1,213 research outputs found
Susceptibility loci for pigmentation and melanoma in relation to Parkinson's disease
No full textGrowing evidence suggests that Parkinson's disease (PD) patients have a lower risk for most types of cancer except for melanoma, which has a modest positive association with PD. Pigmentation genes have been hypothesized to contribute to this association. We therefore examined whether genetic susceptibility loci for pigmentation or melanoma was associated with PD risk in 2 large independent datasets. In the Parkinson's Genes and Environment (PAGE) study, we examined 11 single-nucleotide polymorphisms (SNPs) identified from previous genome-wide association studies (GWAS) of pigmentation or melanoma in relation to PD among 808 PD cases and 1623 controls; furthermore, we also examined the colors of hair, eye, or skin and melanoma in relation to PD. In the International Parkinson's Disease Genomic Consortium (IPDGC), we examined a broader selection of 360 pigmentation or melanoma GWAS SNPs in relation to PD among 5,333 PD cases and 12,019 controls. All participants were non-Hispanic Whites. As expected, in the PAGE study, most SNPs were associated with 1 or more pigmentation phenotypes. However, neither these SNPs nor pigmentation phenotypes were associated with PD risk after Bonferroni correction with the exception of rs4911414 at the ASIP gene (p = .001). A total of 18 PD cases (2.2%) and 26 controls (1.6%) had a diagnosis of melanoma with an odds ratio of 1.3 (95% confidence interval: 0.7-2.4). In the IPDGC analysis, none of the 360 SNPs, including rs4911414, were associated with PD risk after adjusting for multiple comparisons. In conclusion, we did not find significant associations between GWAS SNPs of pigmentation or melanoma and the risk for PD
How we learn to ignore singleton distractors: Suppressing saliency signals or specific features?
No full textSalient visual information can sometimes capture attention despite our goals, however, there are several ways we can minimize or eliminate such distraction. One such way is learned distractor rejection, in which we increasingly ignore salient, irrelevant distractors across repeated exposures. Here we probe the mechanism underlying this learned rejection. What must be learned about the distractor to promote effective ignoring? Specifically, is feature rejection, alone, sufficient to learn rejection of salient distractors, or do the items’ saliency signals need to also be rejected? To test between these possibilities, we used a modified version of the learned distraction rejection paradigm (Vatterott & Vecera, 2012). Participants viewed training blocks containing either a salient singleton distractor, or a set of three non-salient “tripleton” distractors, followed by test blocks in which the distractor was always a salient color singleton. Critically, the distractors in test blocks always shared a feature (color) with the corresponding training blocks. By comparing attentional capture in the test blocks as a function of the preceding training block we were able to observe whether experience with saliency was necessary for learned distractor rejection. Results revealed unexpected difficulties in replicating learned distractor rejection, suggesting the true effect size may be smaller than initially reported. With respect to our main objective, we found no difference in the rejection of test block distractors based on whether participants had viewed salient or non-salient distractors during training. That is, we found similar attenuation of singleton presence costs in the test blocks regardless of whether they followed singleton or tripleton training blocks. These results show that experience in rejecting saliency signals is not a requirement of learned distractor rejection
A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy
No full textHeterozygous loss of function mutations in granulin represent a significant cause of frontotemporal lobar degeneration with ubiquitin and TDP-43 inclusions (FTLD-TDP). We report a novel GRN splice site mutation (c.709-2 A>T), segregating with frontotemporal dementia spectrum in a large family from southern Italy. The GRN c.709-2 A>T is predicted to result in the skipping of exon 8, leading to non-sense mediated mRNA decay. Moreover, the PGRN plasma levels in the GRN c.709-2 A>T carriers were significantly lower (24ng/ml) compared to controls (142.7ng/ml) or family members non-carriers (82.0ng/ml) (p-value=0.005, Kruskal Wallis), suggesting progranulin haploinsufficiency. We do not report any potential pathogenic GRN mutation in a follow-up cohort composed of 6 FTD families and 43 sporadic FTD cases, from the same geographic area. Our study suggests that GRN (c.709-2 A>T) is a novel and likely very rare cause of FTD in this Italian cohort. Finally, in line with previous studies, we show that GRN haploinsufficiency leads to a heterogeneous clinical picture, and plasma progranulin levels may be a reliable tool to identify GRN loss of function mutations. However, given that a) genetic and environmental factors, gender, and age may regulate PGRN plasma levels and b) plasma progranulin levels may not reflect PGRN levels in the central nervous system, we suggest that the measurement of progranulin in the plasma should always be coupled with genetic screening of GRN for mutations
Genetic basis of Parkinson's disease and related disorders
No full textTesis doctoral del Departamento de Biología Celular y Parasitología. Facultad de Biología. Universitat de València.Tesis realizada gracias a:
1. Predoctoral fellowship for the development of doctoral thesis with interests for the industrial sector (I3P-BPD2003-1). February 2004 through October 2005.
