673 research outputs found
Recommended from our members
Speaker Gender and Salience in Sociolinguistic Speech Perception: goose-fronting in Standard Southern British English
Listeners’ perceptions of sound changes may be influenced by priming them with social information about the speaker. It is not clear, however, whether this occurs for sociolinguistic variables that pass below the level of awareness. This article investigates whether visual speaker gender affects the perception of goose-fronting in Standard Southern British English, a sound change that is led by young women yet does not fulfil criteria for sociolinguistic salience. Participants from across the United Kingdom completed a word identification experiment based on a gender-ambiguous synthesized fleece-goose continuum while primed with an image of a man’s or a woman’s face. The study did not find a significant main effect of priming, but men identified fronter tokens as goose when primed with a woman’s face. I argue that sociolinguistic priming effects may be over-stated and that future priming experiments should be designed with maximal statistical power where possible
Recommended from our members
Perceptions of T-glottalling among adolescents in South East England: A sign of 'chavviness', or a key to 'coolness'?
Sociolinguistic research has established that glottal realisations of the voiceless alveolar stop /t/ have become increasingly common in accents of British English. The phenomenon, known as T-glottalling, encompasses the production of word-final and word-medial /t/ using glottal articulations, including creaky voice, pre-glottalisation [ʔt] and glottal replacement [ʔ] (Straw & Patrick, 2007), so that words such as but [bʌt] and butter [bʌtə] may become [bʌʔ] and [bʌʔə] respectively. The change has been documented for some time in Scotland (Macafee, 1997) and Norfolk (Trudgill, 1999) but has since been reported in numerous locations across the UK (see Smith & Holmes–Elliott, 2018 for a recent review). Studies of regional dialect levelling (Kerswill, 2003) have argued that T-glottalling has spread from working-class London speech into neighbouring varieties of South East England and beyond as a form of geographical diffusion (Altendorf & Watt, 2004). Together with other variables showing similar sociolinguistic patterns, such as TH-fronting and L vocalisation, it has been identified as part of a set of ‘youth norms’ used by young people in many urban centres to index a trendy, youthful identity (Williams & Kerswill, 1999; Milroy, 2007; though see Watson, 2006 for an exception in Liverpool), which have elsewhere been referred to as ‘Estuary English’ (Rosewarne, 1984; Altendorf, 2017). In terms of perception, T-glottalling is described as highly salient and stigmatised, frequently attracting comments from lay speakers to the effect that it should be avoided (Wells, 1982; Bennett, 2012), to the extent that mainstream journalistic publications can identify and criticise its use by ‘educated’ speakers such as politicians (e.g. Littlejohn, 2011)
The 14q32 maternally imprinted locus is a major source of longitudinally stable circulating microRNAs as measured by small RNA sequencing
Understanding the normal temporal variation of serum molecules is a critical factor for identifying useful candidate biomarkers for the diagnosis and prognosis of chronic disease. Using small RNA sequencing in a longitudinal study of 66 women with no history of cancer, we determined the distribution and dynamics (via intraclass correlation coefficients, ICCs) of the miRNA profile over 3 time points sampled across 2–5 years in the course of the screening trial, UKCTOCS. We were able to define a subset of longitudinally stable miRNAs (ICC >0.75) that were individually discriminating of women who had no cancer over the study period. These miRNAs were dominated by those originating from the C14MC cluster that is subject to maternal imprinting. This assessment was not significantly affected by common confounders such as age, BMI or time to centrifugation nor alternative methods to data normalisation. Our analysis provides important benchmark data supporting the development of miRNA biomarkers for the impact of life-course exposure as well as diagnosis and prognostication of chronic disease
Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome
A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR-ATRIP Seckel Syndrome to be define
Sonic Hedgehog Gene Delivery to the Rodent Heart Promotes Angiogenesis via iNOS/Netrin-1/PKC Pathway
We hypothesized that genetic modification of mesenchymal stem cells (MSCs) with Sonic Hedgehog (Shh) transgene, a morphogen during embryonic development and embryonic and adult stem cell growth, improved their survival and angiogenic potential in the ischemic heart via iNOS/netrin/PKC pathway.MSCs from young Fisher-344 rat bone marrow were purified and transfected with pCMV Shh plasmid ((Shh)MSCs). Immunofluorescence, RT-PCR and Western blotting showed higher expression of Shh in (Shh)MSCs which also led to increased expression of angiogenic and pro-survival growth factors in (Shh)MSCs. Significantly improved migration and tube formation was seen in (Shh)MSCs as compared to empty vector transfected MSCs ((Emp)MSCs). Significant upregulation of netrin-1 and iNOS was observed in (Shh)MSCs in PI3K independent but PKC dependent manner. For in vivo studies, acute myocardial infarction model was developed in Fisher-344 rats. The animals were grouped to receive 70 microl basal DMEM without cells (group-1) or containing 1x10(6) (Emp)MSCs (group-2) and (Shh)MSCs (group-3). Group-4 received recombinant netrin-1 protein injection into the infarcted heart. FISH and sry-quantification revealed improved survival of (Shh)MSCs post engraftment. Histological studies combined with fluorescent microspheres showed increased density of functionally competent blood vessels in group-3 and group-4. Echocardiography showed significantly preserved heart function indices post engraftment with (Shh)MSCs in group-3 animals.Reprogramming of stem cells with Shh maximizes their survival and angiogenic potential in the heart via iNOS/netrin-1/PKC signaling
