.720, P < 0.001) and negatively with HOMA-%B (r = -0.642, P < 0.001) significantly while serum sFasL was negatively correlated with HOMA-IR (r = -0.483, P < 0.001) and positively with HOMA-%B (r = 0.466, P < 0.001) significantly. Further, the multivariate stepwise regression analysis shows that HOMA-IR contributes significantly to the variance of sFas and sFasL. Our findings suggest that the pancreatic beta cell dysfunction along with increased insulin resistance appears to be associated with apoptotic markers. PMID:21695404

  14. Distinct role of the Fas rs1800682 and FasL rs763110 polymorphisms in determining the risk of breast cancer among Han Chinese females

    PubMed Central

    Wang, Meng; Wang, Zheng; Wang, Xi-Jing; Jin, Tian-Bo; Dai, Zhi-Ming; Kang, Hua-Feng; Guan, Hai-Tao; Ma, Xiao-Bin; Liu, Xing-Han; Dai, Zhi-Jun

    2016-01-01

    Background In recent years, studies have demonstrated that polymorphisms in the promoters of Fas and FasL are significantly associated with breast cancer risk. However, the results of these studies were inconsistent. This case–control study was performed to explore the associations between Fas rs1800682 and FasL rs763110 polymorphisms and breast cancer. Materials and methods A hospital-based case–control study of 560 Han Chinese females with breast cancer (583 controls) was conducted. The MassARRAY system was used to search for a possible association between the disease risk and the two single nucleotide polymorphisms, Fas rs1800682 and FasL rs763110. Statistical analyses were performed using SNPStats software to conduct Pearson’s chi-square tests in five different genetic models. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated after adjustment to age and body mass index. PHASE v2.1 software was used to reconstruct all common haplotypes. Results A statistically significant association was found between Fas rs1800682 and increased breast cancer risk (AG vs AA: OR =1.37, 95% CI =1.06–1.78; AA+AG vs GG: OR =1.32, 95% CI =1.04–1.66), and also it was found that the FasL rs763110 polymorphism may decrease the risk. Stratified analyses demonstrated that the rs763110 polymorphism was associated with lower breast cancer risk among postmenopausal females (heterozygote model: OR =0.69, 95% CI =0.49–0.97; dominant model: OR =0.70, 95% CI =0.51–0.96). The T allele of rs763110 was also associated with a decreased risk of lymph node metastasis (allele model: OR =0.75, 95% CI =0.57–0.97) and an increased risk of the breast cancer being human epidermal growth factor receptor 2 positive (allele model: OR =1.37, 95% CI =1.03–1.18). Moreover, haplotype analysis showed that Ars1800682Trs763110 was associated to a statistically significant degree with lower risk of breast cancer (OR =0.70, 95% CI =0.53–0.91). Conclusion These data suggest that

  15. 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

  16. Using the Internet to Disseminate Educational Material on Atmospheric Composition Change in ACCENT

    NASA Astrophysics Data System (ADS)

    Schuepbach, E.

    2005-12-01

    ACCENT (2004-08) is a Network of Excellence in Atmospheric Composition Change in Framework Programme VI of the European Union (www.accent-network.org). The task "Training and Education" aims at preparing the next generation of atmospheric scientists (up to 3 years after completion of a Ph.D.) for the future of scientific endeavour in the field. Educational events, courses, and training workshops will be offered both on subjects in the field of atmospheric composition change and on essential skills (e.g., communication, networking, interdisciplinarity), and will be paralleled by leadership sessions and Science Cafes to increase the expertise to a common level across Europe (including Accession countries). Integration of female scientists, and (young) scientists from newly associated and emerging countries will be realized through specific schemes (e.g., mentoring, fellowships). Training and Education in ACCENT also aims at triggering the use of New Information and Communication Technologies (NICT). Examples will be presented on the varied use of NICT to disseminate educational material on atmospheric composition change, both at the undergraduate and at the postgraduate level, and to teachers.

  17. Voice onset time and global foreign accent in mature Japanese-English bilinguals

    NASA Astrophysics Data System (ADS)

    Riney, Timothy J.

    2001-05-01

    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.

  18. Acoustic and perceptual effects of overall F0 range in a lexical pitch accent distinction

    NASA Astrophysics Data System (ADS)

    Wade, Travis

    2002-05-01

    A speaker's overall fundamental frequency range is generally considered a variable, nonlinguistic element of intonation. This study examined the precision with which overall F0 is predictable based on previous intonational context and the extent to which it may be perceptually significant. Speakers of Tokyo Japanese produced pairs of sentences differing lexically only in the presence or absence of a single pitch accent as responses to visual and prerecorded speech cues presented in an interactive manner. F0 placement of high tones (previously observed to be relatively variable in pitch contours) was found to be consistent across speakers and uniformly dependent on the intonation of the different sentences used as cues. In a subsequent perception experiment, continuous manipulation of these same sentences between typical accented and typical non-accent-containing versions were presented to Japanese listeners for lexical identification. Results showed that listeners' perception was not significantly altered in compensation for artificial manipulation of preceding intonation. Implications are discussed within an autosegmental analysis of tone. The current results are consistent with the notion that pitch range (i.e., specific vertical locations of tonal peaks) does not simply vary gradiently across speakers and situations but constitutes a predictable part of the phonetic specification of tones.

  19. 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.

  20. Egr family members regulate nonlymphoid expression of Fas ligand, TRAIL, and tumor necrosis factor during immune responses.

    PubMed

    Droin, Nathalie M; Pinkoski, Michael J; Dejardin, Emmanuel; Green, Douglas R

    2003-11-01

    The Fas ligand (FasL)/Fas pathway is crucial for homeostasis of the immune system and peripheral tolerance. Peripheral lymphocyte deletion involves FasL/Fas in at least two ways: coexpression of both Fas and its ligand on T cells, leading to activation-induced cell death, and expression of FasL by nonlymphoid cells, such as intestinal epithelial cells (IEC), that kill Fas-positive T cells. We demonstrate here that superantigen Staphylococcus enterotoxin B (SEB) induced a dramatic upregulation of FasL, TRAIL, and TNF mRNA expression and function in IEC from BALB/c and C57BL/6 mice. Using adoptive transfer in which CD4(+) T cells from OT-2 T-cell receptor transgenic mice were transferred into recipients, we observed an induction in IEC of FasL, TRAIL, and TNF mRNA after administration of antigen. Specific Egr-binding sites have been identified in the 5' promoter region of the FasL gene, and Egr-1, Egr-2, and Egr-3 mRNA in IEC from mice treated with SEB and from transgenic OT-2 mice after administration of antigen was upregulated. Overexpression of Egr-2 and Egr-3 induced endogenous ligand upregulation that was inhibited by overexpression of Egr-specific inhibitor Nab1. These results support a role for Egr family members in nonlymphoid expression of FasL, TRAIL, and TNF. PMID:14560009

  1. 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. PMID:26768135

  2. Evidence for a Novel, Caspase-8-Independent, Fas Death Domain-Mediated Apoptotic Pathway

    PubMed Central

    Katsanis, Emmanuel

    2004-01-01

    Certain caspase-8 null cell lines demonstrate resistance to Fas-induced apoptosis, indicating that the Fas/FasL apoptotic pathway may be caspase-8-dependent. Some reports, however, have shown that Fas induces cell death independent of caspase-8. Here we provide evidence for an alternative, caspase-8-independent, Fas death domain-mediated apoptotic pathway. Murine 12B1-D1 cells express procaspase-3, -8, and -9, which were activated upon the dimerization of Fas death domain. Bid was cleaved and mitochondrial transmembrane potential was disrupted in this apoptotic process. All apoptotic events were completely blocked by the broad-spectrum caspase inhibitor Z-VAD-FMK, but not by other peptide caspase inhibitors. Cyclosporin A (CsA), which inhibits mitochondrial transition pore permeability, blocked neither pore permeability disruption nor caspase activation. However, CsA plus caspase-8 inhibitor blocked all apoptotic events of 12B1-D1 induced by Fas death domain dimerization. Our data therefore suggest that there is a novel, caspase-8-independent, Z-VAD-FMK-inhibitable, apoptotic pathway in 12B1-D1 cells that targets mitochondria directly. PMID:15123887

  3. 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. PMID:17488926

  4. ATM kinase activity modulates Fas sensitivity through the regulation of FLIP in lymphoid cells.

    PubMed

    Stagni, Venturina; di Bari, Maria Giovanna; Cursi, Silvia; Condò, Ivano; Cencioni, Maria Teresa; Testi, Roberto; Lerenthal, Yaniv; Cundari, Enrico; Barilà, Daniela

    2008-01-15

    Ataxia telangiectasia (A-T) is a rare cancer-predisposing genetic disease, caused by the lack of functional ATM kinase, a major actor of the double strand brakes (DSB) DNA-damage response. A-T patients show a broad and diverse phenotype, which includes an increased rate of lymphoma and leukemia development. Fas-induced apoptosis plays a fundamental role in the homeostasis of the immune system and its defects have been associated with autoimmunity and lymphoma development. We therefore investigated the role of ATM kinase in Fas-induced apoptosis. Using A-T lymphoid cells, we could show that ATM deficiency causes resistance to Fas-induced apoptosis. A-T cells up-regulate FLIP protein levels, a well-known inhibitor of Fas-induced apoptosis. Reconstitution of ATM kinase activity was sufficient to decrease FLIP levels and to restore Fas sensitivity. Conversely, genetic and pharmacologic ATM kinase inactivation resulted in FLIP protein up-regulation and Fas resistance. Both ATM and FLIP are aberrantly regulated in Hodgkin lymphoma. Importantly, we found that reconstitution of ATM kinase activity decreases FLIP protein levels and restores Fas sensitivity in Hodgkin lymphoma-derived cells. Overall, these data identify a novel molecular mechanism through which ATM kinase may regulate the immune system homeostasis and impair lymphoma development. PMID:17932249

  5. 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.

  6. Killer B Lymphocytes and Their Fas Ligand Positive Exosomes as Inducers of Immune Tolerance

    PubMed Central

    Klinker, Matthew W.; Fox, David A.

    2015-01-01

    Induction of immune tolerance is a key process by which the immune system is educated to modulate reactions against benign stimuli such as self-antigens and commensal microbes. Understanding and harnessing the natural mechanisms of immune tolerance may become an increasingly useful strategy for treating many types of allergic and autoimmune diseases, as well as for improving the acceptance of solid organ transplants. Our laboratory and others have been interested in the natural ability of some B lymphocytes to express the death-inducing molecule Fas ligand (FasL), and their ability to kill T helper (TH) lymphocytes. We have recently shown that experimental transformation of human B cells by a non-replicative variant of Epstein-Barr virus (EBV) consistently resulted in high expression of functional FasL protein. The production and release of FasL+ exosomes that co-expressed major histocompatibility complex (MHC) class II molecules and had the capacity to kill antigen-specific TH cells was also observed. Several lines of evidence indicate that FasL+ B cells and FasL+MHCII+ exosomes have important roles in natural immune tolerance and have a great deal of therapeutic potential. Taken together, these findings suggest that EBV-immortalized human B lymphoblastoid cell lines could be used as cellular factories for FasL+ exosomes, which would be employed to therapeutically establish and/or regain immune tolerance toward specific antigens. The goals of this review are to summarize current knowledge of the roles of FasL+ B cells and exosomes in immune regulation, and to suggest methods of manipulating killer B cells and FasL+ exosomes for clinical purposes. PMID:25852690

  7. TRPC6 channel activation promotes neonatal glomerular mesangial cell apoptosis via calcineurin/NFAT and FasL/Fas signaling pathways

    PubMed Central

    Soni, Hitesh; Adebiyi, Adebowale

    2016-01-01

    Glomerular mesangial cell (GMC) proliferation and death are involved in the pathogenesis of glomerular disorders. The mechanisms that control GMC survival are poorly understood, but may include signal transduction pathways that are modulated by changes in intracellular Ca2+ ([Ca2+]i) concentration. In this study, we investigated whether activation of the canonical transient receptor potential (TRPC) 6 channels and successive [Ca2+]i elevation alter neonatal GMC survival. Hyperforin (HF)-induced TRPC6 channel activation increased [Ca2+]i concentration, inhibited proliferation, and triggered apoptotic cell death in primary neonatal pig GMCs. HF-induced neonatal GMC apoptosis was not associated with oxidative stress. However, HF-induced TRPC6 channel activation stimulated nuclear translocation of the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1). HF also increased cell death surface receptor Fas ligand (FasL) level and caspase-8 activity in the cells; effects mitigated by [Ca2+]i chelator BAPTA, calcineurin/NFAT inhibitor VIVIT, and TRPC6 channel knockdown. Accordingly, HF-induced neonatal GMC apoptosis was attenuated by BAPTA, VIVIT, Fas blocking antibody, and a caspase-3/7 inhibitor. These findings suggest that TRPC6 channel-dependent [Ca2+]i elevation and the ensuing induction of the calcineurin/NFAT, FasL/Fas, and caspase signaling cascades promote neonatal pig GMC apoptosis. PMID:27383564

  8. Membrane-bound and soluble Fas ligands have opposite functions in photoreceptor cell death following separation from the retinal pigment epithelium

    PubMed Central

    Matsumoto, H; Murakami, Y; Kataoka, K; Notomi, S; Mantopoulos, D; Trichonas, G; Miller, J W; Gregory, M S; Ksander, B R; Marshak-Rothstein, A; Vavvas, D G

    2015-01-01

    Fas ligand (FasL) triggers apoptosis of Fas-positive cells, and previous reports described FasL-induced cell death of Fas-positive photoreceptors following a retinal detachment. However, as FasL exists in membrane-bound (mFasL) and soluble (sFasL) forms, and is expressed on resident microglia and infiltrating monocyte/macrophages, the current study examined the relative contribution of mFasL and sFasL to photoreceptor cell death after induction of experimental retinal detachment in wild-type, knockout (FasL−/−), and mFasL-only knock-in (ΔCS) mice. Retinal detachment in FasL−/− mice resulted in a significant reduction of photoreceptor cell death. In contrast, ΔCS mice displayed significantly more apoptotic photoreceptor cell death. Photoreceptor loss in ΔCS mice was inhibited by a subretinal injection of recombinant sFasL. Thus, Fas/FasL-triggered cell death accounts for a significant amount of photoreceptor cell loss following the retinal detachment. The function of FasL was dependent upon the form of FasL expressed: mFasL triggered photoreceptor cell death, whereas sFasL protected the retina, indicating that enzyme-mediated cleavage of FasL determines, in part, the extent of vision loss following the retinal detachment. Moreover, it also indicates that treatment with sFasL could significantly reduce photoreceptor cell loss in patients with retinal detachment. PMID:26583327

  9. Fas Receptor Expression in Germinal-Center B Cells Is Essential for T and B Lymphocyte Homeostasis

    PubMed Central

    Hao, Zhenyue; Duncan, Gordon S.; Seagal, Jane; Su, Yu-Wen; Hong, Claire; Haight, Jillian; Chen, Nien-Jung; Elia, Andrew; Wakeham, Andrew; Li, Wanda Y.; Liepa, Jennifer; Wood, Geoffrey A.; Casola, Stefano; Rajewsky, Klaus; Mak, Tak W.

    2012-01-01

    SUMMARY Fas is highly expressed in activated and germinal center (GC) B cells but can potentially be inactivated by misguided somatic hypermutation. We employed conditional Fas-deficient mice to investigate the physiological functions of Fas in various B cell subsets. B cell-specific Fas-deficient mice developed fatal lymphoproliferation due to activation of B cells and T cells. Ablation of Fas specifically in GC B cells reproduced the phenotype, indicating that the lymphoproliferation initiates in the GC environment. B cell-specific Fas-deficient mice also showed an accumulation of IgG1+ memory B cells expressing high amounts of CD80 and the expansion of CD28-expressing CD4+ Th cells. Blocking T cell-B cell interaction and GC formation completely prevented the fatal lymphoproliferation. Thus, Fas-mediated selection of GC B cells and the resulting memory B cell compartment is essential for maintaining the homeostasis of both T and B lymphocytes. PMID:18835195

  10. Cytotoxic T Lymphocytes Derived from Patients with Chronic Hepatitis C Virus Infection Kill Bystander Cells via Fas-FasL Interaction

    PubMed Central

    Gremion, Christel; Grabscheid, Benno; Wölk, Benno; Moradpour, Darius; Reichen, Jürg; Pichler, Werner; Cerny, Andreas

    2004-01-01

    The role of Fas-mediated lysis of hepatocytes in hepatitis C virus (HCV)-induced injury is frequently discussed. We therefore analyzed the effect of the number of HCV antigen-expressing cells, the mode of antigen presentation, and the number of cytotoxic T lymphocytes in a coculture system mimicking cellular components of the liver. Here, we show that endogenously processed HCV proteins are capable of inducing bystander killing. We further demonstrate that 0.8 to 1.5% of cells presenting HCV antigens suffice to induce lysis of 10 to 29% of bystander cells, suggesting that the mechanism may be operative at low fractions of infected versus uninfected hepatocytes in vivo. Our data underscore the role of the Fas pathway in HCV-related liver injury and support the exploration of Fas-based treatment strategies for patients with chronic hepatitis C virus infection. PMID:14747581

  11. 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. PMID:19265159

  12. 7 CFR 1484.57 - Will FAS make advance payments to a Cooperator?

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 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....

  13. 7 CFR 1484.57 - Will FAS make advance payments to a Cooperator?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 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....

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

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 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, 2012 CFR

    2012-01-01

    ... 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....

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

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 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. 7 CFR 1484.21 - How does FAS determine which Cooperator program applications are approved?

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... creation, expansion, or maintenance of foreign markets, FAS seeks to identify those projects that would...; (4) The degree to which the proposed project is likely to contribute to the creation, expansion,...

  18. 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…

  19. 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

  20. 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

  1. 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.

  2. 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

  3. Sunlight triggers cutaneous lupus through a CSF-1-dependent mechanism in MRL-Fas(lpr) mice.

    PubMed

    Menke, Julia; Hsu, Mei-Yu; Byrne, Katelyn T; Lucas, Julie A; Rabacal, Whitney A; Croker, Byron P; Zong, Xiao-Hua; Stanley, E Richard; Kelley, Vicki R

    2008-11-15

    Sunlight (UVB) triggers cutaneous lupus erythematosus (CLE) and systemic lupus through an unknown mechanism. We tested the hypothesis that UVB triggers CLE through a CSF-1-dependent, macrophage (Mø)-mediated mechanism in MRL-Fas(lpr) mice. By constructing mutant MRL-Fas(lpr) strains expressing varying levels of CSF-1 (high, intermediate, none), and use of an ex vivo gene transfer to deliver CSF-1 intradermally, we determined that CSF-1 induces CLE in lupus-susceptible MRL-Fas(lpr) mice, but not in lupus-resistant BALB/c mice. UVB incites an increase in Møs, apoptosis in the skin, and CLE in MRL-Fas(lpr), but not in CSF-1-deficient MRL-Fas(lpr) mice. Furthermore, UVB did not induce CLE in BALB/c mice. Probing further, UVB stimulates CSF-1 expression by keratinocytes leading to recruitment and activation of Møs that, in turn, release mediators, which induce apoptosis in keratinocytes. Thus, sunlight triggers a CSF-1-dependent, Mø-mediated destructive inflammation in the skin leading to CLE in lupus-susceptible MRL-Fas(lpr) but not lupus-resistant BALB/c mice. Taken together, CSF-1 is envisioned as the match and lupus susceptibility as the tinder leading to CLE. PMID:18981160

  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. 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

    2016-01-01

    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

  6. Neural correlates of infant accent discrimination: an fNIRS study.

    PubMed

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

    2014-07-01

    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 5-month-olds did, with the locus of discrimination in left anterior perisylvian regions. These neuroimaging results suggest that a developing language network relying crucially on left perisylvian cortices sustains infants' discrimination of similar linguistic varieties within this early period of infancy. PMID:24628942

  7. Fas-mediated elimination of antigen-presenting cells and autoreactive T cells contribute to prevention of autoimmunity

    PubMed Central

    Stranges, Peter. B.; Watson, Jessica; Cooper, Cristie J.; Choisy-Rossi, Caroline-Morgane; Stonebraker, Austin C.; Beighton, Ryan A.; Hartig, Heather; Sundberg, John P.; Servick, Stein; Kaufmann, Gunnar; Fink, Pamela J.; Chervonsky, Alexander V.

    2008-01-01

    Summary Fas (Apo-1, CD95) receptor has been suggested to control T cell expansion by triggering T cell-autonomous apoptosis. This paradigm is based on the extensive lymphoproliferation and systemic autoimmunity in mice and humans lacking Fas or its ligand. However, with systemic loss of Fas, it is unclear whether T cell-extrinsic mechanisms contribute to autoimmunity. We found that tissue-specific deletion of Fas in mouse antigen presenting cells (APC) was sufficient to cause systemic autoimmunity, implying that normally APC are destroyed during immune responses via a Fas-mediated mechanism. Fas expression by APC was increased by exposure to microbial stimuli. Analysis of mice with Fas loss restricted to T cells revealed that Fas indeed controls autoimmune T cells, but not T cells responding to strong antigenic stimulation. Thus, Fas-dependent elimination of APC is a major regulatory mechanism curbing autoimmune responses and acts in concert with Fas-mediated regulation of chronically activated autoimmune T cells. PMID:17509906

  8. The effect of perceived regional accents on individual economic behavior: a lab experiment on linguistic performance, cognitive ratings and economic decisions.

    PubMed

    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

  9. 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

  10. JAK2 inhibitor combined with DC-activated AFP-specific T-cells enhances antitumor function in a Fas/FasL signal-independent pathway

    PubMed Central

    Liu, Yang; Wang, Yue-ru; Ding, Guang-hui; Yang, Ting-song; Yao, Le; Hua, Jie; He, Zhi-gang; Qian, Ming-ping

    2016-01-01

    Objective Combination therapy for cancer is more effective than using only standard chemo- or radiotherapy. Our previous results showed that dendritic cell-activated α-fetoprotein (AFP)-specific T-cells inhibit tumor in vitro and in vivo. In this study, we focused on antitumor function of CD8+ T-cells combined with or without JAK2 inhibitor. Methods Proliferation and cell cycle were analyzed by CCK-8 and flow cytometry. Western blot was used to analyze the expression level of related protein and signaling pathway. Results We demonstrated reduced viability and induction of apoptosis of tumor cells with combination treatment. Intriguingly, cell cycle was blocked at the G1 phase by using AFP-specific CD8+ T-cells combined with JAK2 inhibitor (AG490). Furthermore, an enhanced expression of BAX but no influence on Fas/FasL was detected from the tumor cells. Conclusion These results indicate a Fas/FasL-independent pathway for cellular apoptosis in cancer therapies with the treatment of AFP-specific CD8+ T-cells combined with JAK2 inhibitor. PMID:27499636

  11. Harmol induces apoptosis by caspase-8 activation independently of Fas/Fas ligand interaction in human lung carcinoma H596 cells.