2. National Institutes of Health fellowship for foreign visiting scientists. October
2005 through October 2008.Peer reviewe
Analysis of SCA-2 and SCA-3 repeats in parkinsonism: Evidence of SCA-2 expansion in a family with autosomal dominant Parkinson's disease
No full textThe spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders linked to more than 20 genetic loci. Most often, these diseases are caused by expansion of triplet repeats encoding polyglutamine (polyQ) tracts. The phenotype is variable and can cause a disease that overlaps clinically with Parkinson's disease (PD). <small>L</small>-Dopa-responsive parkinsonism with minimal cerebellar deficits has been described in SCA2 and SCA3. In order to define if mutation at these loci is a common cause of clinically defined parkinsonism we typed the <i>SCA-2</i> and <i>SCA-3</i> repeats for expansion in a series of 280 patients diagnosed with PD or parkinsonism. We identified one pathogenic expansion in <i>SCA-2</i> in a North American family with autosomal dominant parkinsonism
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Contrastive Hyperarticulation in Arabic Geminate and Singleton Stops: How Lexical Competition and Morphology Shape Closure Duration in Behavioral and Neural Speech
No full textThis dissertation investigates the phenomenon of contrastive hyperarticulation under lexical competition–a dynamic enhancement of phonetic cues to preserve perceptual distinctions between lexical competitors–in Qatifi Arabic, a dialect spoken in Saudi Arabia. Research on contrastive hyperarticulation has predominantly focused on languages with linear morphological structures, whereas its dynamics in non-linear systems have received comparatively little attention. Arabic, with its root-and-pattern morphology, offers an ideal yet underexplored domain for such an inquiry. By analyzing Qatifi Arabic, this dissertation advances our understanding of how contrastive hyperarticulation adapts to a distinct morphological system, offering new insights into the dynamics of contrastive hyperarticulation and non-linear morphological systems in lexical competition environments. This study analyzes contrastive hyperarticulation as a function of morphological derivational processes and lexical competition, testing its phonetic correlates in geminate (double consonants)-singleton (single consonants) stop duration contrasts. Furthermore, the research extends its investigation of the phenomenon to advanced neural speech systems, including speech synthesis and automatic speech recognition models. Specifically, it examines whether speech synthesis systems generate contrastive hyperarticulation in geminate-singleton pairs—lexically competing morphemes distinguished solely by duration—and evaluates how automatic speech recognition systems process these enhanced phonetic contrasts in sensitive contexts that includes both competitors. Over the past decade, the phenomenon of contrastive hyperarticulation has garnered increasing attention in linguistic research, yet existing studies have focused overwhelmingly on languages with linear morphological structures. Seyfarth (2016) explored the contrastive hyperarticulation of English morphemic and non-morphemic forms, demonstrating that it is triggered by the phonological plans of morphological relatives. Other studies have examined the durational contrasts of geminate and singleton stops in a mora-timed language and languages with tono-genetic sound change such as Japanese and Korean, respectively (Jeong 2024, Sano 2018). Sano (2018) focused on how lexical competition factors motivate the enhancements of geminate and singleton stops. The findings highlight the role of factors such as the manner of articulation, informativity levels, and the presence or absence of minimal pairs in shaping durational distinctions. Similarly, Wedel et al. (2018) emphasize that contrastive hyperarticulation of English stops operates primarily as a function of lexical competition, contrary to claims that emphasize phonological neighborhood density (Fox et al. 2015, Munson & Solomon 2004). However, existing research has yet to fully reconcile three key dimensions of this phenomenon: while one line of inquiry has focused on contrastive enhancement of morphological units compared to non-morphological phonemes, it has not systematically examined how morphemes in lexical competition conditions influence these enhancements (Losiewicz 1992, Plag et al. 2017, Smith et al. 2012, Walsh & Parker 1983, Yung Song et al. 2013). Another line has investigated geminate and singleton stops in competition-driven environments, yet the geminate phonemes in these studies lack morphological significance in the languages examined (Sano 2018). While a third research strand has highlighted the role of lexical competition in triggering contrasts in English stops (Nelson 2019, Wedel et al. 2018), morphological influences were not within their investigation scope. Notably, most of these studies share a common focus on languages with linear morphological systems, where morphemes and word forms are strung together linearly, while non-concatenative systems remain overlooked. Building on these studies, this dissertation contributes to our understanding of how lexical competition interacts with morphological complexity