Population-scale proteome variation in human induced pluripotent stem cells
Human disease phenotypes are driven primarily by alterations in protein expression and/or function. To date, relatively little is known about the variability of the human proteome in populations and how this relates to variability in mRNA expression and to disease loci. Here, we present the first comprehensive proteomic analysis of human induced pluripotent stem cells (iPSC), a key cell type for disease modelling, analysing 202 iPSC lines derived from 151 donors, with integrated transcriptome and genomic sequence data from the same lines. We characterised the major genetic and non-genetic determinants of proteome variation across iPSC lines and assessed key regulatory mechanisms affecting variation in protein abundance. We identified 654 protein quantitative trait loci (pQTLs) in iPSCs, including disease-linked variants in protein-coding sequences and variants with trans regulatory effects. These include pQTL linked to GWAS variants that cannot be detected at the mRNA level, highlighting the utility of dissecting pQTL at peptide level resolution
Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism
Defects in centrosome, centrosomal-associated and spindle-associated proteins are the most frequent cause of primary microcephaly (PM) and microcephalic primordial dwarfism (MPD) syndromes in humans. Mitotic progression and segregation defects, microtubule spindle abnormalities and impaired DNA damage-induced G2-M cell cycle checkpoint proficiency have been documented in cell lines from these patients. This suggests that impaired mitotic entry, progression and exit strongly contribute to PM and MPD. Considering the vast protein networks involved in coordinating this cell cycle stage, the list of potential target genes that could underlie novel developmental disorders is large. One such complex network, with a direct microtubule-mediated physical connection to the centrosome, is the kinetochore. This centromeric-associated structure nucleates microtubule attachments onto mitotic chromosomes. Here, we described novel compound heterozygous variants in CENPE in two siblings who exhibit a profound MPD associated with developmental delay, simplified gyri and other isolated abnormalities. CENPE encodes centromere-associated protein E (CENP-E), a core kinetochore component functioning to mediate chromosome congression initially of misaligned chromosomes and in subsequent spindle microtubule capture during mitosis. Firstly, we present a comprehensive clinical description of these patients. Then, using patient cells we document abnormalities in spindle microtubule organization, mitotic progression and segregation, before modeling the cellular pathogenicity of these variants in an independent cell system. Our cellular analysis shows that a pathogenic defect in CENP-E, a kinetochore-core protein, largely phenocopies PCNT-mutated microcephalic osteodysplastic primordial dwarfism-type II patient cells. PCNT encodes a centrosome-associated protein. These results highlight a common underlying pathomechanism. Our findings provide the first evidence for a kinetochore-based route to MPD in humans
A global insight into a cancer transcriptional space using pancreatic data: importance, findings and flaws
Despite the increasing wealth of available data, the structure of cancer transcriptional space remains largely unknown. Analysis of this space would provide novel insights into the complexity of cancer, assess relative implications in complex biological processes and responses, evaluate the effectiveness of cancer models and help uncover vital facets of cancer biology not apparent from current small-scale studies. We conducted a comprehensive analysis of pancreatic cancer-expression space by integrating data from otherwise disparate studies. We found (i) a clear separation of profiles based on experimental type, with patient tissue samples, cell lines and xenograft models forming distinct groups; (ii) three subgroups within the normal samples adjacent to cancer showing disruptions to biofunctions previously linked to cancer; and (iii) that ectopic subcutaneous xenografts and cell line models do not effectively represent changes occurring in pancreatic cancer. All findings are available from our online resource for independent interrogation. Currently, the most comprehensive analysis of pancreatic cancer to date, our study primarily serves to highlight limitations inherent with a lack of raw data availability, insufficient clinical/histopathological information and ambiguous data processing. It stresses the importance of a global-systems approach to assess and maximise findings from expression profiling of malignant and non-malignant diseases
- …