    PubMed

    Abe, Akihisa; Yamada, Hiroyuki

    2009-06-01

    The beta-carboline alkaloids are naturally existing plant substances. It is known that these alkaloids have a wide spectrum of neuropharmacological, psychopharmacological, and antitumor effects. Therefore, they have been traditionally used in oriental medicine for the treatment of various diseases including cancers and malaria. In this study, harmol and harmalol, which are beta-carboline alkaloids, were examined for their antitumor effect on human lung carcinoma cell lines, and structure-activity relationship was also investigated. H596, H226, and A549 cells were treated with harmol and harmalol, respectively. Apoptosis was induced by harmol only in H596 cells. In contrast, harmalol had negligible cytotoxicity in three cell lines. Harmol induced caspase-3, caspase-8, and caspase-9 activities and caspase-3 activities accompanied by cleavage of poly-(ADP-ribose)-polymerase. Furthermore, harmol treatment decreased the native Bid protein, and induced the release of cytochrome c from mitochondria to cytosol. The apoptosis induced by harmol was completely inhibited by caspase-8 inhibitor and partially inhibited by caspase-9 inhibitor. The antagonistic antibody ZB4 blocked Fas ligand-induced apoptosis, but had no effect on harmol-induced apoptosis. Harmol had no significant effect on the expression of Fas. In conclusion, our results showed that the harmol could cause apoptosis-inducing effects in human lung H596 cells through caspase-8-dependent pathway but independent of Fas/Fas ligand interaction. PMID:19318910

  12. Fas-antisense long noncoding RNA is differentially expressed during maturation of human erythrocytes and confers resistance to Fas-mediated cell death.

    PubMed

    Villamizar, Olga; Chambers, Christopher B; Mo, Yin-Yuan; Torry, Donald S; Hofstrand, Reese; Riberdy, Janice M; Persons, Derek A; Wilber, Andrew

    2016-05-01

    Long noncoding RNAs (lncRNAs) interact with other RNAs, DNA and/or proteins to regulate gene expression during development. Erythropoiesis is one developmental process that is tightly controlled throughout life to ensure accurate red blood cell production and oxygen transport to tissues. Thus, homeostasis is critical and maintained by competitive outcomes of pro- and anti-apoptotic pathways. LncRNAs are expressed during blood development; however, specific functions are largely undefined. Here, a culture model of human erythropoiesis revealed that lncRNA Fas-antisense 1 (Fas-AS1 or Saf) was induced during differentiation through the activity of essential erythroid transcription factors GATA-1 and KLF1. Saf was also negatively regulated by NF-κB, where decreasing NF-κB activity levels tracked with increasing transcription of Saf. Furthermore, Saf over-expression in erythroblasts derived from CD34(+) hematopoietic stem/progenitor cells of healthy donors reduced surface levels of Fas and conferred protection against Fas-mediated cell death signals. These studies reveal a novel lncRNA-regulated mechanism that modulates a critical cell death program during human erythropoiesis. PMID:27067490

  13. 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.

  14. Beat processing is pre-attentive for metrically simple rhythms with clear accents: an ERP study.

    PubMed

    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

  15. 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

    2001-05-01

    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.

  16. 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

  17. Group A streptococcal growth phase-associated virulence factor regulation by a novel operon (Fas) with homologies to two-component-type regulators requires a small RNA molecule.

    PubMed

    Kreikemeyer, B; Boyle, M D; Buttaro, B A; Heinemann, M; Podbielski, A

    2001-01-01

    A novel growth phase-associated two-component-type regulator, Fas (fibronectin/fibrinogen binding/haemolytic activity/streptokinase regulator), of Streptococcus pyogenes was identified in the M1 genome sequence, based on homologies to the histidine protein kinase (HPK) and response regulator (RR) part of the Staphylococcus aureus Agr and Streptococcus pneumoniae Com quorum-sensing systems. The fas operon, present in all 12 tested M serotypes, was transcribed as polycystronic message (fasBCA) and contained genes encoding two potential HPKs (FasB and FasC) and one RR (FasA). Downstream of fasBCA, we identified a small 300 nucleotide monocistronic transcript, designated fasX, that did not appear to encode true peptide sequences. Measurements of luciferase promoter fusions revealed a growth phase-associated transcription of fasBCA and fasX, with peak activities during the late exponential phase. Insertional mutagenesis disrupting fasBCA and fasA led to a phenotype similar to agr-null mutations in S. aureus, with prolonged expression of extracellular matrix protein-binding adhesins and reduced expression of secreted virulence factors such as streptokinase and streptolysin S. In addition, fasX transcription was dependent on the RR FasA; however, deletion mutagenesis of fasX resulted in a similar phenotype to that of the fasBCA or fasA mutants. Complementation of the fasX deletion mutant, with the fasX gene expressed in trans from a plasmid, restored the wild-type fasBCA regulation pattern. This strongly suggested that fasX, a putative non-translated RNA, is the main effector molecule of the fas regulon. However, using spent culture supernatants from wild-type and fas mutant strains, we were not able to show an influence on the logarithmic growth phase expression of fas and dependent genes. Thus, despite structural and functional similarities between fas and agr, to date the fas operon appears not to be involved in group A streptococcal (GAS) quorum-sensing regulation

  18. In vivo Effects in Melanoma of ROCK Inhibition-Induced FasL Overexpression

    PubMed Central

    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. PMID:26236689

  19. 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. PMID:26236689

  20. 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…

  1. 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. PMID:25504805

  2. 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…

  3. The Wildcat Corpus of Native- and Foreign-Accented English: Communicative Efficiency across Conversational Dyads with Varying Language Alignment Profiles

    ERIC Educational Resources Information Center

    Van Engen, Kristin J.; Baese-Berk, Melissa; Baker, Rachel E.; Choi, Arim; Kim, Midam; Bradlow, Ann R.

    2010-01-01

    This paper describes the development of the Wildcat Corpus of native- and foreign-accented English, a corpus containing scripted and spontaneous speech recordings from 24 native speakers of American English and 52 non-native speakers of English. The core element of this corpus is a set of spontaneous speech recordings, for which a new method of…

  4. 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…

  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. Gender Differences in Motivation and L2 Accent Attainment: An Investigation of Young Kurdish Learners of Turkish

    ERIC Educational Resources Information Center

    Polat, Nihat

    2011-01-01

    Although some earlier studies reported female and child superiority in learning a second language (L2), current research has been inconclusive as to whether, and why, this might be the case. Using a socio-cultural paradigm, this study addresses how motivation, gender and age relate to the attainment of a native-like accent for young Kurdish…

  7. Spoken word recognition in English by Japanese listeners: A case of Japanese-accented and unaccented English words

    NASA Astrophysics Data System (ADS)

    Yoneyama, Kiyoko

    2001-05-01

    The effect of acoustic mismatch between a listener's phonological representations and speech input on spoken word recognition was examined with Japanese learners of English. Imai, Flege, and Walley (2003) recently found that native-Spanish listeners showed a larger neighborhood density effect for unaccented English words than Spanish-accented English words, whereas native-English listeners showed a larger neighborhood density effect for Spanish-accented than unaccented words. We hypothesized that phonological mismatches would occur when native-Japanese listeners respond to unaccented English words than Japanese-accented English words. Further, the effect of the mismatch would be expected to be greater for words from dense versus sparse neighborhoods because Yoneyama (2002) found that Japanese listeners showed neighborhood density effect when they listen to Japanese. This paper reports the results of the experiment where native-Japanese listeners were asked to write down English words that were presented in noise. The words differed in neighborhood density; half were Japanese-accented words that were produced by a Japanese learner of English at a beginner level, the other half were unaccented words that were produced by a native-English listener. The results replicated Imai et al.'s (2003) finding.

  8. 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…

  9. Reactions to Anglo- and Hispanic-American-Accented Speakers: Affect, Identity, Persuasion, and the English-Only Controversy.

    ERIC Educational Resources Information Center

    Giles, Howard; And Others

    1995-01-01

    Examined the reactions of 83 Anglo-American undergraduates to Anglo- and Hispanic-American-accented speakers supporting or opposing the English-only movement in California. Results found that respondents were happier when the Anglo source argued against rather than for English exclusivity, and that respondents' happiness was not affected by…

  10. Determination of the mechanism of action of anti-FasL antibody by epitope mapping and homology modeling.

    PubMed

    Obungu, Victor H; Gelfanova, Valentina; Rathnachalam, Radhakrishnan; Bailey, Anna; Sloan-Lancaster, Joanne; Huang, Lihua

    2009-08-01

    Fas ligand (FasL) is a 40-kDa type II transmembrane protein belonging to the tumor necrosis factor (TNF) family of proteins and binds to its specific receptor, Fas, a member of the TNF receptor family. Membrane-bound FasL can be processed into a soluble form by a metalloprotease similar to that which cleaves TNFalpha. Elevated levels of FasL have been implicated in a wide variety of diseases ranging from cancer to inflammatory abnormalities, which could be targeted by antibody therapy. We generated a fully human high-affinity antibody against FasL that binds to and neutralizes the activity of both soluble and membrane-associated human FasL. In order to elucidate the mechanism of function of this antibody, we have mapped the region and critical residues involved in the recognition of FasL using a combination of homology modeling, immunoprecipitation, hydrogen-deuterium exchange mass spectrometry (H/DXMS), and alanine scanning site-directed mutagenesis. These studies have revealed the antibody binding site on human FasL. Furthermore, through molecular homology modeling, we have proposed a mechanism for the neutralizing activity of this antibody that involves interference with the docking of the ligand to its receptor by the antibody. PMID:19588926

  11. Tumor Necrosis Factor Alpha and Interleukin 1β Up-Regulate Gastric Mucosal Fas Antigen Expression in Helicobacter pylori Infection

    PubMed Central

    Houghton, JeanMarie; Macera-Bloch, Lisa S.; Harrison, Lawrence; Kim, Kyung H.; Korah, Reju M.

    2000-01-01

    Fas-mediated gastric mucosal apoptosis is gaining attention as a cause of tissue damage due to Helicobacter pylori infection. We explored the effects of H. pylori directly, and the effects of the inflammatory environment established subsequent to H. pylori infection, on Fas-mediated apoptosis in a nontransformed gastric mucosal cell line (RGM-1). Exposure to H. pylori-activated peripheral blood mononuclear cells (PBMCs), but not H. pylori itself, induced Fas antigen (Fas Ag) expression, indicating a Fas-regulatory role for inflammatory cytokines in this system. Of various inflammatory cytokines tested, only interleukin 1β and tumor necrosis factor alpha induced Fas Ag expression, and removal of either of these from the conditioned medium abrogated the response. When exposed to Fas ligand, RGM-1 cells treated with PBMC-conditioned medium underwent massive and rapid cell death, interestingly, with a minimal effect on total cell numbers early on. Cell cycle analysis revealed a substantial increase in S phase cells among cells exposed to Fas ligand, suggesting an increase in their proliferative response. Taken together, these data indicate that the immune environment secondary to H. pylori infection plays a critical role in priming gastric mucosal cells to undergo apoptosis or to proliferate based upon their Fas Ag status. PMID:10678925

  12. Rapid and transient palmitoylation of the tyrosine kinase Lck mediates Fas signaling

    PubMed Central

    Akimzhanov, Askar M.; Boehning, Darren

    2015-01-01

    Palmitoylation is the posttranslational modification of proteins with a 16-carbon fatty acid chain through a labile thioester bond. The reversibility of protein palmitoylation and its profound effect on protein function suggest that this modification could play an important role as an intracellular signaling mechanism. Evidence that palmitoylation of proteins occurs with the kinetics required for signal transduction is not clear, however. Here we show that engagement of the Fas receptor by its ligand leads to an extremely rapid and transient increase in palmitoylation levels of the tyrosine kinase Lck. Lck palmitoylation kinetics are consistent with the activation of downstream signaling proteins, such as Zap70 and PLC-γ1. Inhibiting Lck palmitoylation not only disrupts proximal Fas signaling events, but also renders cells resistant to Fas-mediated apoptosis. Knockdown of the palmitoyl acyl transferase DHHC21 eliminates activation of Lck and downstream signaling after Fas receptor stimulation. Our findings demonstrate highly dynamic Lck palmitoylation kinetics that are essential for signaling downstream of the Fas receptor. PMID:26351666

  13. Rapid and transient palmitoylation of the tyrosine kinase Lck mediates Fas signaling.

    PubMed

    Akimzhanov, Askar M; Boehning, Darren

    2015-09-22

    Palmitoylation is the posttranslational modification of proteins with a 16-carbon fatty acid chain through a labile thioester bond. The reversibility of protein palmitoylation and its profound effect on protein function suggest that this modification could play an important role as an intracellular signaling mechanism. Evidence that palmitoylation of proteins occurs with the kinetics required for signal transduction is not clear, however. Here we show that engagement of the Fas receptor by its ligand leads to an extremely rapid and transient increase in palmitoylation levels of the tyrosine kinase Lck. Lck palmitoylation kinetics are consistent with the activation of downstream signaling proteins, such as Zap70 and PLC-γ1. Inhibiting Lck palmitoylation not only disrupts proximal Fas signaling events, but also renders cells resistant to Fas-mediated apoptosis. Knockdown of the palmitoyl acyl transferase DHHC21 eliminates activation of Lck and downstream signaling after Fas receptor stimulation. Our findings demonstrate highly dynamic Lck palmitoylation kinetics that are essential for signaling downstream of the Fas receptor. PMID:26351666

  14. Microsomal prostaglandin E synthase-1 protects against Fas-induced liver injury.

    PubMed

    Yao, Lu; Chen, Weina; Han, Chang; Wu, Tong

    2016-06-01

    Microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme for the synthesis of prostaglandin E2 (PGE2), a proproliferative and antiapoptotic lipid molecule important for tissue regeneration and injury repair. In this study, we developed transgenic (Tg) mice with targeted expression of mPGES-1 in the liver to assess Fas-induced hepatocyte apoptosis and acute liver injury. Compared with wild-type (WT) mice, the mPGES-1 Tg mice showed less liver hemorrhage, lower serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, less hepatic necrosis/apoptosis, and lower level of caspase cascade activation after intraperitoneal injection of the anti-Fas antibody Jo2. Western blotting analysis revealed increased expression and activation of the serine/threonine kinase Akt and associated antiapoptotic molecules in the liver tissues of Jo2-treated mPGES-1 Tg mice. Pretreatment with the mPGES-1 inhibitor (MF63) or the Akt inhibitor (Akt inhibitor V) restored the susceptibility of the mPGES-1 Tg mice to Fas-induced liver injury. Our findings provide novel evidence that mPGES-1 prevents Fas-induced liver injury through activation of Akt and related signaling and suggest that induction of mPGES-1 or treatment with PGE2 may represent important therapeutic strategy for the prevention and treatment of Fas-associated liver injuries. PMID:27102561

  15. Caspase-10 triggers Bid cleavage and caspase cascade activation in FasL-induced apoptosis.

    PubMed

    Milhas, Delphine; Cuvillier, Olivier; Therville, Nicole; Clavé, Patricia; Thomsen, Mogens; Levade, Thierry; Benoist, Hervé; Ségui, Bruno

    2005-05-20

    In contrast to caspase-8, controversy exists as to the ability of caspase-10 to mediate apoptosis in response to FasL. Herein, we have shown activation of caspase-10, -3, and -7 as well as B cell lymphoma-2-interacting domain (Bid) cleavage and cytochrome c release in caspase-8-deficient Jurkat (I9-2) cells treated with FasL. Apoptosis was clearly induced as illustrated by nuclear and DNA fragmentation. These events were inhibited by benzyloxycarbonyl-VAD-fluoromethyl ketone, a broad spectrum caspase inhibitor, indicating that caspases were functionally and actively involved. Benzyloxycarbonyl-AEVD-fluoromethyl ketone, a caspase-10 inhibitor, had a comparable effect. FasL-induced cell death was not completely abolished by caspase inhibitors in agreement with the existence of a cytotoxic caspase-independent pathway. In subpopulations of I9-2 cells displaying distinct caspase-10 expression levels, cell sensitivity to FasL correlated with caspase-10 expression. A robust caspase activation, Bid cleavage, and DNA fragmentation were observed in cells with high caspase-10 levels but not in those with low levels. In vitro, caspase-10, as well as caspase-8, could cleave Bid to generate active truncated Bid (p15). Altogether, our data strongly suggest that caspase-10 can serve as an initiator caspase in Fas signaling leading to Bid processing, caspase cascade activation, and apoptosis. PMID:15772077

  16. 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.

  17. 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

    2014-01-01

    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. PMID:24722570

  18. Functional NK cell repertoires are maintained through IL-2Rα and FasL

    PubMed Central

    Felices, Martin; Lenvik, Todd R.; Ankarlo, Dave E.M.; Foley, Bree; Curtsinger, Julie; Luo, Xianghua; Blazar, Bruce R.; Anderson, Stephen K.; Miller, Jeffrey S.

    2014-01-01

    Acquisition of a functional natural killer (NK) cell repertoire, known as education or licensing, is a complex process mediated through inhibitory receptors that recognize self. We found that NK cells containing self-killer immunoglobulin-like receptors (KIR) for cognate HLA-ligand in vivo were less susceptible to apoptosis. In vitro IL-15 withdrawal showed that uneducated NK cells upregulated Bim and Fas. Conversely, educated NK cells upregulated FasL under these conditions. Induction of cell death and Bim expression on uneducated cells correlated with increased IL-2Rα expression. Overexpression and knockdown studies showed that higher IL-2Rα limits NK cell survival in a novel manner that is independent from the role of IL-2 in activation induced cell death (AICD). To study the role of FasL in induction of IL-2Rαhi NK cell death, a co-culture assay with FasL blocking antibodies was used. IL-15 withdrawal led to FasL dependent killing of IL-2Rαhi NK cells by more educated IL-2Rαlo NK cells. Finally, CMV reactivation induces a potent long-lasting population of licensed NK cells with enhanced survival. These findings show education dependent NK cell survival advantages and killing of uneducated NK result in the maintenance of a functional repertoire, which may be manipulated to exploit NK cells for cancer immunotherapy. PMID:24634493

  19. Hematopoietic Fas Deficiency Does Not Affect Experimental Atherosclerotic Lesion Formation despite Inducing a Proatherogenic State

    PubMed Central

    de Claro, R. Angelo; Zhu, Xiaodong; Tang, Jingjing; Morgan-Stevenson, Vicki; Schwartz, Barbara R.; Iwata, Akiko; Liles, W. Conrad; Raines, Elaine W.; Harlan, John M.

    2011-01-01

    The Fas death receptor (CD95) is expressed on macrophages, smooth muscle cells, and T cells within atherosclerotic lesions. Given the dual roles of Fas in both apoptotic and nonapoptotic signaling, the aim of the present study was to test the effect of hematopoietic Fas deficiency on experimental atherosclerosis in low-density lipoprotein receptor-null mice (Ldlr−/−). Bone marrow from Fas−/− mice was used to reconstitute irradiated Ldlr−/− mice as a model for atherosclerosis. After 16 weeks on an 0.5% cholesterol diet, no differences were noted in brachiocephalic artery lesion size, cellularity, or vessel wall apoptosis. However, Ldlr−/− mice reconstituted with Fas−/− hematopoietic cells had elevated hyperlipidemia [80% increase, relative to wild-type (WT) controls; P < 0.001] and showed marked elevation of plasma levels of CXCL1/KC, CCL2/MCP-1, IL-6, IL-10, IL-12 subunit p70, and soluble Fas ligand (P < 0.01), as well as systemic microvascular inflammation. It was not possible to assess later stages of atherosclerosis because of increased mortality in Fas−/− bone marrow recipients. Our data indicate that hematopoietic Fas deficiency does not affect early atherosclerotic lesion development in Ldlr−/− mice. PMID:21550016

  20. Age-Dependent Changes in FasL (CD95L) Modulate Macrophage Function in a Model of Age-Related Macular Degeneration

    PubMed Central

    Zhao, Hui; Roychoudhury, Jayeeta; Doggett, Teresa A.; Apte, Rajendra S.; Ferguson, Thomas A.

    2013-01-01

    Purpose. We examined the effect of aging on Fas ligand (FasL) function in a mouse model of choroidal neovascularization (CNV). Methods. Young and aged mice were laser treated to induce CNV. Bone marrow chimeras were performed between young and aged mice. FasL protein expression was examined in the eye and soluble FasL (sFasL) was measured in the blood. Young and aged mice were treated with a matrix metalloprotease (MMP) inhibitor and systemic sFasL was neutralized by antibody treatment. Macrophages from young and aged mice were tested for sFasL-mediated cytokine production and migration. Results. The elevated CNV response observed with aging was dependent on bone marrow–derived cells. FasL expression in the eye was increased with age, but decreased following laser treatment. Aged mice had higher levels of sFasL in the blood compared to young mice. Systemic treatment with an MMP inhibitor decreased bloodborne sFasL, and reduced CNV in young and aged mice. Systemic neutralization of sFasL reduced CNV only in aged mice. sFasL increased cytokine production in aged macrophages and proangiogenic M2 macrophages. Aged M2 macrophages had elevated Fas (CD95) expression and displayed increased migration in response to sFasL compared to M1 macrophages derived from young animals. Conclusions. Age modulates FasL function where increased MMP cleavage leads to a loss of function in the eye. The released form of FasL (sFasL) preferentially induces the migration of proangiogenic M2 macrophages into the laser lesions and increases proangiogenic cytokines promoting CNV. FasL may be a viable target for therapeutic intervention in aged-related neovascular disease. PMID:23821188

  1. 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.