to shape contrastive hyperarticulation, focusing on geminate morphemes versus singleton units in Arabic’s non-linear root-and-pattern system. The study provides new insights into how contrastive hyperarticulation functions in morphologically rich languages, particularly under conditions of lexical competition. The dissertation is structured around three studies. The first study involves a behavioral speech production study examining contrastive hyperarticulation in Qatifi Arabic geminate and singleton stops. The study investigates whether the closure durations of geminate morphemes and singleton phonemes are influenced by minimal pair competition. The results reveal asymmetric enhancement patterns: singleton durations are shortened in minimal pair contexts under fast speech rates, while geminate durations remain stable. The disparity suggests that non-linear morphological systems may impose constraints for maintaining phonetic contrasts under lexical competition and morphological complexity. One possible explanation for this asymmetric behavior is that Arabic’s templatic morphology imposes constraints on geminate production: gemination may be produced as a by-product of the root-and-pattern system, making it less susceptible to durational enhancement
than singletons. The second study examines neural speech synthesis, specifically assessing whether the Variational Inference with Adversarial Learning (VITS-TTS) model (Kim et al. 2021) can generate contrastively hyperarticulated geminate and singleton
stops—mirroring the patterns observed in the first study. Given that neural synthesis systems have demonstrated the ability to learn categorical phonological patterns from limited training data (Beguš 2021a,b), this experiment serves as a novel test of whether such models can generate contrastive hyperarticulation patterns based on lexical competition or distributional factors, thereby providing insights into how artificial systems operate under such conditions. While neural models excel at learning categorical distinctions (e.g., geminate vs. singleton), they often struggle with gradient phenomena such as contrastive durations (Hanzlí?ek 2024, Matoušek & Tihelka 2022). Testing whether such systems can replicate human-like enhancement patterns illuminates their capacity to encode phonetic informativity—the dynamic adjustment of cues based on functional demands. This reveals whether artificial systems implicitly learn the statistical dependencies between lexical competition and phonetic realization, or merely approximate surface-level acoustic patterns. Using the same geminate and singleton tokens investigated in the first study, the research fine-tuned VITS-TTS on a specialized corpus and tested its ability to synthesize geminate and singleton consonant contrasts. While VITS-TTS successfully encoded categorical distinctions between geminates and singletons, it failed to generate hyperarticulated forms in minimal pair and non-minimal pair contexts. These results highlight the limitations of current neural architectures in modeling gradient phonetic phenomena, particularly those driven by lexical competition and morphology. The third study evaluates how automatic speech recognition (ASR) systems adapt to competition pressure when resolving contrastively hyperarticulated minimal pairs in shared linguistic contexts, building on two prior findings. Study 1 reveals how orthographic constraints shape hyperarticulation production in Qatifi Arabic, while Study 2 demonstrates synthetic speech systems’ reliance on orthographic markers to disambiguate geminate-singleton contrasts in Modern Standard Arabic. The current work extends this by probing whether ASR models develop latent representations robust enough to recognize competing candidates under acoustic ambiguity. Specifically, it evaluates ASR models’ ability to: (1) decode contrastive hyperarticulation cues in the acoustic signal to distinguish geminate-singleton minimal pairs in a single context, and (2) reconcile these phonetic cues with near-identical orthographic representations that differ only by a geminate marker. For this study, a Transformer-based (Whisper) model (Radford et al. 2023) was fine-tuned on a fully diacritized Modern Standard Arabic dataset. The results demonstrate that Whisper successfully recognizes most minimal pairs in the tested contexts, indicating that the model learns latent representations that jointly encode contrastive hyper-articulated durational cues and orthographic markers. The findings demonstrate that successful recognition requires both bottom-up phonetic learning of enhanced acoustic cues such as separable latent features and top-down orthographic guidance through diacritics to resolve phonetic ambiguities. The findings reveal asymmetric hyperarticulation in Qatifi Arabic, where singleton stops exhibit reduced durations under lexical competition, contrasting with the symmetric enhancement observed in linear morphological systems, such as in English and Japanese. This disparity suggests language-specific dynamics in contrast maintenance. Conversely, results from the synthesis model indicate an absence of hyperarticulated geminate and singleton phonemes—even when controlling for geminate stop distribution and lexical competition environments. This suggests that, unlike human speakers, the synthesis system does not spontaneously implement contrastive enhancement strategies under competitive lexical conditions. In contrast, the speech recognition system demonstrates effective learning of contrastively hyperarticulated forms through learning the latent representations of diacritic-driven orthographic regularization in concert with the emergent learning of high-fidelity phonetic representations to resolve hyperarticulated contrasts