  2. 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

  3. Establishment and Characterization of an In Vitro Model of Fas-Mediated Hepatocyte Cell Death.

    PubMed

    Vinken, Mathieu; Maes, Michaël; Crespo Yanguas, Sara; Willebrords, Joost; Vanhaecke, Tamara; Rogiers, Vera

    2015-01-01

    Fas-mediated apoptosis underlies a plethora of liver pathologies and toxicities. As a consequence, this process is a major research topic in the field of experimental and clinical hepatology. The present chapter describes the setup of an in vitro model of hepatocellular apoptotic cell death. In essence, this system consists of freshly isolated hepatocytes cultured in a monolayer configuration, which are exposed to a combination of Fas ligand and cycloheximide. This in vitro model has been characterized by using a set of well-acknowledged cell death markers. This experimental system allows the study of the entire course of Fas-mediated hepatocellular cell death, going from early apoptosis to secondary necrosis, and hence can serve a broad range of in vitro pharmaco-toxicological purposes. PMID:26272136

  4. Establishment and characterization of an in vitro model of Fas-mediated hepatocyte cell death

    PubMed Central

    Vinken, Mathieu; Maes, Michaël; Yanguas, Sara Crespo; Willebrords, Joost; Vanhaecke, Tamara; Rogiers, Vera

    2015-01-01

    Summary Fas-mediated apoptosis underlies a plethora of liver pathologies and toxicities. As a consequence, this process is a major research topic in the field of experimental and clinical hepatology. The present chapter describes the set-up of an in vitro model of hepatocellular apoptotic cell death. In essence, this system consists of freshly isolated hepatocytes cultured in a monolayer configuration, which are exposed to a combination of Fas ligand and cycloheximide. This in vitro model has been characterized by using a set of well-acknowledged cell death markers. This experimental system allows the study of the entire course of Fas-mediated hepatocellular cell death, going from early apoptosis to secondary necrosis, and hence can serve a broad range of in vitro pharmaco-toxicological purposes. PMID:26272136

  5. Adenoviral vector which delivers FasL-GFP fusion protein regulated by the tet-inducible expression system.

    PubMed

    Rubinchik, S; Ding, R; Qiu, A J; Zhang, F; Dong, J

    2000-05-01

    Fas ligand (FasL) is a member of the tumor necrosis family and when bound to its receptor, Fas, induces apoptosis. It plays important roles in immune response, degenerative and lymphoproliferative diseases, development and tumorigenesis. It is also involved in generation of immune privilege sites in the eye and testis. Harnessing the power of this molecule is expected to lead to a powerful chemotherapeutic. We describe the construction and characterization of replication-deficient adenoviral vectors that express a fusion of murine FasL and green fluorescent protein (GFP). FasL-GFP retains full activity of wild-type FasL, at the same time allowing for easy visualization and quantification in both living and fixed cells. The fusion protein is under the control of a tetracycline-regulated gene expression system. Tight control of expression is achieved by creating a novel 'double recombinant' Ad vector, in which the tet-responsive element and the transactivator element are built into the opposite ends of the same vector to avoid enhancer interference. Expression can be conveniently regulated by tetracycline or its derivatives in a dose-dependent manner. The vector was able to deliver FasL-GFP gene to cells in vitro efficiently, and the expression level and function of the fusion protein was modulated by the concentration of doxycycline. This regulation allows us to produce high titers of the vector by inhibiting FasL expression in an apoptosis-resistant cell line. Induction of apoptosis was demonstrated in all cell lines tested. These results indicate that our vector is a potentially valuable tool for FasL-based gene therapy of cancer and for the study of FasL/Fas-mediated apoptosis and immune privilege. PMID:10845726

  6. Astrocyte reactivity to Fas activation is attenuated in TIMP-1 deficient mice, an in vitro study

    PubMed Central

    Ogier, Crystel; Creidy, Rita; Boucraut, José; Soloway, Paul D; Khrestchatisky, Michel; Rivera, Santiago

    2005-01-01

    Background Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a multifunctional secreted protein with pleiotropic actions, including the inhibition of matrix metalloproteinases (MMPs), cell death/survival and growth promoting activities. After inflammatory challenge, the levels of TIMP-1 are highly and selectively upregulated in astrocytes among glial cells, but little is know about its role in these neural cells. We investigated the influence of TIMP-1 null mutation in the reactivity of cultured astrocytes to pro-inflammatory stimuli with TNF-α and anti-Fas antibody. Results When compared to WT, mutant astrocytes displayed an overall increased constitutive gelatinase expression and were less responsive to Fas-mediated upregulation of MMP-9, of monocyte chemoattractant protein-1 (MCP-1) and of intercellular cell adhesion molecule-1 (ICAM-1), all markers of astrocyte inflammatory response. In contrast, TNF-α treatment induced all these factors similarly regardless of the astrocyte genotype. The incorporation of 3H-thymidin, a marker of cell proliferation, increased in wild-type (WT) astrocytes after treatment with anti-Fas antibody or recombinant TIMP-1 but not in mutant astrocytes. Finally, lymphocyte chemotaxis was differentially regulated by TNF-α in WT and TIMP-1 deficient astrocytes. Conclusion We provide evidence that the alteration of the MMP/TIMP balance in astrocytes influences their reactivity to pro-inflammatory stimuli and that Fas activation modulates the expression of members of the MMP/TIMP axis. We hypothesise that the Fas/FasL transduction pathway and the MMP/TIMP system interact in astrocytes to modulate their inflammatory response to environmental stimuli. PMID:16316466

  7. Educational planning for children with fetal alcohol syndrome.

    PubMed

    Kalberg, Wendy O; Buckley, David

    2006-01-01

    It has now been thirty-two years since Jones and Smith first identified fetal alcohol syndrome (FAS) in the United States. Since then, numerous epidemiology studies have been conducted to determine prevalence rates of this disorder. More recently, the research focus has concentrated on studies to elucidate a neurobehavioral phenotype for the alcohol-exposed population. As a result, the FAS field has learned what types of neurobehavioral issues occur most frequently with these children. This paper discusses the results of neurobehavioral research with alcohol exposed children and how that information can be used to inform school assessment, intervention planning, and support. PMID:16801727

  8. Comparison of ACCENT 2000 Shuttle Plume Data with SIMPLE Model Predictions

    NASA Astrophysics Data System (ADS)

    Swaminathan, P. K.; Taylor, J. C.; Ross, M. N.; Zittel, P. F.; Lloyd, S. A.

    2001-12-01

    The JHU/APL Stratospheric IMpact of PLume Effluents (SIMPLE)model was employed to analyze the trace species in situ composition data collected during the ACCENT 2000 intercepts of the space shuttle Space Transportation Launch System (STS) rocket plume as a function of time and radial location within the cold plume. The SIMPLE model is initialized using predictions for species depositions calculated using an afterburning model based on standard TDK/SPP nozzle and SPF plume flowfield codes with an expanded chemical kinetic scheme. The time dependent ambient stratospheric chemistry is fully coupled to the plume species evolution whose transport is based on empirically derived diffusion. Model/data comparisons are encouraging through capturing observed local ozone recovery times as well as overall morphology of chlorine chemistry.

  9. Polymorphisms of extrinsic death receptor apoptotic genes (FAS -670 G>A, FASL -844 T>C) in coronary artery disease.

    PubMed

    Kishore Kumar, G; Rajesh Kumar, G; Mrudula Spurthi, K; Nivas, S; Chiranjeevi, P; Ali, Altaf; Sahu, S K; Pratibha, N; Surekha Rani, H

    2016-05-01

    Apoptosis plays an important role in atherogenesis and rupture of vulnerable plaques in coronary artery disease. FAS and FAS ligand (FASL) induce apoptosis when FAS binds to FAS-L. However sFas blocks apoptosis by binding to FAS and FASL or sFasL. The present study is sought to examine the role of extrinsic apoptotic genes (FAS, FASL) polymorphism and serum levels of FAS, FASL in the pathogenesis and susceptibility to CAD in south Indian population. The study included 300 CAD patients and 300 healthy controls. Lipid profiles, sFas, sFasL were estimated by commercially available kits. FAS -670 G>A, FASL -844 T>C genotypes were analyzed by PCR-RFLP. Secondary structures of pre mRNA were analyzed by the Vienna RNA webserver and gene-gene and gene-environment interactions were determined by MDR analysis. Total cholesterol, triglyceride and LDL levels were significantly high in CAD patients compared to the controls. Molecular analysis revealed that the frequency of the AA genotype of FAS (54 % vs 27 %) and CC genotypes of FASL (10.3 % vs 1.3 %) were high in CAD patients compared to controls. Secondary structure analysis of FAS and FASL confirmed our molecular analysis. sFas levels were low while serum sFasL were high in CAD patients. MDR analysis revealed synergistic effects of gene polymorphisms and additive effects of epidemiological factors on risk of CAD. Polymorphisms of FAS (-670 G/A), FASL (-844 T/C) and their circulating levels play an important role in the pathology of CAD. PMID:26922070

  10. Inactivated Sendai Virus Strain Tianjin Induces Apoptosis in Breast Cancer MCF-7 Cells by Promoting Caspase Activation and Fas/FasL Expression

    PubMed Central

    Han, Zhe; Li, Xiao-Xia; Li, Mei; Han, Han; Chen, Jun; Zang, Sitao

    2015-01-01

    Abstract Virotherapy represents a promising new approach for treating cancer. Here the authors have analyzed the effect of ultraviolet-inactivated Sendai virus strain Tianjin (UV-Tianjin) on human breast cancer MCF-7 cells in vitro and in vivo. In vitro, UV-Tianjin inhibited the proliferation of MCF-7, MDA-MB-231, and T47D breast cancer cell lines, although MCF-7 cells were most susceptible to UV-Tianjin treatment. Hoechst staining and flow cytometric analysis of UV-Tianjin-treated MCF-7 cells revealed that UV-Tianjin induced apoptosis in a dose-dependent manner. Moreover, UV-Tianjin treatment resulted in reductions in the mitochondria membrane potential of MCF-7 cells and regulated the levels and activities of Bcl-2, Bax, cyt c, caspases, Fas, and Fas ligand (FasL). In vivo, UV-Tianjin inhibited the growth of MCF-7 tumors in nude mice and increased tumor cell apoptosis compared with saline-treated controls. In addition, the percentage of tumor cells positive for cleaved versions of caspase-7, caspase-8, and caspase-9 was higher in UV-Tianjin-treated tumors than in saline-treated controls. In summary, UV-Tianjin exhibited the antitumor activity in human breast cancer MCF-7 cells both in vitro and in vivo. The UV-Tianjin treatment seemed to induce apoptosis by activating both the mitochondrial and death receptor apoptotic pathways. PMID:25517620

  11. Speech motor brain regions are differentially recruited during perception of native and foreign-accented phonemes for first and second language listeners

    PubMed Central

    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. PMID:25232302

  12. Fetal alcohol syndrome: the origins of a moral panic.

    PubMed

    Armstrong, E M; Abel, E L

    2000-01-01

    Since its discovery almost 30 years ago, the fetal alcohol syndrome (FAS) has been characterized in the USA, as a major threat to public health. In part because FAS resonated with broader social concerns in the 1970s and 1980s about alcohol's deleterious effect on American society and about a perceived increase in child abuse and neglect, it quickly achieved prominence as a social problem. In this paper, we demonstrate that, as concern about this social problem escalated beyond the level warranted by the existing evidence, FAS took on the status of a moral panic. Through examples taken from both the biomedical literature and the media about drinking during pregnancy, we illustrate the evolution of this development, and we describe its implications, particularly how it has contributed to a vapid public policy response. PMID:10869248

  13. Fas activation in alveolar epithelial cells induces KC (CXCL1) release by a MyD88-dependent mechanism.

    PubMed

    Farnand, Alex W; Eastman, Alison J; Herrero, Raquel; Hanson, Josiah F; Mongovin, Steve; Altemeier, William A; Matute-Bello, Gustavo

    2011-09-01

    Activation of the Fas/Fas ligand (FasL) system is associated with activation of apoptotic and proinflammatory pathways that lead to the development of acute lung injury. Previous studies in chimeric mice and macrophage-depleted mice suggested that the main effector cell in Fas-mediated lung injury is not a myeloid cell, but likely an epithelial cell. The goal of this study was to determine whether epithelial cells release proinflammatory cytokines after Fas activation, and to identify the relevant pathways. Incubation of the murine alveolar epithelial cell line, MLE-12, with the Fas-activating monoclonal antibody, Jo2, resulted in release of the CXC chemokine, KC, in a dose-dependent manner. KC release was not prevented by the pan-caspase inhibitor, zVAD.fmk. Silencing of the adaptor protein, MyD88, with small interfering (si)RNA resulted in attenuation of KC release in response to Jo2. Fas activation resulted in phosphorylation of the mitogen-activated kinases extracellular signal-regulated kinase (ERK) and c-Jun-N-terminal kinase (JNK), and pharmacologic inhibition of ERK and JNK attenuated KC release in a dose-response manner. Similarly, primary human small airways epithelial cells released IL-8 in response to soluble FasL, and this was abrogated by inhibition of JNK and ERK. In vivo confirmatory studies showed that MyD88-null mice are protected from Fas-induced acute lung injury. In summary, we conclude that Fas induces KC release in MLE-12 cells by a mechanism requiring MyD88, mitogen-activated protein kinases, and likely activator protein-1. PMID:21257927

  14. Osthole prevents anti-Fas antibody-induced hepatitis in mice by affecting the caspase-3-mediated apoptotic pathway.

    PubMed

    Okamoto, Toshihiro; Kawasaki, Toru; Hino, Okio

    2003-02-15

    Fas (Apo-1/CD95) ligand, which is a type II membrane protein, is a major inducer of apoptosis. Osthole is a coumarin derivative present in medicinal plants. The effect of osthole on hepatitis induced by anti-Fas antibody in mice was studied. Pretreatment of mice with osthole (10, 50, and 100 mg/kg, i.p.) prevented the elevation of plasma alanine aminotransferase (ALT) caused by anti-Fas antibody (175 microg/kg, i.v.). Administration of osthole to mice even at a dose of 10 mg/kg significantly inhibited of anti-Fas antibody-induced elevation of plasma ALT. Capase-3 is a cysteine protease, and treatment of mice with anti-Fas antibody caused an elevation of caspase-3 activity at 3.5 and 6 hr. Pretreatment of mice with osthole (100 mg/kg, i.p.) inhibited the elevation of caspase-3 activity caused by anti-Fas antibody. However, the addition of osthole (up to 10(-4)M) to a liver cytosol fraction isolated from mice treated with anti-Fas antibody did not inhibit caspase-3 activity in vitro. Thus, treatment of mice with osthole inhibited caspase-3 activity by an effect upstream of caspase-3 activation. The livers of mice treated with anti-Fas antibody contained apoptotic and dead cells; osthole attenuated the development of this apoptosis and cell death. The present results show that osthole prevented anti-Fas antibody-induced hepatitis by inhibiting the Fas-mediated apoptotic pathway. PMID:12566097

  15. 7 CFR 1580.203 - Determination of eligibility and certification by the Administrator (FAS).

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 10 2014-01-01 2014-01-01 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 FARMERS § 1580.203 Determination...

  16. 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...

  17. 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. PMID:26921445

  18. 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…

  19. 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...

  20. The Global Flood Awareness System (GloFAS) - Overview of Recent Developments

    NASA Astrophysics Data System (ADS)

    Hirpa, F. A.; Zajac, Z.; Revilla-Romero, B.; Ntegeka, V.; Salamon, P.; Thielen, J.; Burek, P.; Kalas, M.; Alfieri, L.; Beck, H.

    2014-12-01

    The Global Flood Awareness System (GloFAS) is an ensemble river discharge forecasting system developed and maintained jointly between the European Commission - Joint Research Centre (JRC) and the European Centre for Medium-range Weather Forecasts (ECMWF). The system consists of a cascade of two models, where the surface and sub-surface runoffs are computed by the Hydrology revised Tiled ECMWF Scheme for Surface Exchange over Land (HTESSEL) while the runoff routing and other hydrodynamic components are modeled by the LISFLOOD model. Since its set up in July 2011, GloFAS has been producing probabilistic discharge forecasts on daily basis at 0.1o spatial resolution with global coverage. The system is undergoing some updates that focus on the improvement of the hydrodynamic model, which include incorporation of an updated river network and river width maps, inclusion of lake and reservoir modules and a better representation of transmission losses. Additionally, a new web interface and web service for communication and visualization of the discharge forecast has been developed. Finally, the use of ECMWF re-forecasts as reference climatology to derive flood warning thresholds in comparison to those of ERA-Interim has also been assessed. In this work we present: 1) an overview of recent advances of GloFAS, 2) the results of an evaluation study which used ECMWF re-forecasts to derive global flood warning thresholds and 3) the role of the GloFAS in the recently launched Global Flood Partnership (GFP).

  1. Fas-mediated apoptosis in clinical remissions of relapsing experimental autoimmune encephalomyelitis

    PubMed Central

    Suvannavejh, Graig C.; Dal Canto, Mauro C.; Matis, Louis A.; Miller, Stephen D.

    2000-01-01

    PLP139-51–induced experimental autoimmune encephalomyelitis (R-EAE) displays a relapsing-remitting paralytic course in female SJL mice. We investigated the role of apoptosis/activation-induced cell death (AICD) in the spontaneous recovery from acute disease. Clinical EAE was significantly enhanced in Fas (CD95/APO-1)–deficient SJL lpr/lpr mice, which displayed significantly increased mean peak clinical scores, reduced remission rates, and increased mortality when compared with their SJL +/lpr littermates. PLP139-151–specific proliferative responses were fairly equivalent in the 2 groups, but draining lymph node T cells from SJL lpr/lpr mice produced dramatically increased levels of IFN-γ. Central nervous system (CNS) Fas and FasL mRNA levels in wild-type SJL (H-2s) mice peaked just before spontaneous disease remission and gradually declined as disease remitted. We applied the terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) assay to detect apoptosis in situ in spinal cords of mice at various clinical stages of EAE. Most TUNEL+ cells were found during active periods of inflammation: the acute, peak, and relapse time points. Significantly fewer apoptotic cells were observed at preclinical and remission time points. Collectively, these findings indicate that Fas-mediated apoptosis/AICD plays a major role in the spontaneous remission after the initial acute inflammatory episode and represents an important intrinsic mechanism in regulation of autoimmune responses. PMID:10642601

  2. Oral vaccination against Helicobacter pylori infection is not effective in mice with Fas ligand deficiency.

    PubMed

    Avitzur, Yaron; Galindo-Mata, Esther; Jones, Nicola L

    2005-12-01

    The aim of this study was to delineate the role of the Fas pathway in vaccination against Helicobacter pylori. C57BL/6 and Fas ligand-deficient (gld) mice were divided into 3 groups: control, H. pylori infected, and orally vaccinated (H. pylori whole cell sonicate and cholera toxin adjuvant). Oral vaccination prevented H. pylori colonization in 78% of C57BL/6 mice compared to only 18% of gld mice. Vaccination did not alter the degree of apoptosis in either strain of mice. Vaccination led to significant increase in interleukin (IL)-5 and IL-10 in C57BL/6 but not gld mice. H. pylori infection increased interferon (IFN)-gamma levels in C57BL/6 but not in gld mice while vaccination had no effect on IFN-gamma levels in either strain. Oral vaccination is not effective in Fas ligand-deficient mice likely owing to lack of effective cytokine responses. This indicates that the Fas pathway plays a critical role in promoting an appropriate effector response following H. pylori vaccination. PMID:16416178

  3. 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...

  4. 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...

  5. 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...

  6. 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...

  7. BI-1 enhances Fas-induced cell death through a Na+/H+-associated mechanism

    PubMed Central

    Lee, Geum-Hwa; Kim, Hyung-Ryong; Chae, Han-Jung

    2014-01-01

    The role of Bax inhibitor-1 (BI-1) in the protective mechanism against apoptotic stimuli has been studied; however, as little is known about its role in death receptor-mediated cell death, this study was designed to investigate the effect of BI-1 on Fas-induced cell death, and the underlying mechanisms. HT1080 adenocarcinoma cells were cultured in high concentration of glucose media and transfected with vector alone (Neo cells) or BI-1-vector (BI-1 cells), and treated with Fas. In cell viability, apoptosis, and caspase-3 analyses, the BI-1 cells showed enhanced sensitivity to Fas. Fas significantly decreased cytosolic pH in BI-1 cells, compared with Neo cells, and this decrease correlated with BI-1 oligomerization, mitochondrial Ca2+ accumulation, and significant inhibition of sodium-hydrogen exchanger (NHE) activity. Compared with Neo cells, a single treatment of BI-1 cells with the NHE inhibitor EIPA or siRNA against NHE significantly increased cell death, which suggests that the viability of BI-1 cells is affected by the maintenance of intracellular pH homeostasis through NHE. [BMB Reports 2014; 47(7): 393-398] PMID:24314142

  8. 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

  9. Corruption of the Fas Pathway Delays the Pulmonary Clearance of Murine Osteosarcoma Cells, Enhances Their Metastatic Potential, and Reduces the Effect of Aerosol Gemcitabine

    PubMed Central

    Gordon, Nancy; Koshkina, Nadezhda V.; Jia, Shu-Fang; Khanna, Chand; Mendoza, Arnulfo; Worth, Laura L.; Kleinerman, Eugenie S.

    2015-01-01

    Purpose Pulmonary metastases continue to be a significant problem in osteosarcoma. Apoptosis dysfunction is known to influence tumor development. Fas (CD95, APO-1)/FasL is one of the most extensively studied apoptotic pathways. Because FasL is constitutively expressed in the lung, cells that express Fas should be eliminated by lung endothelium. Cells with low or no cell surface Fas expression may be able to evade this innate defense mechanism. The purpose of these studies was to evaluate Fas expression in osteosarcoma lung metastases and the effect of gemcitabine on Fas expression and tumor growth. Experimental Design and Results Using the K7M2 murine osteosarcoma model, Fas expression was quantified using immunohistochemistry. High levels of Fas were present in primary tumors, but no Fas expression was present in actively growing lung metastases. Blocking the Fas pathway using Fas-associated death domain dominant-negative delayed tumor cell clearance from the lung and increased metastatic potential. Treatment of mice with aerosol gemcitabine resulted in increased Fas expression and subsequent tum or regression. Conclusions We conclude that corruption of the Fas pathway is critical to the ability of osteosarcoma cells to grow in the lung. Agents such as gemcitabine that up-regulate cell surface Fas expression may therefore be effective in treating osteosarcoma lung metastases. These data also suggest that an additional mechanism by which gemcitabine induces regression of osteosarcoma lung metastases is mediated by enhancing the sensitivity of the tumor cells to the constitutive FasL in the lung. PMID:17671136

  10. A novel interaction linking the FAS-II and phthiocerol dimycocerosate (PDIM) biosynthetic pathways.

    PubMed

    Kruh, Nicole A; Borgaro, Janine G; Ruzsicska, Béla P; Xu, Hua; Tonge, Peter J

    2008-11-14

    The fatty acid biosynthesis (FAS-II) pathway in Mycobacterium tuberculosis generates long chain fatty acids that serve as the precursors to mycolic acids, essential components of the mycobacterial cell wall. Enzymes in the FAS-II pathway are thought to form one or more noncovalent multi-enzyme complexes within the cell, and a bacterial two-hybrid screen was used to search for missing components of the pathway and to furnish additional data on interactions involving these enzymes in vivo. Using the FAS-II beta-ketoacyl synthase, KasA, as bait, an extensive bacterial two-hybrid screen of a M. tuberculosis genome fragment library unexpectedly revealed a novel interaction between KasA and PpsB as well as PpsD, two polyketide modules involved in the biosynthesis of the virulence lipid phthiocerol dimycocerosate (PDIM). Sequence analysis revealed that KasA interacts with PpsB and PpsD in the region of the acyl carrier domain of each protein, raising the possibility that lipids could be transferred between the FAS-II and PDIM biosynthetic pathways. Subsequent studies utilizing purified proteins and radiolabeled lipids revealed that fatty acids loaded onto PpsB were transferred to KasA and also incorporated into long chain fatty acids synthesized using a Mycobacterium smegmatis lysate. These data suggest that in addition to producing PDIMs, the growing phthiocerol product can also be shuttled into the FAS-II pathway via KasA as an entry point for further elongation. Interactions between these biosynthetic pathways may exist as a simple means to increase mycobacterial lipid diversity, enhancing functionality and the overall complexity of the cell wall. PMID:18703500

  11. The aryl hydrocarbon receptor predisposes hepatocytes to Fas-mediated apoptosis.

    PubMed

    Park, Kyung-Tae; Mitchell, Kristen A; Huang, Gengming; Elferink, Cornelis J

    2005-03-01

    Liver homeostasis is achieved by the removal of diseased and damaged hepatocytes and their coordinated replacement to maintain a constant liver cell mass. Cirrhosis, viral hepatitis, and toxic drug effects can all trigger apoptosis in the liver as a means of removing the unwanted cells, and the Fas "death receptor" pathway comprises a major physiological mechanism by which this occurs. The susceptibility to Fas-mediated apoptosis is, in part, a function of the hepatocyte's proteome. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known to influence apoptosis, conceivably by regulating the expression of genes involved in apoptotic signaling. In this article, we present evidence demonstrating that AhR expression and function promote apoptosis in liver cells in response to Fas stimulation. Reintroduction of the AhR into the AhR-negative BP8 hepatoma cells as well as into primary hepatocytes from AhR knockout mice increases the magnitude of cell death in response to Fas ligand. Enhanced apoptosis correlates with increased caspase activity and mitochondrial cytochrome c release but not with the expression of several Bcl-2 family proteins. In vivo studies showed that in contrast to wild-type mice, AhR knockout mice are protected from the lethal effects of the anti-Fas Jo2 antibody. Moreover, down-regulation of the aryl hydrocarbon receptor nuclear translocator protein in vivo by adenovirus-mediated RNA interference to suppress AhR activity provided wild-type mice partial protection from Jo2-induced lethality. PMID:15550680

  12. Hispanic counselors' race and accent and Euro Americans' universal-diverse orientation: a study of initial perceptions.

    PubMed

    Fuertes, J N; Gelso, C J

    2000-05-01

    This study examined Euro American participants' initial perceptions of male Hispanic counselors. Two hundred twelve college students evaluated male Hispanic counselors whose race was White, Mestizo (a mix of White European and Native American ancestry), or Black and who spoke English with or without a Spanish accent. The participants' perceptions were analyzed in the context of their scores on universal-diverse orientation, a new theory and measure of multicultural awareness (M. L. Miville et al., 1999). Results suggest that participants' perceptions of the Hispanic counselors as attractive, expert, and trustworthy, as well as their willingness to work with them in long-term therapy, were affected by the counselors' race and accent and by the participants' level of universal-diverse orientation. These results are discussed in the context of relevant literature, and recommendations for future research in this area are provided. PMID:10910533

  13. 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. PMID:24604009

  14. The functional origin of the foreign accent: evidence from the syllable-frequency effect in bilingual speakers.

    PubMed

    Alario, F-Xavier; Goslin, Jeremy; Michel, Violaine; Laganaro, Marina

    2010-01-01

    Individuals who speak more than one language often do so with a foreign accent in their second language. Previous investigations have focused on the acoustic phonetic properties of speech, showing how language-learning history shapes the occurrence of accent. By contrast, little is known about the phonological and phonetic representations that allow the production of each language within one speaker. We investigated this issue via the syllable-frequency effect, thought to index the retrieval of syllable-size representations during speech production. We tested French-Spanish early and late bilinguals in a task in which the materials' syllabic frequency in both languages was manipulated. The frequency of syllables in the nonspoken language affected performance only with late bilinguals. This is interpreted as evidence that syllabic representations are shared across languages in late bilinguals but are separate in early bilinguals. One of the functional origins of foreign accent in late bilinguals may be the retrieval of syllabic representations shared across languages. PMID:20424016

  15. 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. PMID:23253142

  16. 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. PMID:18606644

  17. FAS/FASL are dysregulated in chordoma and their loss-of-function impairs zebrafish notochord formation

    PubMed Central

    Libera, Laura; Boari, Nicola; Mortini, Pietro; Bellipanni, Gianfranco; Giordano, Antonio; Cotelli, Franco; Riva, Paola

    2014-01-01

    Chordoma is a rare malignant tumor that recapitulates the notochord phenotype and is thought to derive from notochord remnants not correctly regressed during development. Apoptosis is necessary for the proper notochord development in vertebrates, and the apoptotic pathway mediated by Fas and Fasl has been demonstrated to be involved in notochord cells regression. This study was conducted to investigate the expression of FAS/FASL pathway in a cohort of skull base chordomas and to analyze the role of fas/fasl homologs in zebrafish notochord formation. FAS/FASL expression was found to be dysregulated in chordoma leading to inactivation of the downstream Caspases in the samples analyzed. Both fas and fasl were specifically expressed in zebrafish notochord sorted cells. fas and fasl loss-of-function mainly resulted in larvae with notochord multi-cell-layer jumps organization, larger vacuolated notochord cells, defects in the peri-notochordal sheath structure and in vertebral mineralization. Interestingly, we observed the persistent expression of ntla and col2a1a, the zebrafish homologs of the human T gene and COL2A1 respectively, which are specifically up-regulated in chordoma. These results demonstrate for the first time the dysregulation of FAS/FASL in chordoma and their role in notochord formation in the zebrafish model, suggesting their possible implication in chordoma onset. PMID:25071022

  18. In vivo modulation of the expressions of Fas and CD25 by intravenous immunoglobulin in common variable immunodeficiency.

    PubMed

    Artac, Hasibe; Kara, Reyhan; Reisli, Ismail

    2010-03-01

    Although the presence of physiologic anti-CD95 (Fas, APO-1) autoantibodies in intravenous immunoglobulin (IVIG) preparations is known, the effects of these antibodies in patients with common variable immunodeficiency are unclear (CVID). The aim of the study was to assess the effects of IVIG in Fas expression, activation markers and the subsets of T cells in patients with CVID. We studied 15 cases with CVID and 10 healthy controls with no signs of immunodeficiency. The Fas expression of T cells, activation markers (CD25, CD69 and HLA-DR) and T-cell subsets were analyzed by four-color flow cytometry. We found that the Fas expression of CD3+ T cells in patients was significantly higher than in controls. In addition, there was a significant increase in the Fas expression of CD3+ T cells and CD4+ T cells, and the CD25 expression of CD3+ and CD4+ T cells after IVIG supplementation (P < 0.05). The CD69 and HLA-DR expressions of T cells and CD8+ T cells were not affected by IVIG infusion. Our observation showed that IVIG replacement causes an increase in the Fas and CD25 expressions in patients with CVID. These data suggest that the Fas protein may have an important role in the effects of IVIG for the control of autoimmunity in patients with CVID, as well as in the generation of autoimmune disease. PMID:19730984

  19. Up-regulation of Fas (CD95) and induction of apoptosis in intestinal epithelial cells by nematode-derived molecules.

    PubMed

    Kuroda, Akio; Uchikawa, Ryuichi; Matsuda, Shinji; Yamada, Minoru; Tegoshi, Tatsuya; Arizono, Naoki

    2002-08-01

    Infection by the intestinal nematode Nippostrongylus brasiliensis induces acceleration of apoptosis in the small intestinal villus epithelial cells in vivo. In the present study, we examined whether worm extract or excretory-secretory product induces apoptosis in the rat intestinal epithelial cell line IEC-6 in vitro. In the presence of worm extract or excretory-secretory product (> or =6 microg/ml), IEC-6 cell growth was significantly suppressed, and there was a concomitant increase in the number of detached cells in culture dishes. Detached cells showed nuclear fragmentation, activation of caspase-3, and specific cleavage of poly(ADP-ribose) polymerase, suggesting that apoptosis was induced in these cells. Semiquantitative reverse transcription-PCR showed that expression of Fas (CD95) mRNA was up-regulated as early as 6 h after addition of excretory-secretory product, while Fas ligand expression and p53 expression were not up-regulated. Fluorescence-activated cell sorter analyses revealed a significant increase in Fas expression and a slight increase in FasL expression in IEC-6 cells cultured in the presence of excretory-secretory product, while control IEC-6 cells expressed neither Fas or FasL. These results indicated that N. brasiliensis worms produce and secrete biologically active molecules that trigger apoptosis in intestinal epithelial cells together with up-regulation of Fas expression, although the mechanism of induction of apoptosis remains to be elucidated. PMID:12117905

  20. 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. PMID:27375266

  1. 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. PMID:23937299

  2. 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.

  3. Testing Theories about Ethnic Markers: Ingroup Accent Facilitates Coordination, Not Cooperation.

    PubMed

    Jensen, Niels Holm; Petersen, Michael Bang; Høgh-Olesen, Henrik; Ejstrup, Michael

    2015-06-01

    In recent years, evolutionary psychologists and anthropologists have debated whether ethnic markers have evolved to solve adaptive problems related to interpersonal coordination or to interpersonal cooperation. In the present study, we add to this debate by exploring how individuals living in a modern society utilize the accents of unfamiliar individuals to make social decisions in hypothetical economic games that measure interpersonal trust, generosity, and coordination. A total of 4603 Danish participants completed a verbal-guise study administered over the Internet. Participants listened to four speakers (two local and two nonlocal) and played a hypothetical Dictator Game, Trust Game, and Coordination Game with each of them. The results showed that participants had greater faith in coordinating successfully with local speakers than with nonlocal speakers. The coordination effect was strong for individuals living in the same city as the particular speakers and weakened as the geographical distance between the participants and the speakers grew. Conversely, the results showed that participants were not more generous toward or more trusting of local speakers compared with nonlocal speakers. Taken together, the results suggest that humans utilize ethnic markers of unfamiliar individuals to coordinate behavior rather than to cooperate. PMID:26003842

  4. 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

  5. Effects of acoustic variability in the perceptual learning of non-native-accented speech sounds.

    PubMed

    Wade, Travis; Jongman, Allard; Sereno, Joan

    2007-01-01

    This study addressed whether acoustic variability and category overlap in non-native speech contribute to difficulty in its recognition, and more generally whether the benefits of exposure to acoustic variability during categorization training are stable across differences in category confusability. Three experiments considered a set of Spanish-accented English productions. The set was seen to pose learning and recognition difficulty (experiment 1) and was more variable and confusable than a parallel set of native productions (experiment 2). A training study (experiment 3) probed the relative contributions of category central tendency and variability to difficulty in vowel identification using derived inventories in which these dimensions were manipulated based on the results of experiments 1 and 2. Training and test difficulty related straightforwardly to category confusability but not to location in the vowel space. Benefits of high-variability exposure also varied across vowel categories, and seemed to be diminished for highly confusable vowels. Overall, variability was implicated in perception and learning difficulty in ways that warrant further investigation. PMID:17914280

  6. Major Histocompatibility Complex Class II Inhibits Fas Antigen-Mediated Gastric Mucosal Cell Apoptosis through Actin-Dependent Inhibition of Receptor Aggregation

    PubMed Central

    Stoicov, Calin; Cai, Xun; Li, Hanchen; Klucevsek, Kristine; Carlson, Jane; Saffari, Reza; Houghton, JeanMarie

    2005-01-01

    Escape from normal apoptotic controls is thought to be essential for the development of cancer. During Helicobacter pylori infection, the leading cause of gastric cancer, activation of the Fas antigen (Fas Ag) apoptotic pathway is responsible for early atrophy and tissue loss. As disease progresses, metaplastic and dysplastic glands arise which express Fas Ag but are resistant to apoptosis and are believed to be the precursor cells for adenocarcinoma. In this report, we show that one mechanism of acquired Fas resistance is inhibition of receptor aggregation via a major histocompatibility complex class II (MHCII)-mediated, actin-dependent mechanism. For these studies we used the well-described C57BL/6 mouse model of Helicobacter pylori and Helicobacter felis infection. Under normal conditions, Fas Ag is expressed at low levels, and MHCII expression on gastric mucosal cells is negligible. With infection and inflammation, both receptors are upregulated, and 6.1% of gastric mucosal cells express MHCII in combination with Fas Ag. Using the rat gastric mucosal cell line RGM-1 transfected with murine Fas Ag and MHCIIαβ chains, we demonstrate that MHCII prevents Fas receptor aggregation and inhibits Fas-mediated signaling through its effects on the actin cytoskeleton. Depolymerization of actin with cytochalasin D allows receptors to aggregate and restores Fas sensitivity. These findings offer one mechanism by which gastric mucosal cells acquire Fas resistance. PMID:16177302

  7. 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. PMID:27011046

  8. The Educational Attainment of Children with Fetal Alcohol Syndrome. Recommendations and Reports.

    ERIC Educational Resources Information Center

    Gessner, Bradford; Bischoff, Herbert; Perham-Hester, Kathy; Chandler, Bruce; Middaugh, John

    This study examined the educational records of 36 children who met all or most of the criteria for fetal alcohol syndrome (FAS) and who were referred to special education in Anchorage, Fairbanks, or Juneau (Alaska) school districts. Thirty of the children were found to have medical comorbidities independent of the findings generally associated…

  9. Fetal Alcohol Syndrome and Fetal Alcohol and Other Drug Effects. A Guide for Teachers.

    ERIC Educational Resources Information Center

    New Jersey State Dept. of Education, Trenton. Div. of General Academic Education.

    This curriculum guide on Fetal Alcohol Syndrome (FAS) is intended to help meet New Jersey secondary-level learning objectives in the area of chemical health education. The guide is organized into six sections, each with a conceptual statement, content outline, specific objectives, and lesson plans. The six sections and corresponding major concepts…

  10. Oncogenic Ras suppresses ING4-TDG-Fas axis to promote apoptosis resistance

    PubMed Central

    Sun, Jie; Shen, Qi; Lu, Haiqi; Jiang, Zhinong; Xu, Wenxia; Feng, Lifeng; Li, Ling; Wang, Xian; Cai, Xiujun; Jin, Hongchuan

    2015-01-01

    Ras is aberrantly activated in many cancers and active DNA demethylation plays a fundamental role to establish DNA methylation pattern which is of importance to cancer development. However, it was unknown whether and how Ras regulate DNA demethylation during carcinogenesis. Here we found that Ras downregulated thymine-DNA glycosylase (TDG), a DNA demethylation enzyme, by inhibiting the interaction of transcription activator ING4 with TDG promoter. TDG recruited histone lysine demethylase JMJD3 to the Fas promoter and activated its expression, thus restoring sensitivity to apoptosis. TDG suppressed in vivo tumorigenicity of xenograft pancreatic cancer. Thus, we speculate that reversing Ras-mediated ING4 inhibition to activate Fas expression is a potential therapeutic approach for Ras-driven cancers. PMID:26544625

  11. Interferon-γ Induces Fas Trafficking and Sensitization to Apoptosis in Vascular Smooth Muscle Cells via a PI3K- and Akt-Dependent Mechanism

    PubMed Central

    Rosner, Dalya; Stoneman, Victoria; Littlewood, Trevor; McCarthy, Nicola; Figg, Nichola; Wang, Yinong; Tellides, George; Bennett, Martin

    2006-01-01

    Vascular smooth muscle cell (VSMC) apoptosis occurs in advanced atherosclerotic plaques where it may contribute to plaque instability. VSMCs express the death receptor Fas but are relatively resistant to Fas-induced apoptosis due in part to the intracellular sequestration of Fas. Although inflammatory cytokines such as interferon (IFN)-γ present in plaques can prime VSMCs to FasL-induced death, the mechanism of this effect is unclear. We examined Fas expression and FasL-induced apoptosis in human VSMCs in response to IFN-γ. IFN-γ induced Fas trafficking to the cell surface within 24 hours, an effect that required Jak2/Stat1 activity. IFN-γ also stimulated Akt activity, and both Fas trafficking and Stat1 activation were inhibited by blocking PI3K, Akt, or Jak-2. IFN-γ increased Fas-induced apoptosis in vitro by 46 ± 8% (mean ± SEM, P = 0.04), an event that could be abrogated by inhibition of PI3K, Akt, or Jak-2. IFN-γ also increased Fas-induced apoptosis in vivo 7.5- to 15-fold (P < 0.05) in human arteries transplanted into immunodeficient mice, accompanied by increased Fas and phospho-Ser727-Stat1. We conclude that IFN-γ primes VSMCs to Fas-induced apoptosis, in part by relocation of Fas to the cell surface, a process that involves PI3K, Akt, and Jak-2/Stat1. IFN-γ present in plaques may co-operate with FasL to induce VSMC apoptosis in atherosclerosis. PMID:16723718

  12. Adoptive Transfer of Dendritic Cells Expressing Fas Ligand Modulates Intestinal Inflammation in a Model of Inflammatory Bowel Disease

    PubMed Central

    de Jesus, Edelmarie Rivera; Isidro, Raymond A; Cruz, Myrella L; Marty, Harry; Appleyard, Caroline B

    2016-01-01

    Background Inflammatory bowel diseases (IBD) are chronic relapsing inflammatory conditions of unknown cause and likely result from the loss of immunological tolerance, which leads to over-activation of the gut immune system. Gut macrophages and dendritic cells (DCs) are essential for maintaining tolerance, but can also contribute to the inflammatory response in conditions such as IBD. Current therapies for IBD are limited by high costs and unwanted toxicities and side effects. The possibility of reducing intestinal inflammation with DCs genetically engineered to over-express the apoptosis-inducing FasL (FasL-DCs) has not yet been explored. Objective Investigate the immunomodulatory effect of administering FasL-DCs in the rat trinitrobenzene sulfonic acid (TNBS) model of acute colitis. Methods Expression of FasL on DCs isolated from the mesenteric lymph nodes (MLNs) of normal and TNBS-colitis rats was determined by flow cytometry. Primary rat bone marrow DCs were transfected with rat FasL plasmid (FasL-DCs) or empty vector (EV-DCs). The effect of these DCs on T cell IFNγ secretion and apoptosis was determined by ELISPOT and flow cytometry for Annexin V, respectively. Rats received FasL-DCs or EV-DCs intraperitoneally 96 and 48 hours prior to colitis induction with TNBS. Colonic T cell and neutrophil infiltration was determined by immunohistochemistry for CD3 and myeloperoxidase activity assay, respectively. Macrophage number and phenotype was measured by double immunofluorescence for CD68 and inducible Nitric Oxide Synthase. Results MLN dendritic cells from normal rats expressed more FasL than those from colitic rats. Compared to EV-DCs, FasL-DCs reduced T cell IFNγ secretion and increased T cell apoptosis in vitro. Adoptive transfer of FasL-DCs decreased macroscopic and microscopic damage scores and reduced colonic T cells, neutrophils, and proinflammatory macrophages when compared to EV-DC adoptive transfer. Conclusion FasL-DCs are effective at treating colonic

  13. 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

  14. Autoantigen-Specific B Cell Activation in FAS-Deficient Rheumatoid Factor Immunoglobulin Transgenic Mice

    PubMed Central

    Wang, Haowei; Shlomchik, Mark J.

    1999-01-01

    In systemic autoimmune disease, self-tolerance fails, leading to autoantibody production. A central issue in immunology is to understand the origins of activated self-reactive B cells. We have used immunoglobulin (Ig) transgenic mice to investigate the regulation of autoreactive B cells with specificity for self-IgG2a (the rheumatoid factor [RF] specificity) to understand how normal mice regulate RF autoantibodies and how this fails in autoimmune mice. We previously showed that normal mice do not tolerize the AM14 RF clone, nor do they appear to activate it. Here we show that in Fas-deficient autoimmune mice, the picture is quite different. RF B cells are activated to divide and secrete, but only when the autoantigen is present. Thus, B cells that are ignored rather than anergized in normal mice can be stimulated to produce autoantibody in Fas-deficient mice. This demonstrates a novel developmental step at which intact Fas–Fas ligand signaling is required to regulate B cells in order to prevent autoimmunity. These data also establish the relevance of ignorant self-specific B cells to autoantibody production in disease and prove that in the case of the RF specificity, the nominal autoantigen IgG2a is the driving autoantigen in vivo. PMID:10477549

  15. Flotillin-2 Modulates Fas Signaling Mediated Apoptosis after Hyperoxia in Lung Epithelial Cells

    PubMed Central

    Wei, Shuquan; Moon, Hyung-Geun; Zheng, Yijie; Liang, Xiaoliang; An, Chang Hyeok; Jin, Yang

    2013-01-01

    Lipid rafts are subdomains of the cell membrane with distinct protein composition and high concentrations of cholesterol and glycosphingolipids. Raft proteins are thought to mediate diverse cellular processes including signal transduction. However, its cellular mechanisms remain unclear. Caveolin-1 (cav-1, marker protein of caveolae) has been thought as a switchboard between extracellular matrix (ECM) stimuli and intracellular signals. Flotillin-2/reggie-1(Flot-2) is another ubiquitously expressed raft protein which defines non-caveolar raft microdomains (planar raft). Its cellular function is largely uncharacterized. Our novel studies demonstrated that Flot-2, in conjunction with cav-1, played important functions on controlling cell death via regulating Fas pathways. Using Beas2B epithelial cells, we found that in contrast to cav-1, Flot-2 conferred cytoprotection via preventing Fas mediated death-inducing signaling complex (DISC) formation, subsequently suppressed caspase-8 mediated extrinsic apoptosis. Moreover, Flot-2 reduced the mitochondria mediated intrinsic apoptosis by regulating the Bcl-2 family and suppressing cytochrome C release from mitochondria to cytosol. Flot-2 further modulated the common apoptosis pathway and inhibited caspase-3 activation via up-regulating the members in the inhibitor of apoptosis (IAP) family. Last, Flot-2 interacted with cav-1 and limited its expression. Taken together, we found that Flot-2 protected cells from Fas induced apoptosis and counterbalanced the pro-apoptotic effects of cav-1. Thus, Flot-2 played crucial functions in cellular homeostasis and cell survival, suggesting a differential role of individual raft proteins. PMID:24204853

  16. Ginsenoside Rh2 induces ligand-independent Fas activation via lipid raft disruption

    SciTech Connect

    Yi, Jae-Sung; Choo, Hyo-Jung; Cho, Bong-Rae; Kim, Hwan-Myung; Kim, Yong-Nyun; Ham, Young-Mi; Ko, Young-Gyu

    2009-07-24

    Lipid rafts are plasma membrane platforms mediating signal transduction pathways for cellular proliferation, differentiation and apoptosis. Here, we show that membrane fluidity was increased in HeLa cells following treatment with ginsenoside Rh2 (Rh2), as determined by cell staining with carboxy-laurdan (C-laurdan), a two-photon dye designed for measuring membrane hydrophobicity. In the presence of Rh2, caveolin-1 appeared in non-raft fractions after sucrose gradient ultracentrifugation. In addition, caveolin-1 and GM1, lipid raft landmarkers, were internalized within cells after exposure to Rh2, indicating that Rh2 might disrupt lipid rafts. Since cholesterol overloading, which fortifies lipid rafts, prevented an increase in Rh2-induced membrane fluidity, caveolin-1 internalization and apoptosis, lipid rafts appear to be essential for Rh2-induced apoptosis. Moreover, Rh2-induced Fas oligomerization was abolished following cholesterol overloading, and Rh2-induced apoptosis was inhibited following treatment with siRNA for Fas. This result suggests that Rh2 is a novel lipid raft disruptor leading to Fas oligomerization and apoptosis.