Catheter ablation for ventricular tachycardia
No full textSudden cardiac death due to ventricular arrhythmias remains the most common cause of death in developed nations. Implantable cardioverter defibrillators have been shown to improve mortality in high-risk groups for ventricular tachyarrhythmias, but they are not curative, with the risk of arrhythmia recurrence remaining unaltered. It is also important to remember that ventricular tachycardia (VT) in the setting of a structurally normal heart is often not associated with an increased risk of sudden death and catheter ablation is a potentially curative procedure in this cohort. Recent advances in catheter ablation for VT have increased the efficacy in creating adequate lesions, accurate three-dimensional maps and mapping haemodynamically unstable VT, all of which have increased the utility of this modality in the treatment of ventricular arrhythmias. In this article, we review the recent advances that have fuelled renewed interest in catheter ablation of VT, its clinical utility and who should be referred.H. S. Lim, C. B. Singleton, M. Alasady and A. D. McGaviga
Log R Ratio and B Allele plots for Two Samples Showing Genomic Duplication
No full text<div><p>Genomic duplication is indicated by an increase in log R ratio and B allele frequency clusters outside of the expected values of 1 (B/B), 0.5 (A/B), and 0 (A/A).</p><p>(A) Shows duplication of a small segment on Chromosome 1 (red arrow).</p><p>(B) Shows duplication of a region of approximately 7 Mb on Chromosome 21, outlined in red. This region contains APP, and the duplication mutation results in a neurodegenerative phenotype (courtesy of J. Hardy).</p></div
How we learn to ignore singleton distractors: Suppressing saliency signals or specific features?
No full textHumans have an impressive ability to engage feature-based suppression to avoid processing irrelevant information. Previous research has shown that one way humans suppress irrelevant information is though experience with the distracting stimuli’s features (De Tommaso & Turatto, 2019; Vatterott & Vecera, 2012; Won & Geng, 2018). Vatterott and Vecera (2012) originally studied the time course of distractor rejection by comparing singleton presence costs at the beginning of blocks of search trials to those at the end of blocks. Using this method, they observed an attenuation of attentional capture as participants repeatedly viewed distracting stimuli. This study along with several others that followed (De Tommaso & Turatto, 2019; Gaspelin & Luck, 2018; Stilwell & Vecera, 2019, 2020; Vatterott et al., 2018) provide strong evidence that, with sufficient experience, distractors can be efficiently rejected based on first order features, such as color. However, in many of these studies, the to-be-ignored distractors were always salient color singletons. Therefore, although previous research has made it clear that distractors can be suppressed though experience with their specific features, even when they are salient, it remains unclear what role salience plays in the rejection process. In other words, when the to-be-suppressed distractor is salient, it is unknown whether feature suppression is sufficient to avoid distraction or if additional suppression of saliency signals is necessary to achieve efficient distractor rejection. In the current study we’re seeking to test whether experience with first order distractor features (color) will allow for effective distractor rejection when the critical distractor suddenly becomes salient
A randomised controlled trial on the effect of nurse-led educational intervention at the time of catheter ablation for atrial fibrillation on quality of life, symptom severity and rehospitalisation
No full textBackground: Atrial Fibrillation (AF) is a common condition associated with impaired quality of life (QOL) and recurrent hospitalisation. Catheter ablation for AF is a well-established treatment for symptomatic patients despite medical therapy. We sought to examine the effect of point specific nurse-led education on QOL, AF symptomatology and readmission rate post AF ablation. Methods: Forty-one patients undergoing AF ablation were randomised to Nurse Intervention (NI) versus Control (C), n=22 vs. 19. Both groups were well matched with respect to age, sex and AF subtype. All patients completed SF36 and AF Symptom Checklist, Frequency and Severity Scale questionnaires at baseline and six months post ablation. The NI group underwent nurse education on admission, prior to discharge, and with telephone contact. Results: Baseline SF-36 and AF Symptom Checklist, Frequency and Severity scores were similar. The NI group showed significant differences compared to Control with respect to higher QOL on the SF-36 score of Physical Functioning and Vitality at six months. There were significant improvements in seven components of the AF Symptom Checklist, Frequency and Severity at six months in the NI group with a trend in a further seven. There was no difference in AF related hospital readmissions at six months between C and NI groups (10.5% vs. 13.6%, p=ns). Conclusion: Nurse-led education at time of AF ablation is associated with improved QOL and reduced symptom frequency and severity compared to usual care.John L. Bowyer, Phillip J. Tully, Anand N. Ganesan, Fahd K. Chahadi, Cameron B. Singleton, Andrew D. McGaviga
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