  17. Fas activation of the p38 mitogen-activated protein kinase signalling pathway requires ICE/CED-3 family proteases.

    PubMed Central

    Juo, P; Kuo, C J; Reynolds, S E; Konz, R F; Raingeaud, J; Davis, R J; Biemann, H P; Blenis, J

    1997-01-01

    The Fas receptor mediates a signalling cascade resulting in programmed cell death (apoptosis) within hours of receptor cross-linking. In this study Fas activated the stress-responsive mitogen-activated protein kinases, p38 and JNK, within 2 h in Jurkat T lymphocytes but not the mitogen-responsive kinase ERK1 or pp70S6k. Fas activation of p38 correlated temporally with the onset of apoptosis, and transfection of constitutively active MKK3 (glu), an upstream regulator of p38, potentiated Fas-induced cell death, suggesting a potential involvement of the MKK3/p38 activation pathway in Fas-mediated apoptosis. Fas has been shown to require ICE (interleukin-1 beta-converting enzyme) family proteases to induce apoptosis from studies utilizing the cowpox ICE inhibitor protein CrmA, the synthetic tetrapeptide ICE inhibitor YVAD-CMK, and the tripeptide pan-ICE inhibitor Z-VAD-FMK. In this study, crmA antagonized, and YVAD-CMK and Z-VAD-FMK completely inhibited, Fas activation of p38 kinase activity, demonstrating that Fas-dependent activation of p38 requires ICE/CED-3 family members and conversely that the MKK3/p38 activation cascade represents a downstream target for the ICE/CED-3 family proteases. Intriguingly, p38 activation by sorbitol and etoposide was resistant to YVAD-CMK and Z-VAD-FMK, suggesting the existence of an additional mechanism(s) of p38 regulation. The ICE/CED-3 family-p38 regulatory relationship described in the current work indicates that in addition to the previously described destructive cleavage of substrates such as poly(ADP ribose) polymerase, lamins, and topoisomerase, the apoptotic cysteine proteases also function to regulate stress kinase signalling cascades. PMID:8972182

  18. Surface tethered epidermal growth factor protects proliferating and differentiating multipotential stromal cells from FasL induced apoptosis

    PubMed Central

    Rodrigues, Melanie; Blair, Harry; Stockdale, Linda; Griffith, Linda; Wells, Alan

    2012-01-01

    Multipotential stromal cells, or mesenchymal stem cells, (MSC) have ben proposed as aids in regenerating bone and adipose tissues, as these cells form osteoblasts and adipocytes. A major obstacle to this use of MSC is the initial loss of cells post-implantation. This cell death in part, is due to ubiquitous non-specific inflammatory cytokines such as FasL generated in the implant site. Our group previously found that soluble epidermal growth factor (sEGF) promotes MSC expansion. Further, tethering EGF onto a two-dimensional surface (tEGF) altered MSC responses, by restricting epidermal growth factor receptor (EGFR) to the cell surface, causing sustained activation of EGFR, and promoting survival from FasL-induced death. sEGF by causing internalization of EGFR does not support MSC survival. However, for tEGF to be useful in bone regeneration, it needs to allow for MSC differentiation into osteoblasts while also protecting emerging osteoblasts from apoptosis. tEGF did not block induced differentiation of MSCs into osteoblasts, or adipocytes, a common default MSC-differentiation pathway. MSC-derived pre-osteoblasts showed increased Fas levels and became more susceptible to FasL induced death, which tEGF prevented. Differentiating adipocytes underwent a reduction in Fas expression and became resistant to FasL-induced death, with tEGF having no further survival effect. tEGF protected undifferentiated MSC from combined insults of FasL, serum deprivation and physiologic hypoxia. Additionally, tEGF was dominant in the face of sEGF to protect MSC from FasL-induced death. Our results suggest that MSCs and differentiating osteoblasts need protective signals to survive in the inflammatory wound milieu and that tEGF can serve this function. PMID:22948863

  19. Mouse interleukin-12/FasTI: A novel bi-functional fusion protein for cancer immuno/gene therapy.

    PubMed

    Yang, Xi; Tietje, Ashlee H; Yu, Xianzhong; Wei, Yanzhang

    2016-06-01

    Whereas cancer immunotherapy with cytokines in recent research was demonstrated effective in activating immune response against tumor cells, one major obstacle with the use of these cytokines is their severe side effects when delivered systemically at high doses. Another challenge is that advanced tumor cells often evade immunosurveillance of the immune system as well as of the Fas-mediated apoptosis by various mechanisms. We report the design and preliminary evaluation of the antitumor activity of a novel fusion protein-mIL-12/FasTI, consisting of mouse interleukin-12 and the transmembrane and intracellular domains of mouse Fas. The fusion construct (pmIL-12/FasTI) was transfected into mouse lung carcinoma cell line TC-1. Stable cell clones expressing the fusion protein were established as assayed by RT-PCR and immunohistochemistry. ELISA and cell proliferation analyses demonstrated that NK cells were effectively activated by the fusion protein with increased IFN-γ production and cytotoxicity. Enhanced caspase-3 activity of the clones when co-cultured with NK cells indicated that apoptosis was induced through Fas/FasL signaling pathway. The preliminary results suggest a synergized anticancer activity of the fusion protein. It may represent a promising therapeutic agent for cancer treatment. PMID:27081758

  20. Purification and properties of the fatty acids synthetase complex from Neurospora crassa, and the nature of the fas-mutation.

    PubMed Central

    Elovson, J

    1975-01-01

    A procedure is described for the purification of the fatty acid synthetase complex (FAS) from Neurospora crassa. The enzyme complex has a molecular weight of 2.3 times 10(6), contains 6 mol of 4'-phosphopantetheine per mol, and on polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate gives a single band, or a closely spaced doublet, which comigrates with standard myosin (molecular weight, 2 times 10(5)). Since the slightly retarded component in the doublet accounts for all protein-bound 4'-phosphopantetheine, the complex appears to be made up of 11 to 12 equally sized subunits, 6 of which carry the acyl carrier protein function. In this unusual arrangement, notably the lack of the low-molecular-weight acyl carrier protein component seen in other FAS systems, as well as in its enzymatic properties, the Neurospora FAS complex is quite similar to the yeast enzyme. The FAS complex of a saturated fatty acid-requiring mutant, previously disignated cel-, contains less than 2% of the 4'-phosphopantetheine prosthetic groups found in the wild-type complex. The leaky phenotype of this mutant, here designated fas-, is accounted for by a residual fatty acid synthesizing activity in its FAS complex, which is several-fold higher than expected from its residual content of 4'-phosphopanthetheine. Images PMID:126228

  1. Extra Cellular Matrix Derived Metabolite Regulates Angiogenesis by FasL Mediated Apoptosis

    PubMed Central

    Verma, Raj K.; Gunda, Venugopal; Pawar, Smita C.; Sudhakar, Yakkanti Akul

    2013-01-01

    Object Antiangiogenic treatments are beginning to give promising outcomes in many vascular diseases including tumor angiogenesis. In this current study the antiangiogenic and pro-apoptotic actions of α1(IV)NC1 and its N- and C- peptides α1S1(IV)NC1, α1S2(IV)NC1 were investigated in-vitro and in-vivo. Study Method Endothelial cells (ECs) were treated with α1(IV)NC1, α1S1(IV)NC1, α1S2(IV)NC1 and in-vitro proliferation, migration, tube formation and apoptotic assays were executed. FasL, Fas, Caspase-8, -3 and PARP activations were studied using immunoblotting analysis using specific antibodies. Also the in-vivo antiangiogenic and pro-apoptotic effects were tested using α1(IV)NC1 in a mice model. Results Like α1(IV)NC1, its N- and C- terminal α1S2(IV)NC1 and α1S1(IV)NC1 domains posses anti-proliferative, pro-apoptotic activity and inhibit ECs migration and tube formation in-vitro. Both α1S1(IV)NC1 and α1S2(IV)NC1 domains promote apoptosis by activating FasL and down stream apoptotic events including activation of caspase-8, -3 and PARP cleavage in a dose dependent manner in-vitro in ECs. Tumors in mice showed apoptotic TUNEL positive microvasculature upon α1(IV)NC1 treatment, indicating inhibition of tumor angiogenesis and tumor growth. Further, the antitumor activity of α1(IV)NC1 was abrogated when caspase-3 inhibitor was used. These results conform additional properties of α1(IV)NC1 as an endogenous angioinhibitor that induces apoptosis in-vitro and in-vivo by activating FasL mediated caspase-3. Significance α1(IV)NC1 and its N- and C- terminal α1S1(IV)NC1 and α1S2(IV)NC1 domains also posses pro-apoptotic and angioinhibitory activity in-vitro and in-vivo. α1(IV)NC1 regulates tumor angiogenesis by activating FasL mediated apoptosis in-vitro and in-vivo. These results demonstrate that α1(IV)NC1 and its peptides inhibit neo-vascular diseases. PMID:24324608

  2. Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling.

    PubMed

    Yang, Fei; Wei, Yinxiang; Cai, Zhijian; Yu, Lei; Jiang, Lingling; Zhang, Chengyan; Yan, Huanmiao; Wang, Qingqing; Cao, Xuetao; Liang, Tingbo; Wang, Jianli

    2015-01-01

    The Fas/FasL system transmits intracellular apoptotic signaling, inducing cell apoptosis. However, Fas signaling also exerts non-apoptotic functions in addition to inducing tumor cell apoptosis. For example, Fas signaling induces lung cancer tumor cells to produce prostaglandin E2 (PGE2) and recruit myeloid-derived suppressor cells (MDSCs). Activated cytotoxic T lymphocytes (CTLs) induce and express high levels of FasL, but the effects of Fas activation initiated by FasL in CTLs on apoptosis-resistant tumor cells remain largely unclear. We purified activated CD8(+) T cells from OT-1 mice, evaluated the regulatory effects of Fas activation on tumor cell escape and investigated the relevant mechanisms. We found that CTLs induced tumor cells to secrete PGE2 and increase tumor cell-mediated chemoattraction of MDSCs via Fas signaling, which was favorable to tumor growth. Our results indicate that CTLs may participate in the tumor immune evasion process. To the best of our knowledge, this is a novel mechanism by which CTLs play a role in tumor escape. Our findings implicate a strategy to enhance the antitumor immune response via reduction of negative immune responses to tumors promoted by CTLs through Fas signaling. PMID:24769795

  3. Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling

    PubMed Central

    Yang, Fei; Wei, Yinxiang; Cai, Zhijian; Yu, Lei; Jiang, Lingling; Zhang, Chengyan; Yan, Huanmiao; Wang, Qingqing; Cao, Xuetao; Liang, Tingbo; Wang, Jianli

    2015-01-01

    The Fas/FasL system transmits intracellular apoptotic signaling, inducing cell apoptosis. However, Fas signaling also exerts non-apoptotic functions in addition to inducing tumor cell apoptosis. For example, Fas signaling induces lung cancer tumor cells to produce prostaglandin E2 (PGE2) and recruit myeloid-derived suppressor cells (MDSCs). Activated cytotoxic T lymphocytes (CTLs) induce and express high levels of FasL, but the effects of Fas activation initiated by FasL in CTLs on apoptosis-resistant tumor cells remain largely unclear. We purified activated CD8+ T cells from OT-1 mice, evaluated the regulatory effects of Fas activation on tumor cell escape and investigated the relevant mechanisms. We found that CTLs induced tumor cells to secrete PGE2 and increase tumor cell-mediated chemoattraction of MDSCs via Fas signaling, which was favorable to tumor growth. Our results indicate that CTLs may participate in the tumor immune evasion process. To the best of our knowledge, this is a novel mechanism by which CTLs play a role in tumor escape. Our findings implicate a strategy to enhance the antitumor immune response via reduction of negative immune responses to tumors promoted by CTLs through Fas signaling. PMID:24769795

  4. FasL Expression on Human Nucleus Pulposus Cells Contributes to the Immune Privilege of Intervertebral Disc by Interacting with Immunocytes

    PubMed Central

    Liu, Zhi-Heng; Sun, Zhen; Wang, Hai-Qiang; Ge, Jun; Jiang, Ting-Shuai; Chen, Yu-Fei; Ma, Ying; Wang, Chen; Hu, Sheng; Samartzis, Dino; Luo, Zhuo-Jing

    2013-01-01

    The mechanisms of immune privilege in human nucleus pulposus (NP) remain unclear. Accumulating evidence indicates that Fas ligand (FasL) might play an important role in the immune privilege of the disc. We aimed for addressing the role of FasL expression in human intervertebral disc degeneration (IDD) and immune privilege in terms of the interaction between NP cells and immunocytes via the FasL-Fas machinery. We collected NP specimens from 20 patients with IDD as degenerative group and 8 normal cadaveric donors as control. FasL expression was detected by qRT-PCR, western blotting and flow cytometry (FCM). We also collected macrophages and CD8+ T cells from the peripheral blood of patients with IDD for co-cultures with NP cells. And macrophages and CD8+ T cells were harvested for apoptosis analysis by FCM after 2 days of co-cultures. We found that FasL expression in mRNA, protein and cellular resolutions demonstrated a significant decrease in degenerative group compared with normal control (p<0.05). FCM analysis found that human NP cells with increased FasL expression resulted in significantly increased apoptosis ratio of macrophages and CD8+ T cells. Our study demonstrated that FasL expression tends to decrease in degenerated discs and FasL plays an important role in human disc immune privilege, which might provide a novel target for the treatment strategies for IDD. PMID:23801893

  5. Innovative estimation of survival using log-normal survival modelling on ACCENT database

    PubMed Central

    Chapman, J W; O'Callaghan, C J; Hu, N; Ding, K; Yothers, G A; Catalano, P J; Shi, Q; Gray, R G; O'Connell, M J; Sargent, D J

    2013-01-01

    Background: The ACCENT database, with individual patient data for 20 898 patients from 18 colon cancer clinical trials, was used to support Food and Drug Administration (FDA) approval of 3-year disease-free survival as a surrogate for 5-year overall survival. We hypothesised substantive differences in survival estimation with log-normal modelling rather than standard Kaplan–Meier or Cox approaches. Methods: Time to relapse, disease-free survival, and overall survival were estimated using Kaplan–Meier, Cox, and log-normal approaches for male subjects aged 60–65 years, with stage III colon cancer, treated with 5-fluorouracil-based chemotherapy regimens (with 5FU), or with surgery alone (without 5FU). Results: Absolute differences between Cox and log-normal estimates with (without) 5FU varied by end point. The log-normal model had 5.8 (6.3)% higher estimated 3-year time to relapse than the Cox model; 4.8 (5.1)% higher 3-year disease-free survival; and 3.2 (2.2)% higher 5-year overall survival. Model checking indicated greater data support for the log-normal than the Cox model, with Cox and Kaplan–Meier estimates being more similar. All three model types indicate consistent evidence of treatment benefit on both 3-year disease-free survival and 5-year overall survival; patients allocated to 5FU had 5.0–6.7% higher 3-year disease-free survival and 5.3–6.8% higher 5-year overall survival. Conclusion: Substantive absolute differences between estimates of 3-year disease-free survival and 5-year overall survival with log-normal and Cox models were large enough to be clinically relevant, and warrant further consideration. PMID:23385733

  6. Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity.

    PubMed

    Schneider, P; Holler, N; Bodmer, J L; Hahne, M; Frei, K; Fontana, A; Tschopp, J

    1998-04-20

    Human Fas ligand (L) (CD95L) and tumor necrosis factor (TNF)-alpha undergo metalloproteinase-mediated proteolytic processing in their extracellular domains resulting in the release of soluble trimeric ligands (soluble [s]FasL, sTNF-alpha) which, in the case of sFasL, is thought to be implicated in diseases such as hepatitis and AIDS. Here we show that the processing of sFasL occurs between Ser126 and Leu127. The apoptotic-inducing capacity of naturally processed sFasL was reduced by >1,000-fold compared with membrane-bound FasL, and injection of high doses of recombinant sFasL in mice did not induce liver failure. However, soluble FasL retained its capacity to interact with Fas, and restoration of its cytotoxic activity was achieved both in vitro and in vivo with the addition of cross-linking antibodies. Similarly, the marginal apoptotic activity of recombinant soluble TNF-related apoptosis-inducing ligand (sTRAIL), another member of the TNF ligand family, was greatly increased upon cross-linking. These results indicate that the mere trimerization of the Fas and TRAIL receptors may not be sufficient to trigger death signals. Thus, the observation that sFasL is less cytotoxic than membrane-bound FasL may explain why in certain types of cancer, systemic tissue damage is not detected, even though the levels of circulating sFasL are high. PMID:9547332

  7. Magnitude of phonetic distinction predicts success at early word learning in native and non-native accents

    PubMed Central

    Escudero, Paola; Best, Catherine T.; Kitamura, Christine; Mulak, Karen E.

    2014-01-01

    Although infants perceptually attune to native vowels and consonants well before 12 months, at 13–15 months, they have difficulty learning to associate novel words that differ by their initial consonant (e.g., BIN and DIN) to their visual referents. However, this difficulty may not apply to all minimal pair novel words. While Canadian English (CE) 15-month-olds failed to respond to a switch from the newly learned word DEET to the novel non-word DOOT, they did notice a switch from DEET to DIT (Curtin et al., 2009). Those authors argued that early word learners capitalize on large phonetic differences, seen in CE DEET–DIT, but not on smaller phonetic differences, as in CE DEET–DOOT. To assess this hypothesis, we tested Australian English (AusE) 15-month-olds, as AusE has a smaller magnitude of phonetic difference in both novel word pairs. Two groups of infants were trained on the novel word DEET and tested on the vowel switches in DIT and DOOT, produced by an AusE female speaker or the same CE female speaker as in Curtin et al. (2009). If the size of the phonetic distinction plays a more central role than native accent experience in early word learning, AusE children should more easily recognize both of the unfamiliar but larger CE vowel switches than the more familiar but smaller AusE ones. The results support our phonetic-magnitude hypothesis: AusE children taught and tested with the CE-accented novel words looked longer to both of the switch test trials (DIT, DOOT) than same test trials (DEET), while those who heard the AusE-accented tokens did not notice either switch. Implications of our findings for models of early word learning are discussed. PMID:25324793

  8. Altered erythrocyte membrane fatty acid profile in typical Rett syndrome: effects of omega-3 polyunsaturated fatty acid supplementation.

    PubMed

    Signorini, Cinzia; De Felice, Claudio; Leoncini, Silvia; Durand, Thierry; Galano, Jean-Marie; Cortelazzo, Alessio; Zollo, Gloria; Guerranti, Roberto; Gonnelli, Stefano; Caffarelli, Carla; Rossi, Marcello; Pecorelli, Alessandra; Valacchi, Giuseppe; Ciccoli, Lucia; Hayek, Joussef

    2014-11-01

    This study mainly aims at examining the erythrocyte membrane fatty acid (FAs) profile in Rett syndrome (RTT), a genetically determined neurodevelopmental disease. Early reports suggest a beneficial effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on disease severity in RTT. A total of 24 RTT patients were assigned to ω-3 PUFAs-containing fish oil for 12 months in a randomized controlled study (average DHA and EPA doses of 72.9, and 117.1mg/kgb.w./day, respectively). A distinctly altered FAs profile was detectable in RTT, with deficient ω-6 PUFAs, increased saturated FAs and reduced trans 20:4 FAs. FAs changes were found to be related to redox imbalance, subclinical inflammation, and decreased bone density. Supplementation with ω-3 PUFAs led to improved ω-6/ω-3 ratio and serum plasma lipid profile, decreased PUFAs peroxidation end-products, normalization of biochemical markers of inflammation, and reduction of bone hypodensity as compared to the untreated RTT group. Our data indicate that a significant FAs abnormality is detectable in the RTT erythrocyte membranes and is partially rescued by ω-3 PUFAs. PMID:25240461

  9. B cells are required for lupus nephritis in the polygenic, Fas-intact MRL model of systemic autoimmunity.

    PubMed

    Chan, O T; Madaio, M P; Shlomchik, M J

    1999-10-01

    B cells are required for both the expression of lupus nephritis and spontaneous T cell activation/memory cell accumulation in MRL-Faslpr mice (MRL/lpr). Autoimmunity in the MRL/lpr strain is the result of Fas-deficiency and multiple background genes; however, the precise roles of background genes vs Fas-deficiency have not been fully defined. Fas-deficiency (i.e., the lpr defect) is required in B cells for optimal autoantibody expression, raising the possibility that the central role for B cells in MRL/lpr mice may not extend to MRL/+ mice and, thus, to lupus models that do not depend on Fas-deficiency ("polygenic lupus"). To address this issue, B cell-deficient, Fas-intact MRL/+ mice (JHd-MRL/) were created; and disease was evaluated in aged animals (>9 mo). The JHd-MRL/+ animals did not develop nephritis or vasculitis at a time when the B cell-intact littermates had severe disease. In addition, while activated/memory CD4+ and CD8+ T cells accumulated in B cell-intact mice, such accumulation was substantially inhibited in the absence of B cells. This effect appeared to be restricted to the MRL strain because it was not seen in B cell-deficient BALB/c mice (JHd-BALB) of similar ages. The results indicate that B cells are essential in promoting systemic autoimmunity in a Fas-independent model. Therefore, B cells have an important role in pathogenesis, generalizable to lupus models that depend on multiple genes even when Fas expression is intact. The results provide further rationale for B cell suppression as therapy for systemic lupus erythematosus. PMID:10490951

  10. Inducing local T cell apoptosis with anti-Fas-functionalized polymeric coatings fabricated via surface-initiated photopolymerizations

    PubMed Central

    Hume, Patrick S.; Anseth, Kristi S.

    2010-01-01

    Cell encapsulation has long been investigated as a means to achieve transplant immunoprotection as it creates a physical barrier between allograft tissue and host immune cells. Encapsulation with passive barrier materials alone, however, is generally insufficient to protect donor tissue from rejection, because small cytotoxic molecules produced by activated T cells can diffuse readily into the capsule and mediate allograft death. As a means to provide bioactive protection for polymeric encapsulation devices, we investigated a functionalized polymeric coating that mimics a natural T cell regulation pathway. T cells are regulated in vivo via Fas, a well-known ‘death receptor,’ whereby effector cells express Fas ligand and elicit T cell apoptosis upon binding the Fas receptor on a T cell surface. Anti-Fas antibodies are capable of replicating this effect and induce T cell apoptosis in solution. Here, an iniferter-based living radical polymerization was utilized to fabricate surface-anchored polymer chains containing poly(ethylene glycol) with covalently-incorporated pendant anti-Fas antibody. Using this reaction mechanism, we demonstrate fabrication conditions that yield surface densities in excess of 1.5 ng/cm2 of incorporated therapeutic, as detected by ELISA. Additionally, we show that coatings containing anti-Fas antibody induced significant T cell apoptosis, 21±2 % of cells, after 24 hours. Finally, the incorporation of a T cell adhesion ligand, intracellular adhesion molecule-1, along with anti-Fas antibody, yielded even higher levels of apoptosis, 34±1% of T cells, compared to either signal alone. PMID:20138358

  11. Deletion of Mir155 Prevents Fas-Induced Liver Injury through Up-Regulation of Mcl-1

    PubMed Central

    Chen, Weina; Han, Chang; Zhang, Jinqiang; Song, Kyoungsub; Wang, Ying; Wu, Tong

    2016-01-01

    Fas-induced apoptosis is involved in diverse liver diseases. Herein, we investigated the effect of Mir155 deletion on Fas-induced liver injury. Wild-type (WT) mice and Mir155 knockout (KO) mice were i.p. administered with the anti-Fas antibody (Jo2) to determine animal survival and the extent of liver injury. After Jo2 injection, the Mir155 KO mice exhibited prolonged survival versus the WT mice (P < 0.01). The Mir155 KO mice showed lower alanine aminotransferase and aspartate aminotransferase levels, less liver tissue damage, fewer apoptotic hepatocytes, and lower liver tissue caspase 3/7, 8, and 9 activities compared with the WT mice, indicating that Mir155 deletion prevents Fas-induced hepatocyte apoptosis and liver injury. Hepatocytes isolated from Mir155 KO mice also showed resistance to Fas-induced apoptosis, in vitro. Higher protein level of myeloid cell leukemia-1 (Mcl-1) was also observed in Mir155 KO hepatocytes compared to WT hepatocytes. A miR-155 binding site was identified in the 3′-untranslated region of Mcl-1 mRNA; Mcl1 was identified as a direct target of miR-155 in hepatocytes. Consistently, pretreatment with a siRNA specific for Mcl1 reversed Mir155 deletion–mediated protection against Jo2-induced liver tissue damage. Finally, restoration of Mir155 expression in Mir155 KO mice abolished the protection against Fas-induced hepatocyte apoptosis. Taken together, these findings demonstrate that deletion of Mir155 prevents Fas-induced hepatocyte apoptosis and liver injury through the up-regulation of Mcl1. PMID:25794705

  12. Fraxetin inhibits the induction of anti-Fas IgM, tumor necrosis factor-alpha and interleukin-1beta-mediated apoptosis by Fas pathway inhibition in human osteoblastic cell line MG-63.

    PubMed

    Kuo, Po-Lin; Huang, Yu-Ting; Chang, Cheng-Hsiung; Chang, Jiunn-Kae

    2006-07-01

    The survival of osteoblast cells is one of the determinants of the development of osteoporosis in patients with inflamed synovium, such as in rheumatoid arthritis (RA). By means of alkaline phosphatase (ALP) activity and osteocalcin ELISA assay, we have shown that fraxetin exhibits a significant induction of differentiation in the human osteoblast-like cell line MG-63. In addition, we also assessed whether fraxetin affects inflammatory cytokine-mediated apoptosis in osteoblast cells. TNF-alpha or IL-1beta enhance apoptotic DNA fragmentation in anti-Fas IgM-treated MG-63 cells by increasing Fas receptor expression. However, TNF-alpha or IL-1beta treatment alone does not induce apoptosis. Treatment of MG-63 cells with fraxetin not only inhibited anti-Fas IgM-induced apoptosis, but also blocked the synergetic effect of anti-Fas IgM with TNF-alpha or IL-1beta on cell death. The apoptotic inhibition of fraxetin is associated with inhibition of TNF-alpha and IL-1beta-mediated Fas expression and enhancement of FLIP expression, resulting in a decrease of caspase-8 and caspase-3 activation. These results indicate a potential use of fraxetin in preventing osteoporosis by inhibiting inflammatory cytokine-mediated apoptosis in osteoblast cells. PMID:16714221

  13. Conditioned medium from alternatively activated macrophages induce mesangial cell apoptosis via the effect of Fas

    SciTech Connect

    Huang, Yuan; Luo, Fangjun; Li, Hui; Jiang, Tao; Zhang, Nong

    2013-11-15

    During inflammation in the glomerulus, the proliferation of myofiroblast-like mesangial cells is commonly associated with the pathological process. Macrophages play an important role in regulating the growth of resident mesangial cells in the glomeruli. Alternatively activated macrophage (M2 macrophage) is a subset of macrophages induced by IL-13/IL-4, which is shown to play a repair role in glomerulonephritis. Prompted by studies of development, we performed bone marrow derived macrophage and rat mesangial cell co-culture study. Conditioned medium from IL-4 primed M2 macrophages induced rat mesangial cell apoptosis. The pro-apoptotic effect of M2 macrophages was demonstrated by condensed nuclei stained with Hoechst 33258, increased apoptosis rates by flow cytometry analysis and enhanced caspase-3 activation by western blot. Fas protein was up-regulated in rat mesangial cells, and its neutralizing antibody ZB4 partly inhibited M2 macrophage-induced apoptosis. The up-regulated arginase-1 expression in M2 macrophage also contributed to this apoptotic effect. These results indicated that the process of apoptosis triggered by conditioned medium from M2 macrophages, at least is partly conducted through Fas in rat mesangial cells. Our findings provide compelling evidence that M2 macrophages control the growth of mesangial cells in renal inflammatory conditions. - Highlights: • Conditioned-medium from M2 macrophages induces rat mesangial cell (MsC) apoptosis. • M2 macrophage conditioned medium exerts its pro-apoptotic effects via Fas ligand. • Arginase-1 activity in M2 macrophages plays a role in inducing apoptosis in rat MsC.

  14. Loss of α(E)-catenin promotes Fas mediated apoptosis in tubular epithelial cells

    PubMed Central

    Wang, Xinhui; Parrish, Alan R.

    2015-01-01

    The aging kidney undergoes structural and functional alterations which make it more susceptible to drug-induced acute kidney injury (AKI). Previous studies in our lab have shown that the expression of α(E)-catenin is decreased in aged kidney and loss of α(E)-catenin potentiates AKI-induced apoptosis, but not necrosis, in renal tubular epithelial cells (NRK-52E cells). However, the specific apoptotic pathway underlying the increased AKI-induced cell death is not yet understood. In this study, cells were challenged with nephrotoxicant cisplatin to induce AKI. A ~5.5-fold increase in Fas expression in C2 (stable α(E)-catenin knockdown) relative to NT3 (non-targeted control) cells was seen. Increased caspase-8 and -9 activation was induced by cisplatin in C2 as compared to NT3 cells. In addition, decreased Bcl-2 expression and increased BID cleavage and cytochrome C release were detected in C2 cells after cisplatin challenge. Treating the cells with cisplatin, in combination with a Bcl-2 inhibitor, decreased the viability of NT3 cells to the same level as C2 cells after cisplatin. Furthermore, caspase-3/-7 activation is blocked by Fas, caspase-8, caspase-9 and pan-caspase inhibitors. These inhibitors also completely abolished the difference in viability between NT3 and C2 cells in response to cisplatin. These results demonstrate a Fas-mediated apoptotic signaling pathway that is enhanced by the age-dependent loss of α(E)-catenin in renal tubule epithelial cells. PMID:25894537

  15. Cytotoxic effect through fas/APO-1 expression due to vitamin K in human glioma cells.

    PubMed

    Sun, L K; Yoshii, Y; Miyagi, K

    2000-03-01

    Congeners of vitamin K have been found to inhibit growth in various rodent and human tumor cells, but the mechanisms of the inhibitory action are still not well understood. To investigate the modes of actions of vitamin K, we used several vitamin K analogs and examined their cytotoxic effect for human glioma cell lines RBR17T and U251. The analogs included vitamin K1 (VK1), vitamin K2 (VK2), vitamin K3 (VK3), and geranylgeraniol (GGO) which form an unsaturated side chain of VK2. Cell viability was estimated by MTT assay. DNA fragmentation was demonstrated by gel electrophoresis and flow cytometry. In order to study the mechanism of apoptosis, we measured the changes of intracellular reactive oxygen intermediates (ROI) and Fas/APO-1 expression by flow cytometry. The results showed: (1) VK2, VK3, and GGO inhibited cell growth; (2) VK3 had a more potent cytotoxic effect than VK2, and VK3 enhanced the cytotoxic effect of antitumor agents (ACNU and IFN-beta) in RBR17T cells; (3) VK2, VK3, and GGO induce apoptosis: (4) VK3 increased the expression of Fas/APO-1 although VK2 and GGO did not increase its expression in glioma cells; (5) VK3 increased the production of intracellular ROI. Catalase and reduced glutathione (GSH) inhibited production of intracellular ROI and antagonized inhibition of cell-growth induced by VK3, but failed to antagonize that of VK2 and GGO. We hypothesize that VK3 induces apoptosis by promoting the generation of intracellular ROI and Fas/APO-1 expression. On the other hand, VK2 and GGO induce apoptosis but most likely by some other unknown pathway. PMID:10930097

  16. Effects of noise, reverberation and foreign accent on native and non-native listeners' performance of English speech comprehension.

    PubMed

    Peng, Z Ellen; Wang, Lily M

    2016-05-01

    A large number of non-native English speakers may be found in American classrooms, both as listeners and talkers. Little is known about how this population comprehends speech in realistic adverse acoustical conditions. A study was conducted to investigate the effects of background noise level (BNL), reverberation time (RT), and talker foreign accent on native and non-native listeners' speech comprehension, while controlling for English language abilities. A total of 115 adult listeners completed comprehension tasks under 15 acoustic conditions: three BNLs (RC-30, RC-40, and RC-50) and five RTs (from 0.4 to 1.2 s). Fifty-six listeners were tested with speech from native English-speaking talkers and 59 with native Mandarin-Chinese-speaking talkers. Results show that, while higher BNLs were generally more detrimental to listeners with lower English proficiency, all listeners experienced significant comprehension deficits above RC-40 with native English talkers. This limit was lower (i.e., above RC-30), however, with Chinese talkers. For reverberation, non-native listeners as a group performed best with RT up to 0.6 s, while native listeners performed equally well up to 1.2 s. A matched foreign accent benefit has also been identified, where the negative impact of higher reverberation does not exist for non-native listeners who share the talker's native language. PMID:27250170

  17. Study of accent-based music speech protocol development for improving voice problems in stroke patients with mixed dysarthria.

    PubMed

    Kim, Soo Ji; Jo, Uiri

    2013-01-01

    Based on the anatomical and functional commonality between singing and speech, various types of musical elements have been employed in music therapy research for speech rehabilitation. This study was to develop an accent-based music speech protocol to address voice problems of stroke patients with mixed dysarthria. Subjects were 6 stroke patients with mixed dysarthria and they received individual music therapy sessions. Each session was conducted for 30 minutes and 12 sessions including pre- and post-test were administered for each patient. For examining the protocol efficacy, the measures of maximum phonation time (MPT), fundamental frequency (F0), average intensity (dB), jitter, shimmer, noise to harmonics ratio (NHR), and diadochokinesis (DDK) were compared between pre and post-test and analyzed with a paired sample t-test. The results showed that the measures of MPT, F0, dB, and sequential motion rates (SMR) were significantly increased after administering the protocol. Also, there were statistically significant differences in the measures of shimmer, and alternating motion rates (AMR) of the syllable /K$\\inve$/ between pre- and post-test. The results indicated that the accent-based music speech protocol may improve speech motor coordination including respiration, phonation, articulation, resonance, and prosody of patients with dysarthria. This suggests the possibility of utilizing the music speech protocol to maximize immediate treatment effects in the course of a long-term treatment for patients with dysarthria. PMID:23422471

  18. Dis/Abling States, Dis/Abling Citizenship: Young Aboriginal Mothers and the Medicalization of Fetal Alcohol Syndrome

    ERIC Educational Resources Information Center

    Salmon, Amy

    2007-01-01

    This article draws on data collected in group interviews with six young, urban Aboriginal mothers whose lives have included substance use and Fetal Alcohol Syndrome/ Fetal Alcohol Effects (hereafter FAS/FAE) to highlight the multiple and often contradictory ways in which disability as a constituent of social relations is defined in public policy…

  19. Children with Fetal Alcohol Syndrome and Fetal Alcohol Effects: Patterns of Performance on IQ and Visual Motor Ability.

    ERIC Educational Resources Information Center

    Kopera-Frye, Karen; Zielinski, Sharon

    This study explored relationships between intelligence and visual motor ability and patterns of impairment of visual motor ability in children prenatally affected by alcohol. Fourteen children (mean age 8.2 years) diagnosed with fetal alcohol syndrome (FAS) and 50 children with possible fetal alcohol effects (FAE) were assessed with the Bender…

  20. Nonlinear Schwarz-Fas Methods for Unstructured Finite Element Elliptic Problems

    SciTech Connect

    Jones, J E; Vassilevski, P S; Woodward, C S

    2002-09-30

    This paper provides extensions of an element agglomeration AMG method to nonlinear elliptic problems discretized by the finite element method on general unstructured meshes. The method constructs coarse discretization spaces and corresponding coarse nonlinear operators as well as their Jacobians. We introduce both standard (fairly quasi-uniformly coarsened) and non-standard (coarsened away) coarse meshes and respective finite element spaces. We use both kind of spaces in FAS type coarse subspace correction (or Schwarz) algorithms. Their performance is illustrated on a number of model problems. The coarsened away spaces seem to perform better than the standard spaces for problems with nonlinearities in the principal part of the elliptic operator.

  1. Fas receptor is expressed in human lung squamous cell carcinomas, whereas bcl-2 and apoptosis are not pronounced: a preliminary report.

    PubMed Central

    Hellquist, H. B.; Olejnicka, B.; Jadner, M.; Andersson, T.; Sederholm, C.

    1997-01-01

    We report a pilot study on the Fas receptor (APO-1, CD95) in vivo in 15 human squamous cell (non-small) carcinomas and ten normal bronchial specimens. The principal aim was to investigate whether the so-called death receptor, Fas, is present in these tumours. Ligation of Fas promptly induces apoptosis, particularly in T Jurkat cells in vitro, and expression of Fas on human cancer would thus theoretically be of great interest. The immunoreactivity for the anti-apoptotic protein Bcl-2 was also investigated, and the degree of apoptosis was evaluated by TdT dUTP nick end labelling (TUNEL) and conventional morphological criteria. Fas was present in all initial tumours but absent in control tissue, that is in the potential precursor cells of bronchial epithelium (P = 0.001). Fas was not detectable after radiotherapy (P = 0.03). We propose that radiotherapy induces an early selection of tumour cells rather than a down-regulation of Fas. Both Bcl-2 and apoptosis (TUNEL) were generally expressed at a modest level. In agreement with other studies, we did not find any significant correlation between Bcl-2 and prognosis, or between Bcl-2 and TUNEL. Hence, in this preliminary report, we have demonstrated Fas receptor in human squamous cell carcinomas in vivo. This is a novel finding, and the apparent absence of Fas after radiotherapy may have important therapeutic implications. Images Figure 1 PMID:9231916

  2. Malabsorption Syndromes

    MedlinePlus

    ... syndrome, your small intestine cannot absorb nutrients from foods. Causes of malabsorption syndromes include Celiac disease Lactose intolerance Short bowel syndrome. This happens after surgery to ...

  3. Production of Multiple Brain-Like Ganglioside Species Is Dispensable for Fas-Induced Apoptosis of Lymphoid Cells

    PubMed Central

    Carpentier, Stéphane; Levade, Thierry; Cuvillier, Olivier; Portoukalian, Jacques

    2011-01-01

    Activation of an acid sphingomyelinase (aSMase) leading to a biosynthesis of GD3 disialoganglioside has been associated with Fas-induced apoptosis of lymphoid cells. The present study was undertaken to clarify the role of this enzyme in the generation of gangliosides during apoptosis triggered by Fas ligation. The issue was addressed by using aSMase-deficient and aSMase-corrected cell lines derived from Niemann-Pick disease (NPD) patients. Fas cross-linking elicited a rapid production of large amounts of complex a- and b-series species of gangliosides with a pattern and a chromatographic behavior as single bands reminiscent of brain gangliosides. The gangliosides were synthesized within the first ten minutes and completely disappeared within thirty minutes after stimulation. Noteworthy is the observation that GD3 was not the only ganglioside produced. The production of gangliosides and the onset of apoptotic hallmarks occurred similarly in both aSMase-deficient and aSMase-corrected NPD lymphoid cells, indicating that aSMase activation is not accountable for ganglioside generation. Hampering ganglioside production by inhibiting the key enzyme glucosylceramide synthase did not abrogate the apoptotic process. In addition, GM3 synthase-deficient lymphoid cells underwent Fas-induced apoptosis, suggesting that gangliosides are unlikely to play an indispensable role in transducing Fas-induced apoptosis of lymphoid cells. PMID:21629700

  4. Candida albicans up-regulates the Fas-L expression in liver Natural Killer and Natural Killer T cells.

    PubMed

    Renna, María Sol; Figueredo, Carlos Mauricio; Rodríguez-Galán, María Cecilia; Icely, Paula Alejandra; Cejas, Hugo; Cano, Roxana; Correa, Silvia Graciela; Sotomayor, Claudia Elena

    2015-11-01

    After Candida albicans arrival to the liver, the local production of proinflammatory cytokines and the expanded intrahepatic lymphocytes (IHL) can be either beneficial or detrimental to the host. Herein we explored the balance between protective inflammatory reaction and liver damage, focusing our study on the contribution of TNF-α and Fas-Fas-L pathways in the hepatocellular apoptosis associated to C. albicans infection. A robust tissue reaction and a progressive increase of IL-1β, IL-6 and TNF-α were observed in infected animals. Blocking the biological activity of TNF-α did not modify the number of apoptotic cells observed in C. albicans infected animals. Fas-L molecule was up regulated on purified hepatic mononuclear cells and its expression progressed with the infection. In the IHL compartment, the absolute number of Fas-L+ NK and NKT cells increased on days 1 and 3 of the infection. C. albicans was also able to up regulate Fas-L expression in normal liver NK and NKT cells after in vitro contact. The innate receptor TLR2 was involved in this phenomenon. In the interplay between host factors and evasion strategies exploited by pathogens, the mechanism supported here could represent an additional way that allows this fungus to circumvent protective immune responses in the liver. PMID:26101139

  5. Production of multiple brain-like ganglioside species is dispensable for fas-induced apoptosis of lymphoid cells.

    PubMed

    Popa, Iuliana; Therville, Nicole; Carpentier, Stéphane; Levade, Thierry; Cuvillier, Olivier; Portoukalian, Jacques

    2011-01-01

    Activation of an acid sphingomyelinase (aSMase) leading to a biosynthesis of GD3 disialoganglioside has been associated with Fas-induced apoptosis of lymphoid cells. The present study was undertaken to clarify the role of this enzyme in the generation of gangliosides during apoptosis triggered by Fas ligation. The issue was addressed by using aSMase-deficient and aSMase-corrected cell lines derived from Niemann-Pick disease (NPD) patients. Fas cross-linking elicited a rapid production of large amounts of complex a- and b-series species of gangliosides with a pattern and a chromatographic behavior as single bands reminiscent of brain gangliosides. The gangliosides were synthesized within the first ten minutes and completely disappeared within thirty minutes after stimulation. Noteworthy is the observation that GD3 was not the only ganglioside produced. The production of gangliosides and the onset of apoptotic hallmarks occurred similarly in both aSMase-deficient and aSMase-corrected NPD lymphoid cells, indicating that aSMase activation is not accountable for ganglioside generation. Hampering ganglioside production by inhibiting the key enzyme glucosylceramide synthase did not abrogate the apoptotic process. In addition, GM3 synthase-deficient lymphoid cells underwent Fas-induced apoptosis, suggesting that gangliosides are unlikely to play an indispensable role in transducing Fas-induced apoptosis of lymphoid cells. PMID:21629700

  6. The role of MAPK and FAS death receptor pathways in testicular germ cell apoptosis induced by lead.

    PubMed

    Dong, Shuying; Liang, Duoping; An, Na; Jia, Li; Shan, Yujuan; Chen, Chao; Sun, Kuo; Niu, Fei; Li, Huiyan; Fu, Songbin

    2009-09-01

    The aim of the present study is to investigate gene expression involved in the signal pathway of MAPK and death signal receptor pathway of FAS in lead-induced apoptosis of testicular germ cells. First, cell viabilities were determined by MTT assay. Second, using single cell gel-electrophoresis test (comet assay) and TUNEL staining technique, apoptotic rate and cell apoptosis localization of testicular germ cells were measured in mice treated with 0.15%, 0.3%, and 0.6% lead, respectively. Third, the immunolocalization of K-ras, c-fos, Fas, and active caspase-3 proteins was determined by immunohistochemistry. Finally, changes in the translational levels of K-ras, c-fos, Fas, and active caspase-3 were further detected by western blot analysis. Our results showed that lead could significantly induce testicular germ cell apoptosis in a dose-dependent manner (P<0.01). The mechanisms were closely related to the increased expressions of K-ras, c-fos, Fas, and active caspase-3 in apoptotic germ cells. In conclusion, K-ras/c-fos and Fas/caspase-3 death signaling receptor pathways were involved in the lead-induced apoptosis of the testicular germ cells in mice. PMID:19727529

  7. The small regulatory RNA FasX controls pilus expression and adherence in the human bacterial pathogen group A Streptococcus

    PubMed Central

    Liu, Zhuyun; Treviño, Jeanette; Ramirez-Peña, Esmeralda; Sumby, Paul

    2012-01-01

    Summary Bacterial pathogens use cell-surface-associated adhesion molecules to promote host attachment and colonization, and the ability to modulate adhesion expression is critical to pathogen success. Here, we show that the human-specific pathogen the group A Streptococcus (GAS) uses a small regulatory RNA (sRNA) to regulate the expression of adhesive pili. The fibronectin / fibrinogen-binding / haemolytic-activity / streptokinase-regulator-X (FasX) sRNA, previously shown to positively regulate expression of the secreted virulence factor streptokinase (SKA), negatively regulates the production of pili on the GAS cell surface. FasX base-pairs to the extreme 5’ end of mRNA from the pilus biosynthesis operon, and this RNA:RNA interaction reduces the stability of the mRNA, while also inhibiting translation of at least the first gene in the pilus biosynthesis operon (cpa, which encodes a minor pilin protein). The negative regulation of pilus expression by FasX reduces the ability of GAS to adhere to human keratinocytes. Our findings cement FasX sRNA as an important regulator of virulence factor production in GAS and identify that FasX uses at least three distinct mechanisms, positive (ska mRNA) and negative (pilus operon mRNA) regulation of mRNA stability, and negative regulation of mRNA translation (cpa mRNA), to post-transcriptionally regulate target mRNAs during infection. PMID:22882718

  8. Data in support of transcriptional regulation and function of Fas-antisense long noncoding RNA during human erythropoiesis

    PubMed Central

    Villamizar, Olga; Chambers, Christopher B.; Mo, Yin-Yuan; Torry, Donald S.; Hofstrand, Reese; Riberdy, Janice M.; Persons, Derek A.; Wilber, Andrew

    2016-01-01

    This paper describes data related to a research article titled, “Fas-antisense long noncoding RNA is differentially expressed during maturation of human erythrocytes and confers resistance to Fas-mediated cell death” [1]. Long noncoding RNAs (lncRNAs) are increasingly appreciated for their capacity to regulate many steps of gene expression. While recent studies suggest that many lncRNAs are functional, the scope of their actions throughout human biology is largely undefined including human red blood cell development (erythropoiesis). Here we include expression data for 82 lncRNAs during early, intermediate and late stages of human erythropoiesis using a commercial qPCR Array. From these data, we identified lncRNA Fas-antisense 1 (Fas-AS1 or Saf) described in the research article. Also included are 5′ untranslated sequences (UTR) for lncRNA Saf with transcription factor target sequences identified. Quantitative RT-PCR data demonstrate relative levels of critical erythroid transcription factors, GATA-1 and KLF1, in K562 human erythroleukemia cells and maturing erythroblasts derived from human CD34+ cells. End point and quantitative RT-PCR data for cDNA prepared using random hexamers versus oligo(dT)18 revealed that lncRNA Saf is not effectively polyadenylated. Finally, we include flow cytometry histograms demonstrating Fas levels on maturing erythroblasts derived from human CD34+ cells transduced using mock conditions or with lentivirus particles encoding for Saf. PMID:27141526

  9. Data in support of transcriptional regulation and function of Fas-antisense long noncoding RNA during human erythropoiesis.

    PubMed

    Villamizar, Olga; Chambers, Christopher B; Mo, Yin-Yuan; Torry, Donald S; Hofstrand, Reese; Riberdy, Janice M; Persons, Derek A; Wilber, Andrew

    2016-06-01

    This paper describes data related to a research article titled, "Fas-antisense long noncoding RNA is differentially expressed during maturation of human erythrocytes and confers resistance to Fas-mediated cell death" [1]. Long noncoding RNAs (lncRNAs) are increasingly appreciated for their capacity to regulate many steps of gene expression. While recent studies suggest that many lncRNAs are functional, the scope of their actions throughout human biology is largely undefined including human red blood cell development (erythropoiesis). Here we include expression data for 82 lncRNAs during early, intermediate and late stages of human erythropoiesis using a commercial qPCR Array. From these data, we identified lncRNA Fas-antisense 1 (Fas-AS1 or Saf) described in the research article. Also included are 5' untranslated sequences (UTR) for lncRNA Saf with transcription factor target sequences identified. Quantitative RT-PCR data demonstrate relative levels of critical erythroid transcription factors, GATA-1 and KLF1, in K562 human erythroleukemia cells and maturing erythroblasts derived from human CD34(+) cells. End point and quantitative RT-PCR data for cDNA prepared using random hexamers versus oligo(dT)18 revealed that lncRNA Saf is not effectively polyadenylated. Finally, we include flow cytometry histograms demonstrating Fas levels on maturing erythroblasts derived from human CD34(+) cells transduced using mock conditions or with lentivirus particles encoding for Saf. PMID:27141526

  10. Fetal alcohol syndrome among children aged 7-9 years - Arizona, Colorado, and New York, 2010.

    PubMed

    Fox, Deborah J; Pettygrove, Sydney; Cunniff, Christopher; O'Leary, Leslie A; Gilboa, Suzanne M; Bertrand, Jacquelyn; Druschel, Charlotte M; Breen, April; Robinson, Luther; Ortiz, Linnette; Frías, Jaime L; Ruttenber, Margaret; Klumb, Donald; Meaney, F John

    2015-01-30

    Fetal alcohol syndrome (FAS) is a serious birth defect and developmental disorder caused by in utero exposure to alcohol. Assessment of the public health burden of FAS through surveillance has proven difficult; there is wide variation in reported prevalence depending on the study population and surveillance method. Generally, records-based birth prevalence studies report estimates of 0.2-1.5 per 1,000 live births, whereas studies that use in-person, expert assessment of school-aged children in a community report estimates of 6-9 per 1,000 population. The Fetal Alcohol Syndrome Surveillance Network II addressed some of the challenges in records-based ascertainment by assessing a period prevalence of FAS among children aged 7‒9 years in Arizona, Colorado, and New York. The prevalence across sites ranged from 0.3 to 0.8 per 1,000 children. Prevalence of FAS was highest among American Indian/Alaska Native children and lowest among Hispanic children. These estimates continue to be much lower than those obtained from studies using in-person, expert assessment. Factors that might contribute to this discrepancy include 1) inadequate recognition of the physical and behavioral characteristics of FAS by clinical care providers; 2) insufficient documentation of those characteristics in the medical record; and 3) failure to consider prenatal alcohol exposure with diagnoses of behavioral and learning problems. Addressing these factors through training of medical and allied health providers can lead to practice changes, ultimately increasing recognition and documentation of the characteristics of FAS. PMID:25632951

  11. Current Sociopolitical, Sociocultural, and Sociolinguistic Issues of Latino Immigrants in Julia Álvarez's Novel "How the García Girls Lost Their Accents"

    ERIC Educational Resources Information Center

    Molina-Naar, José

    2016-01-01

    The sociopolitical, sociocultural, and sociolinguistic issues many Latino immigrants face as they embark on the process of adjusting to American society have been depicted by many Hispanic American writers in the United States. Julia Álvarez's "How the García Girls Lost Their Accents" attempts to raise awareness of these issues through…

  12. "I like the Americans...but I Certainly Don't Aim for an American Accent": Language Attitudes, Vitality and Foreign Language Learning in Denmark

    ERIC Educational Resources Information Center

    Ladegaard, Hans J.; Sachdev, Itesh

    2006-01-01

    The power and status of America in the world today are undeniable. This paper presents some empirical data about the attitudes and perceptions Danish learners of EFL have about British and American English. Ninety-six EFL learners participated in a verbal-guise experiment that involved rating different accents of English: American, Australian,…

  13. The Accented EFL Teacher: Classroom Implications (El acento del profesor de inglés como lengua extranjera: implicaciones pedagógicas)

    ERIC Educational Resources Information Center

    Arboleda Arboleda, Argemiro; Castro Garcés, Ángela Yicely

    2012-01-01

    This article reports the findings of a research study on how significant having a foreign accent is for non-native English as a foreign language teachers and learners at university level. It points out the perceptions that teachers and students have about the most relevant issues in the teaching and learning processes. Data were collected by means…

  14. FAS Grafted Electrospun Poly(vinyl alcohol) Nanofiber Membranes with Robust Superhydrophobicity for Membrane Distillation.

    PubMed

    Dong, Zhe-Qin; Wang, Bao-Juan; Ma, Xiao-hua; Wei, Yong-Ming; Xu, Zhen-Liang

    2015-10-14

    This study develops a novel type of electrospun nanofiber membranes (ENMs) with high permeability and robust superhydrophobicity for membrane distillation (MD) process by mimicking the unique unitary microstructures of ramee leaves. The superhydrophobic ENMs were fabricated by the eletrospinning of poly(vinyl alcohol) (PVA), followed by chemical cross-linking with glutaraldehyde and surface modification via low surface energy fluoroalkylsilane (FAS). The resultant FAS grafted PVA (F-PVA) nanofiber membranes were endowed with self-cleaning properties with water contact angles of 158° and sliding angles of 4° via the modification process, while retaining their high porosities and interconnected open structures. For the first time, the robust superhydrophobicity of the ENMs for MD was confirmed by testing the F-PVA nanofiber membranes under violent ultrasonic treatment and harsh chemical conditions. Furthermore, vacuum membrane distillation experiments illustrated that the F-PVA membranes presented a high and stable permeate flux of 25.2 kg/m2 h, 70% higher than those of the commercial PTFE membranes, with satisfied permeate conductivity (<5 μm/cm) during a continuous test of 16 h (3.5 wt % NaCl as the feed solution, and feed temperature and permeate pressure were set as 333 K and 9 kPa, respectively), suggesting their great potentials in myriad MD processes such as high salinity water desalination and volatile organiccompounds removal. PMID:26411526

  15. GloFAS - global ensemble streamflow forecasting and flood early warning

    NASA Astrophysics Data System (ADS)

    Alfieri, L.; Burek, P.; Dutra, E.; Krzeminski, B.; Muraro, D.; Thielen, J.; Pappenberger, F.

    2013-03-01

    Anticipation and preparedness for large-scale flood events have a key role in mitigating their impact and optimizing the strategic planning of water resources. Although several developed countries have well-established systems for river monitoring and flood early warning, figures of populations affected every year by floods in developing countries are unsettling. This paper presents the Global Flood Awareness System (GloFAS), which has been set up to provide an overview on upcoming floods in large world river basins. GloFAS is based on distributed hydrological simulation of numerical ensemble weather predictions with global coverage. Streamflow forecasts are compared statistically to climatological simulations to detect probabilistic exceedance of warning thresholds. In this article, the system setup is described, together with an evaluation of its performance over a two-year test period and a qualitative analysis of a case study for the Pakistan flood, in summer 2010. It is shown that hazardous events in large river basins can be skilfully detected with a forecast horizon of up to 1 month. In addition, results suggest that an accurate simulation of initial model conditions and an improved parameterization of the hydrological model are key components to reproduce accurately the streamflow variability in the many different runoff regimes of the earth.

  16. Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways

    PubMed Central

    Timmins, Jenelle M.; Ozcan, Lale; Seimon, Tracie A.; Li, Gang; Malagelada, Cristina; Backs, Johannes; Backs, Thea; Bassel-Duby, Rhonda; Olson, Eric N.; Anderson, Mark E.; Tabas, Ira

    2009-01-01

    ER stress–induced apoptosis is implicated in various pathological conditions, but the mechanisms linking ER stress–mediated signaling to downstream apoptotic pathways remain unclear. Using human and mouse cell culture and in vivo mouse models of ER stress–induced apoptosis, we have shown that cytosolic calcium resulting from ER stress induces expression of the Fas death receptor through a pathway involving calcium/calmodulin-dependent protein kinase IIγ (CaMKIIγ) and JNK. Remarkably, CaMKIIγ was also responsible for processes involved in mitochondrial-dependent apoptosis, including release of mitochondrial cytochrome c and loss of mitochondrial membrane potential. CaMKII-dependent apoptosis was also observed in a number of cultured human and mouse cells relevant to ER stress–induced pathology, including cultured macrophages, endothelial cells, and neuronal cells subjected to proapoptotic ER stress. Moreover, WT mice subjected to systemic ER stress showed evidence of macrophage mitochondrial dysfunction and apoptosis, renal epithelial cell apoptosis, and renal dysfunction, and these effects were markedly reduced in CaMKIIγ-deficient mice. These data support an integrated model in which CaMKII serves as a unifying link between ER stress and the Fas and mitochondrial apoptotic pathways. Our study also revealed what we believe to be a novel proapoptotic function for CaMKII, namely, promotion of mitochondrial calcium uptake. These findings raise the possibility that CaMKII inhibitors could be useful in preventing apoptosis in pathological settings involving ER stress–induced apoptosis. PMID:19741297

  17. The organization of RNA contacts by PTB for regulation of FAS splicing

    PubMed Central

    Mickleburgh, Ian; Kafasla, Panagiota; Cherny, Dmitry; Llorian, Miriam; Curry, Stephen; Jackson, Richard J.; Smith, Christopher W.J.

    2014-01-01

    Post-transcriptional steps of gene expression are regulated by RNA binding proteins. Major progress has been made in characterizing RNA-protein interactions, from high resolution structures to transcriptome-wide profiling. Due to the inherent technical challenges, less attention has been paid to the way in which proteins with multiple RNA binding domains engage with target RNAs. We have investigated how the four RNA recognition motif (RRM) domains of Polypyrimidine tract binding (PTB) protein, a major splicing regulator, interact with FAS pre-mRNA under conditions in which PTB represses FAS exon 6 splicing. A combination of tethered hydroxyl radical probing, targeted inactivation of individual RRMs and single molecule analyses revealed an unequal division of labour between the four RRMs of PTB. RNA binding by RRM4 is the most important for function despite the low intrinsic binding specificity and the complete lack of effect of disrupting individual RRM4 contact points on the RNA. The ordered RRM3-4 di-domain packing provides an extended binding surface for RNA interacting at RRM4, via basic residues in the preceding linker. Our results illustrate how multiple alternative low-specificity binding configurations of RRM4 are consistent with repressor function as long as the overall ribonucleoprotein architecture provided by appropriate di-domain packing is maintained. PMID:24957602

  18. Antiinflammatory Effects of CD95 Ligand (FasL)-induced Apoptosis

    PubMed Central

    Gao, Yakun; Herndon, John M.; Zhang, Hui; Griffith, Thomas S.; Ferguson, Thomas A.

    1998-01-01

    Apoptosis is critical to homeostasis of multicellular organisms. In immune privileged sites such as the eye, CD95 ligand (FasL)-induced apoptosis controls dangerous inflammatory reactions that can cause blindness. Recently, we demonstrated that apoptotic cell death of inflammatory cells was a prerequisite for the induction of immune deviation after antigen presentation in the eye. In this report, we examine the mechanism by which this takes place. Our results show that Fas- mediated apoptosis of lymphoid cells leads to rapid production of interleukin (IL)-10 in these cells. The apoptotic cells containing IL-10 are responsible for the activation of immune deviation through interaction with antigen-presenting cells (APC). In support of this, we found that apoptotic cells from IL-10+/+ animals fed to APC in vitro promote Th2 cell differentiation, whereas apoptotic IL-10−/− cells, as well as nonapoptotic cells, favor Th1 induction. Thus, apoptotic cell death and tolerance are linked through the production of an antiinflammatory cytokine to prevent dangerous and unwanted immune responses that might compromise organ integrity. PMID:9730890

  19. Methods for surveillance of fetal alcohol syndrome: The Fetal Alcohol Syndrome Surveillance Network II (FASSNetII) - Arizona, Colorado, New York, 2009 - 2014.

    PubMed

    O'Leary, Leslie A; Ortiz, Linnette; Montgomery, April; Fox, Deborah J; Cunniff, Christopher; Ruttenber, Margaret; Breen, April; Pettygrove, Sydney; Klumb, Don; Druschel, Charlotte; Frías, Jaime L; Robinson, Luther K; Bertrand, Jacquelyn; Ferrara, Kelly; Kelly, Maureen; Gilboa, Suzanne M; Meaney, F John

    2015-03-01

    Surveillance of fetal alcohol syndrome (FAS) is important for monitoring the effects of prenatal alcohol exposure and describing the public health burden of this preventable disorder. Building on the infrastructure of the Fetal Alcohol Syndrome Surveillance Network (FASSNet, 1997-2002), in 2009 the Centers for Disease Control and Prevention awarded 5-year cooperative agreements to three states, Arizona, Colorado, and New York, to conduct population-based surveillance of FAS. The Fetal Alcohol Syndrome Surveillance Network II (FASSNetII, 2009-2014) developed a surveillance case definition based on three clinical criteria: characteristic facial features, central nervous system abnormalities, and growth deficiency. FASSNetII modified the FASSNet methods in three important ways: (1) estimation of a period prevalence rather than birth prevalence; (2) surveillance of FAS among school-age children (ages 7-9 years) to better document the central nervous system abnormalities that are not apparent at birth or during infancy; and (3) implementation of an expert clinical review of abstracted data for probable and confirmed cases classified through a computerized algorithm. FASSNetII abstracted data from multiple sources including birth records, medical records from child development centers or other specialty clinics, and administrative databases such as hospital discharge and Medicaid. One challenge of FASSNetII was its limited access to non-medical records. The FAS prevalence that could be estimated was that of the population identified through an encounter with the healthcare system. Clinical and public health programs that identify children affected by FAS provide critical information for targeting preventive, medical and educational services in this vulnerable population. PMID:25761572

  20. Isaac's Syndrome

    MedlinePlus

    ... syndrome (also known as neuromyotonia, Isaacs-Mertens syndrome, continuous muscle fiber activity syndrome, and quantal squander syndrome) is a rare neuromuscular disorder caused by hyperexcitability and continuous firing of ... which include progressive muscle stiffness, continuously contracting ...

  1. The human immunodeficiency virus type 1 tat protein enhances Cryptosporidium parvum-induced apoptosis in cholangiocytes via a Fas ligand-dependent mechanism.

    PubMed

    O'Hara, Steven P; Small, Aaron J; Nelson, Jeremy B; Badley, Andrew D; Chen, Xian-Ming; Gores, Gregory J; Larusso, Nicholas F

    2007-02-01

    While Cryptosporidium parvum infection of the intestine has been reported in both immunocompetent and immunocompromised individuals, biliary infection is seen primarily in adult AIDS patients and is associated with development of AIDS cholangiopathy. However, the mechanisms of pathogen-induced AIDS cholangiopathy remain unclear. Since we previously demonstrated that the Fas/Fas ligand (FasL) system is involved in paracrine-mediated C. parvum cytopathicity in cholangiocytes, we also tested the potential synergistic effects of human immunodeficiency virus type 1 (HIV-1) transactivator of transcription (Tat)-mediated FasL regulation on C. parvum-induced apoptosis in cholangiocytes by semiquantitative reverse transcription-PCR, immunoblotting, immunofluorescence analysis, and immunogold electron microscopy. H69 cells do not express CXCR4 and CCR5, which are receptors required for direct HIV-1 viral infection. However, recombinant biologically active HIV-1-associated Tat protein increased FasL expression in the cytoplasm of cholangiocytes without a significant increase in apoptosis. We found that C. parvum-induced apoptosis was associated with translocation of intracellular FasL to the cell membrane surface and release of full-length FasL from infected H69 cells. Tat significantly (P < 0.05) increased C. parvum-induced apoptosis in bystander cells in a dose-dependent manner. Moreover, Tat enhanced both C. parvum-induced FasL membrane translocation and release of full-length FasL. In addition, the FasL neutralizing antibody NOK-1 and the caspase-8 inhibitor Z-IETD-fmk both blocked C. parvum-induced apoptosis in cholangiocytes. The data demonstrated that HIV-1 Tat enhances C. parvum-induced cholangiocyte apoptosis via a paracrine-mediated, FasL-dependent mechanism. Our results suggest that concurrent active HIV replication, with associated production of Tat protein, and C. parvum infection synergistically increase cholangiocyte apoptosis and thus jointly contribute to

  2. Fas Ligand DNA Enhances a Vaccination Effect by Coadministered DNA Encoding a Tumor Antigen through Augmenting Production of Antibody against the Tumor Antigen

    PubMed Central

    Zhong, Boya; Ma, Guangyu; Sato, Ayako; Shimozato, Osamu; Liu, Hongdan; Shingyoji, Masato; Tada, Yuji; Tatsumi, Koichiro; Shimada, Hideaki; Hiroshima, Kenzo; Tagawa, Masatoshi

    2015-01-01

    Interaction of Fas and Fas ligand (FasL) plays an important role in the regulation of immune responses by inducing apoptosis of activated cells; however, a possible role of FasL in DNA vaccination has not been well understood. We examined whether administration of DNA encoding FasL gene enhanced antitumor effects in mice that were vaccinated with DNA expressing a putative tumor antigen gene, β-galactosidase (β-gal). Growth of β-gal-positive Colon 26 tumors was retarded in the syngeneic mice immunized with β-gal and FasL DNA compared with those vaccinated with β-gal or FasL DNA. We did not detect increased numbers of β-gal-specific CD8+ T cells in lymph node of mice that received combination of β-gal and FasL DNA, but amounts of anti-β-gal antibody increased with the combination but not with β-gal or FasL DNA injection alone. Subtype analysis of anti-β-gal antibody produced by the combination of β-gal and FasL DNA or β-gal DNA injection showed that IgG2a amounts were greater in mice injected with both DNA than those with β-gal DNA alone, but IgG2b amounts were lower in both DNA-injected than β-gal DNA-injected mice. These data suggest that FasL is involved in boosting humoral immunity against a gene product encoded by coinjected DNA and enhances the vaccination effects. PMID:25759847

  3. Significant association between FasL gene -844T/C polymorphism and risk to hepatocellular carcinoma in Egyptian patients.

    PubMed

    Khalifa, Rania H; Bahgat, Dina M Rasheed; Darwish, Hatem Abdel Hamid; Shahin, Rasha Mohamad Hosny

    2016-04-01

    Fas/Fas ligand (FasL) system is the most critical apoptotic signaling entity in the extrinsic apoptotic pathway; hence mutations affecting this pathway may prevent the immune system from the removal of newly-formed tumor cells, and thus lead to tumor formation. The present study investigated the association between the FasL -844T/C polymorphism and the risk of hepatocellular carcinoma (HCC) in a cohort of Egyptian patients and explored the relationship of various clinical and pathological parameters with this single nucleotide polymorphism (SNP). Blood samples were withdrawn from hundred HCC patients and 100 age-, sex- and ethnically matched controls. The FasL -844T/C (rs763110) gene polymorphism was typed from genomic DNA using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. Genotype distributions and allelic frequencies between patients and control subjects showed that the TT homozygous patients were two times more likely to develop HCC (p=0.011). Also, the T allele was found to be a significant risk factor for the disease (OR 1.970, 95% CI 1.250-3.105, p=0.003). No association was detected between different parameters of the disease and the SNP. For the first time, our results suggest that the -844T/C polymorphism in the FasL gene confers risk to HCC. The alarming increase in the incidence of HCC in Egypt encourages further studies to document our results in a larger sample, and recommends more genetic studies hoping to define a genomic risk prediction specific to this cancer in our population. PMID:26891954

  4. Functional analysis of miR-181a and Fas involved in hepatitis B virus-related hepatocellular carcinoma pathogenesis

    SciTech Connect

    Zou, Chengcheng; Chen, Juan; Chen, Ke; Wang, Sen; Cao, Yiyi; Zhang, Jinnan; Sheng, Yanrui; Huang, Ailong; Tang, Hua

    2015-02-15

    The hepatitis B virus (HBV) is responsible for most of hepatocellular carcinoma (HCC). However, whether HBV plays an important role during hepatocarcinogenesis through effecting miRNAs remains unknown. Here, we reported that HBV up-regulated microRNA-181a (miR-181a) by enhancing its promoter activity. Simultaneously, we found that miR-181a inhibited apoptosis in vitro and promoted tumor cell growth in vivo. TNF receptor superfamily member 6 (Fas) was further identified as a target of miR-181a. We also found that Fas could reverse the apoptosis-inhibition effect induced by miR-181a. Moreover, HBV could inhibit cell apoptosis by down-regulating Fas expression, which could be reversed by miR-181a inhibitor. Our data demonstrated that HBV suppressed apoptosis of hepatoma cells by up-regulating miR-181a expression and down-regulating Fas expression, which may provide a new understanding of the mechanism in HBV-related HCC pathogenesis. - Highlights: • HBV could up-regulate miR-181a expression by interacting with nt−800 to +240 in its promoter region in HCC cell lines. • HBV could down-regulate Fas expression and suppress apoptosis of hepatoma cells, which could be reversed by miR-181a inhibitor. • Up-regulation of miR-181a promoted proliferation of hepatoma cells and repressed apoptosis, which could be reversed by Fas. • Our study provides a new understanding of the mechanism in HBV-related HCC pathogenesis.

  5. Nailfold capillaroscopic changes in Kindler syndrome

    PubMed Central

    Dobrev, Hristo P.; Vutova, Nina I.

    2015-01-01

    Summary Kindler syndrome (KS), the fourth major type of hereditary epidermolysis bullosa (HEB), is a rare, autosomal recessive disorder characterized by skin fragility and blistering at birth followed by development of marked photosensitivity and progressive poikilodermatous skin changes in later years. We reported here the case of a 54-year-old woman, who fulfills the diagnostic criteria of KS type of HEB, putting accent on the nailfold capillaroscopic changes. Using videocapillaroscopy we observed pronounced alterations in finger nail capillaries including reduction in capillary density, features of neoangiogenesis (architectural derangement, elongated loops, extremely tortuous, bushy or branching capillaries, thin, branching and interconnected capillaries), enlarged and giant capillaries. We consider the changes observed as an adaptive mechanism that compensate the loss of capillaries due to chronic periungual trauma. Further studies with larger number of patients are needed to confirm the significance of capillaroscopy findings for patients with HEB. PMID:26668784

  6. Influence of Fas on the regulation of the response of an anti-nuclear antigen B cell clonotype to foreign antigen.

    PubMed

    Alabyev, Boris; Vuyyuru, Raja; Manser, Tim

    2008-10-01

    A peripheral B cell tolerance checkpoint appears to be operative during the germinal center (GC) reaction. We previously showed that a transgenic BCR clonotype that is 'dual reactive' for the hapten arsonate (Ars) and nuclear auto-antigens is stimulated to enter the GC response via Ars immunization. However, the participation of this clonotype in this response wanes with time and it gives rise to few memory B cells capable of mounting a secondary anti-Ars IgG response. Enforced expression of Bcl-2 partially rescues the GC and memory B cell responses of this clonotype, suggesting that apoptotic pathways are involved in the action of the GC tolerance checkpoint. Since GC B cells substantially up-regulate levels of expression of the Fas apoptotic death receptor, we determined whether an intrinsic Fas deficient could rescue the participation of this clonotype in the GC response. It could not, strongly indicating that Fas expression by autoreactive GC B cells is not necessary for their elimination. In addition, experiments in which Fas-sufficient dual reactive clonotype B cells were transferred to Fas-deficient hosts revealed an absence of participation of these B cells in the GC and IgG anti-Ars responses. We present data consistent with the idea that T cells in Fas-deficient hosts are primed to express elevated levels of FasL and eliminate antigen-activated B cells that up-regulate Fas. PMID:18689725

  7. Balanced effect of PACAP and FasL on granule cell death during cerebellar development: a morphological, functional and behavioural characterization.

    PubMed

    Allais, Aurélie; Burel, Delphine; Roy, Vincent; Arthaud, Sébastien; Galas, Ludovic; Isaac, Emma Rachel; Desfeux, Arnaud; Parent, Bénédicte; Fournier, Alain; Chapillon, Pierre; Sherwood, Nancy McKeown; Vaudry, Hubert; Gonzalez, Bruno José

    2010-04-01

    It is now established that the development of the CNS requires equilibrium between cell survival and apoptosis. Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts a powerful protective effect on cerebellar granule cells by inhibiting the caspase 3. In contrast, Fas ligand (FasL) plays an essential role during ontogenesis in eliminating supernumerary neurons by apoptosis. To determine if PACAP and FasL interact during cerebellar development, we characterized the effects of these factors on cerebellar morphogenesis and caspase 3 activity in PACAP+/+ and PACAP-/- mice. First, we demonstrated in vivo that PACAP is able to reverse the diminution of internal granule cell layer thickness induced by FasL in PACAP+/+ and PACAP-/- mice. Second, ex vivo and immunohistochemical studies revealed that interaction between FasL and PACAP occurs through the caspase 3 activity. Third, behavioural study showed a significant difference for the PACAP + FasL group in the righting reflex test at P8 which does not persist at P60. Finally, a time course study revealed that the pro-apoptotic effect of FasL characterized at P8 was followed by a progressive compensatory mechanism in caspase 3 activity and bromodeoxyuridine incorporation. These data suggest that PACAP and FasL interact during cerebellar development to control apoptosis of granule cells and may affect some motor cerebellar functions. PMID:20050979

  8. Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas.

    PubMed

    Kong, Sinyi; Yang, Yi; Xu, Yuanming; Wang, Yajun; Zhang, Yusi; Melo-Cardenas, Johanna; Xu, Xiangping; Gao, Beixue; Thorp, Edward B; Zhang, Donna D; Zhang, Bin; Song, Jianxun; Zhang, Kezhong; Zhang, Jianning; Zhang, Jinping; Li, Huabin; Fang, Deyu

    2016-09-13

    Humoral immunity involves multiple checkpoints during B-cell development, maturation, and activation. The cell death receptor CD95/Fas-mediated apoptosis plays a critical role in eliminating the unwanted activation of B cells by self-reactive antigens and in maintaining B-cell homeostasis through activation-induced B-cell death (AICD). The molecular mechanisms controlling AICD remain largely undefined. Herein, we show that the E3 ubiquitin ligase Hrd1 protected B cells from activation-induced cell death by degrading the death receptor Fas. Hrd1-null B cells exhibited high Fas expression during activation and rapidly underwent Fas-mediated apoptosis, which could be largely inhibited by FasL neutralization. Fas mutation in Hrd1 KO mice abrogated the increase in B-cell AICD. We identified Hrd1 as the first E3 ubiquitin ligase of the death receptor Fas and Hrd1-mediated Fas destruction as a molecular mechanism in regulating B-cell immunity. PMID:27573825

  9. Lifeguard inhibition of Fas-mediated apoptosis: A possible mechanism for explaining the cisplatin resistance of triple-negative breast cancer cells.

    PubMed

    Radin, Daniel; Lippa, Arnold; Patel, Parth; Leonardi, Donna

    2016-02-01

    Triple-negative breast cancer does not express estrogen receptor-α, progesterone or the HER2 receptor making hormone or antibody therapy ineffective. Cisplatin may initiate p73-dependent apoptosis in p53 mutant cell lines through Fas trimerization and Caspase-8 activation and Bax up regulation and subsequent Caspase-9 activation. The triple-negative breast cancer, MDA-MB-231, overexpresses the protein Lifeguard, which inhibits Fas-mediated apoptosis by inhibiting Caspase-8 activation after Fas trimerization. The relationship between Fas, Lifeguard and cisplatin is investigated by down regulating Lifeguard via shRNA. Results demonstrate that cisplatin's efficacy increases when Lifeguard is down regulated. Lifeguard Knockdown MDA-MB-231 continue to decrease in cell viability from 24 to 48h after cisplatin treatment while no additional decrease in viability is observed in the Wild-Type MDA over the same period. Higher Caspase-8 activity in the Lifeguard knockdown MDA after cisplatin administration could explain the significant decrease in cell viability from 24 to 48h. This cell type is also more sensitive to Fas ligand-mediated reductions in cell viability, confirming Lifeguard's anti-apoptotic function through the Fas receptor. This research suggests that the efficacy of chemotherapy acting through the Fas pathway would increase if Lifeguard were not overexpressed to inhibit Fas-mediated apoptosis. PMID:26796280

  10. Fas (CD95) Induces Macrophage Pro-Inflammatory Chemokine Production via a MyD88-dependent, Caspase-independent Pathway

    PubMed Central

    Altemeier, William A.; Zhu, Xiaodong; Berrington, William R.; Harlan, John M.; Liles, W. Conrad

    2015-01-01

    Activation of the prototypical death receptor, Fas (CD95), can induce both caspase-dependent cell death and production of pro-inflammatory chemokines, leading to neutrophil recruitment and end-organ injury. The precise mechanism(s), by which Fas upregulates chemokine production and release, is currently unclear. We hypothesized that Fas-induced chemokine release by macrophages is dependent on the MyD88 adapter molecule and independent of caspase activity. To test this hypothesis, we measured chemokine response to Fas activation both in RAW 264.7 cells with RNAi-attenuated MyD88 expression and in MyD88-deficient primary macrophages. We found that Fas-induced chemokine release was abrogated in the absence of MyD88. In vivo, MyD88−/− mice had impaired CXCL1/KC release and polymorphonuclear cell recruitment in response to intratracheal treatment with the Fas-activating monoclonal antibody, Jo-2. Furthermore, Fas-induced chemokine release was not dependent on either IL-1 receptor signaling or on caspase activity. We conclude that MyD88 plays an integral role in Fas-induced macrophage-mediated inflammation. PMID:17576821

  11. The role of prosodic breaks and pitch accents in grouping words during on-line sentence processing.

    PubMed

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

    2011-09-01

    The present study addresses the question whether accentuation and prosodic phrasing can have a similar function, namely, to group words in a sentence together. Participants listened to locally ambiguous sentences containing object- and subject-control verbs while ERPs were measured. In Experiment 1, these sentences contained a prosodic break, which can create a certain syntactic grouping of words, or no prosodic break. At the disambiguation, an N400 effect occurred when the disambiguation was in conflict with the syntactic grouping created by the break. We found a similar N400 effect without the break, indicating that the break did not strengthen an already existing preference. This pattern held for both object- and subject-control items. In Experiment 2, the same sentences contained a break and a pitch accent on the noun following the break. We argue that the pitch accent indicates a broad focus covering two words [see Gussenhoven, C. On the limits of focus projection in English. In P. Bosch & R. van der Sandt (Eds.), Focus: Linguistic, cognitive, and computational perspectives. Cambridge: University Press, 1999], thus grouping these words together. For object-control items, this was semantically possible, which led to a "good-enough" interpretation of the sentence. Therefore, both sentences were interpreted equally well and the N400 effect found in Experiment 1 was absent. In contrast, for subject-control items, a corresponding grouping of the words was impossible, both semantically and syntactically, leading to processing difficulty in the form of an N400 effect and a late positivity. In conclusion, accentuation can group words together on the level of information structure, leading to either a semantically "good-enough" interpretation or a processing problem when such a semantic interpretation is not possible. PMID:20961171

  12. Fas-Associated Protein with Death Domain Regulates Notch Signaling during Muscle Regeneration.

    PubMed

    Zhang, Rong; Wang, Lu; He, Liangqiang; Yang, Bingya; Yao, Chun; Du, Pan; Xu, Qiang; Cheng, Wei; Hua, Zi-Chun

    2014-01-01

    Notch signaling plays critical roles during myogenesis by promoting the proliferation and inhibiting the differentiation of myogenic progenitors. However, the mechanism of the temporal regulation of Notch signaling during the myogenic lineage progression remains elusive. In the present study, we show that a constitutively phosphoryl-mimicking mutation of Fas-associated death domain (FADD-D) enhances Notch-1 signaling and compromises Wnt signaling in both cultured myoblasts and regenerating muscles, which results in inhibited myogenic differentiation and muscle regeneration. Inhibition of Notch signaling recovers the regeneration ability in injured FADD-D muscles through rescuing Wnt signaling. Furthermore, we found that protein kinase Cα mediates FADD-D-induced Notch-1 signaling by stabilizing Notch-1. Collectively, these data identify a novel mechanism for the temporal regulation of Notch signaling during myogenic lineage progression and muscle regeneration. PMID:26303234

  13. A novel cisplatin mediated apoptosis pathway is associated with acid sphingomyelinase and FAS proapoptotic protein activation in ovarian cancer.

    PubMed

    Maurmann, L; Belkacemi, L; Adams, N R; Majmudar, P M; Moghaddas, S; Bose, R N

    2015-07-01

    Platinum-based anticancer drugs, including cisplatin and carboplatin, have been cornerstones in the treatment of solid tumors. We report here that these DNA-damaging agents, particularly cisplatin, induce apoptosis through plasma membrane disruption, triggering FAS death receptor via mitochondrial (intrinsic) pathways. Our objectives were to: quantify the composition of membrane metabolites; and determine the potential involvement of acid sphingomyelinase (ASMase) in the FAS-mediated apoptosis in ovarian cancer after cisplatin treatment. The resulting analysis revealed enhanced apoptosis as measured by: increased phosphocholine, and glycerophosphocholine; elevated cellular energetics; and phosphocreatine and nucleoside triphosphate concentrations. The plasma membrane alterations were accompanied by increased ASMase activity, leading to the upregulation of FAS, FASL and related pro-apoptotic BAX and PUMA genes. Moreover FAS, FASL, BAX, PUMA, CASPASE-3 and -9 proteins were upregulated. Our findings implicate ASMase activity and the intrinsic pathways in cisplatin-mediated membrane demise, and contribute to our understanding of the mechanisms by which ovarian tumors may become resistant to cisplatin. PMID:25846011

  14. Acrolein enhances epigenetic modifications, FasL expression and hepatocyte toxicity induced by anti-HIV drug Zidovudine.

    PubMed

    Ghare, Smita S; Donde, Hridgandh; Chen, Wei-Yang; Barker, David F; Gobejishvilli, Leila; McClain, Craig J; Barve, Shirish S; Joshi-Barve, Swati

    2016-09-01

    Zidovudine (AZT) remains the mainstay of antiretroviral therapy against HIV in resource-poor countries; however, its use is frequently associated with hepatotoxicity. Not all HIV patients on AZT develop hepatotoxicity, and the determining factors are unclear. Alcohol consumption and cigarette smoking are known risk factors for HIV hepatotoxicity, and both are significant sources of acrolein, a highly reactive and toxic aldehyde. This study examines the potential hepatotoxic interactions between acrolein and AZT. Our data demonstrate that acrolein markedly enhanced AZT-induced transcriptionally permissive histone modifications (H3K9Ac and H3K9Me3) allowing the recruitment of transcription factor NF-kB and RNA polymerase II at the FasL gene promoter, resulting in FasL upregulation and apoptosis in hepatocytes. Notably, the acrolein scavenger, hydralazine prevented these promoter-associated epigenetic changes and inhibited FasL upregulation and apoptosis induced by the combination of AZT and acrolein, as well as AZT alone. Our data strongly suggest that acrolein enhancement of promoter histone modifications and FasL upregulation are major pathogenic mechanisms driving AZT-induced hepatotoxicity. Moreover, these data also indicate the therapeutic potential of hydralazine in mitigating AZT hepatotoxicity. PMID:27238871

  15. Identification of Single Nucleotide Polymorphism Marker and Association Analysis of Marbling Score in Fas Gene of Hanwoo

    PubMed Central

    Kim, Seung-Chang; Lee, Seung-Hwan; Lee, Ji-Woong; Kim, Tae-Hun; Choi, Bong-Hwan

    2016-01-01

    The Fas (APO-1, TNFRSF6) gene known as a member of the tumor necrosis factor receptor superfamily was selected for DNA marker development in Korean cattle. It is a cell membrane protein and mediates programmed cell death (apoptosis). We discovered single nucleotide polymorphisms (SNPs) within Fas gene in order to develop novel DNA markers related to economical traits at the genomic level. The sequences of whole exon and 1 kb range of both front and back of the gene were determined by direct-sequencing methods using 24 cattle. A total of 55 SNPs were discovered and we selected 31 common polymorphic sites considering their allele frequencies, haplotype-tagging status and linkage disequilibrium (LD) for genotyping in larger-scale subjects. The SNPs were confirmed genotype through the SNaPshot method (n = 274) and were examined for a possible genetic association between Fas polymorphisms and marbling score. So, the SNPs that were identified significant are g.30256G>C, g.31474C>A, g.31940A>G, and g.32982G>A. These results suggest that SNPs of Fas gene were associated with intramuscular fat content of meat quality traits in Korean cattle. PMID:26732324

  16. Kupffer Cells Protect Liver Sinusoidal Endothelial Cells from Fas-Dependent Apoptosis in Sepsis by Down-Regulating gp130

    PubMed Central

    Hutchins, Noelle A.; Chung, Chun-Shiang; Borgerding, Joshua N.; Ayala, Carol A.; Ayala, Alfred

    2014-01-01

    Endothelial cell (EC) dysfunction is a key feature of multiple organ injury, the primary cause of fatality seen in critically ill patients. Although the development of EC dysfunction in the heart and lung is well studied in sepsis, it remains unclear in the liver. Herein, we report that liver sinusoidal ECs (LSECs; defined as CD146+CD45−) exhibit increased intercellular adhesion molecule-1 (CD54) and Fas in response to sepsis induced by cecal ligation and puncture (CLP). By using magnetically enriched LSEC (CD146+) populations, we show evidence of marked apoptosis, with a twofold decline in viable LSECs in CLP animals compared with sham controls. These changes and increased serum alanine aminotransferase levels were all mitigated in septic Fas−/− and Fas ligand−/− animals. Although we previously reported increased numbers of Fas ligand expressing CD8+ T lymphocytes in the septic liver, CD8+ T-cell deficiency did not reverse the onset of LSEC apoptosis/damage. However, Kupffer cell depletion with clodronate liposomes resulted in greater apoptosis and Fas expression after CLP and a decrease in glycoprotein 130 expression on LSECs, suggesting that STAT3 activation may protect these cells from injury. Our results document a critical role for death receptor–mediated LSEC injury and show the first evidence that Kupffer cells are essential to the viability of LSECs, which appears to be mediated through glycoprotein 130 expression in sepsis. PMID:23306157

  17. Raman microscopy at the subcellular level: a study on early apoptosis in endothelial cells induced by Fas ligand and cycloheximide.

    PubMed

    Czamara, Krzysztof; Petko, Filip; Baranska, Malgorzata; Kaczor, Agnieszka

    2016-02-21

    High spatially resolved Raman microscopy was applied to study the early apoptosis in endothelial cells and chemical and structural changes induced by this process. Application of cluster analysis enabled separation of signals due to various subcellular organelles and compartments such as the nuclei, nucleoli, endoplasmic reticulum or cytoplasm and analysis of alterations locally at the subcellular level. Different stimuli, i.e. Fas ligand, a tumor necrosis factor, and cycloheximide, an inhibitor of eukaryotic protein biosynthesis, were applied to induce apoptotic mechanisms. Due to different mechanisms of action, the changes observed in subcellular structures were different for FasL and cycloheximide. Although in both cases a statistically significant decrease of the protein level was observed in all studied cellular structures, the increase of the nucleic acids content locally in apoptotic nuclei was considerably more pronounced upon FasL-induced apoptosis compared to the cycloheximide one. Additionally, apoptosis invokes also a decrease of the proteins with the α-helix protein structure selectively for FasL in the cytoplasm and endoplasmic reticulum. PMID:26765153

  18. Mechanisms of liver fibrosis associated with experimental Fasciola hepatica infection: roles of Fas2 proteinase and hepatic stellate cell activation.

    PubMed

    Marcos, Luis A; Terashima, Angélica; Yi, Pedro; Andrade, Roy; Cubero, Francisco J; Albanis, Efsevia; Gotuzzo, Eduardo; Espinoza, Jose R; Friedman, Scott L

    2011-02-01

    We have evaluated the possible mechanisms of liver fibrosis caused by Fasciola hepatica in an animal model and in culture using immortalized human stellate cells. Liver biopsies of F. hepatica-infected rats were performed at wk 8 and 16. Serum-starved LX-2 cells, a human stellate cell line, were exposed to increasing concentrations of Fas2 antigen. The expression of key fibrosis-related genes was evaluated by qRT-PCR. There was a significant correlation between fibrogenic gene expression and both intensity and duration of infection. LX-2 cells exposed to Fas2 showed progressively increased expression of mRNAs for Collagen I, alpha-smooth muscle-actin, platelet-derived growth factor beta receptor, and tissue inhibitor of metalloproteinase II; inhibition of Fas2 cysteine proteinase activity by E-64 abrogated these increases, suggesting that the protease activity of Fas2 is involved in fibrogenic stimulation. In summary, F. hepatica infection is associated with up-regulation of mRNAs associated with hepatic fibrogenesis in vivo and in activated hepatic stellate cells. PMID:21348611

  19. Novel Type II Fatty Acid Biosynthesis (FAS II) Inhibitors as Multistage Antimalarial Agents

    PubMed Central

    Schrader, Florian C.; Glinca, Serghei; Sattler, Julia M.; Dahse, Hans-Martin; Afanador, Gustavo A.; Prigge, Sean T.; Lanzer, Michael; Mueller, Ann-Kristin; Klebe, Gerhard; Schlitzer, Martin

    2013-01-01

    Malaria is a potentially fatal disease caused by Plasmodium parasites and poses a major medical risk in large parts of the world. The development of new, affordable antimalarial drugs is of vital importance as there are increasing reports of resistance to the currently available therapeutics. In addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. At this point, a patient might already be suffering from the symptoms associated with the disease and could additionally be infectious to an Anopheles mosquito. These insects act as a vector, subsequently spreading the disease to other humans. In order to cure not only malaria but prevent transmission as well, a drug must target both the blood- and pre-erythrocytic liver stages of the parasite. P. falciparum (Pf) enoyl acyl carrier protein (ACP) reductase (ENR) is a key enzyme of plasmodial type II fatty acid biosynthesis (FAS II). It has been shown to be essential for liver-stage development of Plasmodium berghei and is therefore qualified as a target for true causal chemoprophylaxis. Using virtual screening based on two crystal structures of PfENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds that are effective against multiple stages of the malaria parasite. These two most promising derivatives were found to inhibit blood-stage parasite growth with IC50 values of 1.7 and 3.0 µm and lead to a more prominent developmental attenuation of liver-stage parasites than the gold-standard drug, primaquine. PMID:23341167

  20. Fas-Induced Apoptosis Increases Hepatocyte Tissue Factor Procoagulant Activity In Vitro and In Vivo

    PubMed Central

    Lopez, Michelle; Kopec, Anna K.; Joshi, Nikita; Geddings, Julia E.; Cline, Holly; Towery, Keara L.; Rockwell, Cheryl E.; Mackman, Nigel; Luyendyk, James P.

    2014-01-01

    Hepatocyte (HPC) apoptosis occurs in association with hepatotoxic responses and chronic liver disease, and is coupled to activation of the blood coagulation cascade. HPCs have been shown to express tissue factor (TF), the primary activator of blood coagulation, in a form that lacks procoagulant activity. In this study, we determined the effect of inducing HPC apoptosis on the procoagulant activity of TF. Treatment of primary mouse HPCs with the Fas death receptor agonist (anti-CD95 antibody, Jo2) triggered apoptosis as shown by cleavage of caspase-3, increased caspase-3 proteolytic activity, and cell surface exposure of phosphatidylserine (PS). Jo2-induced apoptosis significantly increased TF-dependent factor Xa generation by HPCs. Moreover, Jo2 treatment was associated with increased levels of microparticle-associated TF procoagulant activity in the culture medium. Pretreatment with a caspase-3 inhibitor significantly reduced Jo2-induced HPC TF activity and prevented the increase in microparticle-associated TF procoagulant activity. Application of the high-affinity PS-binding protein lactadherin inhibited TF-dependent factor Xa generation by Jo2-treated HPCs and dramatically reduced microparticle-associated TF procoagulant activity. Treatment of wild-type mice with a sublethal dose of Jo2 was associated with a robust increase in the activation of coagulation as measured by plasma thrombin-antithrombin (TAT) levels; whereas mice with liver-specific TF deficiency had significantly lower TAT levels. Overall, the results indicate that Fas-initiated, caspase-3-dependent HPC apoptosis increases TF procoagulant activity through a mechanism involving PS externalization. This suggests that activation of liver TF likely contributes to the procoagulant state associated with HPC apoptosis in liver toxicity and disease. PMID:25015658