Discourse-Related Effects on Speech Durations: A Challenge for Models of Speech Production

With topic labeling providing an analysis of the text's organization, the experiment reported here investigated the relation between the structure of the text and the durational patterns produced when it was read aloud. Durations were chosen for study in part because much previous work has concentrated on F0. In addition, acoustic durations in English are known to be affected by segment identity and local context in a way that F0 is not, so it is interesting to see whether, like F0, durations are also affected by the overall organization of the discourse. The present paper focuses on the interactions between discourse organization and durations, and how these may reveal drawbacks in current models of speech production

The characterizations of spontaneous and vaccine-driven antigen-specific cytotoxic T lymphocyte responses in melanoma patients.

The last decade has witnessed a huge expansion in the field of Tumour Immunology. A large number of tumour antigens recognized by T lymphocytes have been identified and new techniques have enabled the direct ex vivo analysis of epitope-specific cytotoxic T lymphocytes (CTL). These developments provide the tools with which spontaneous tumour antigen-specific CTL responses can be characterized in detail, have facilitated the development of antigen-specific tumour immunotherapeutic strategies, and have heralded a new era of immunomonitoring in clinical trials. In this work, ex vivo phenotypic and functional analyses of CTL specific for an HLA-A*0201-restricted epitope encoded by the mel an-A tumour differentiation antigen (melan-A₂₆-₃₅) were performed on samples from melanoma patients and normal healthy donors. Ex vivo tetramer analysis revealed circulating melan-A₂₆-₃₅-specific T lymphocytes in 50% of both patients and normal donors. Phenotypic analysis of tetramer+ cells was correlated with ex vivo assays of CTL function. In the normal donors and approximately 50% of patients, the melan-A₂₆-₃₅-specific cells were always phenotypically and functionally naIve. However, in the remaining patients, a proportion of melan-A₂₆-₃₅-specific cells were phenotypically antigen-experienced, and functional responses to peptide could readily be detected ex vivo. The observation in patients, that tumour antigen-specific CTL responses with effector function are "too little, too late", provided the basis for a clinical trial of recombinant plasmid DNA and Modified Vaccinia Ankara in patients with surgically-treated melanoma and a high risk of disease recurrence. Both vaccines were engineered to encode the same polyepitope string of seven HLA-A2-and HLA-Alrestricted tumour antigen epitopes, including the high affinity melan-A₂₆-₃₅ analogue. Immunomonitoring, which included detailed kinetic analyses of tetramer+ cells, demonstrated that MV A was capable of generating an expansion of melan-A₂₆-₃₅-specific CTL with effector function in approximately 50% of patients. However, no responses to the other tumour antigen epitopes were seen. A detailed analysis of CTL responses specific for recently-identified vaccinia-encoded epitopes (including a new epitope identified as part of this work) demonstrated that CTL responses specific for the viral vector were dominant over those for the recombinant epitopes. This finding has important implications for the future design of recombinant viral vaccmes.Thesis (Ph.D.) -- University of Adelaide, Dept. of Medicine, 200

SARS-CoV-2 transmission dynamics should inform policy

Funding: JM is supported in part by the U.S. National Institute of Allergy and Infectious Diseases [K01AI122853].It is generally agreed that striking a balance between resuming economic and social activities and keeping the effective reproductive number (R0) below 1 using non-pharmaceutical interventions is an important goal until and even after effective vaccines become available. Therefore, the need remains to understand how the virus is transmitted in order to identify high-risk environments and activities that disproportionately contribute to its spread so that effective preventative measures could be put in place. Contact tracing and household studies in particular provide robust evidence about the parameters of transmission. In this viewpoint, we discuss the available evidence from large-scale, well-conducted contact tracing studies from across the world and argue that SARS-CoV-2 transmission dynamics should inform policy decisions about mitigation strategies for targeted interventions according to the needs of the society by directing attention to the settings, activities and socioeconomic factors associated with the highest risks of transmission.PostprintPeer reviewe

The long-term impact of folic acid in pregnancy on offspring DNA methylation : follow-up of the Aberdeen folic acid supplementation trial (AFAST)

Funding This work was supported by the NIHR Bristol Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. R.C.R., G.C.S., N.K., T.G., G.D.S. and C.L.R. work in a unit that receives funds from the University of Bristol and the UK Medical Research Council (MC_UU_12013/1, MC_UU_12013/2 and MC_UU_12013/8). This work was also supported by CRUK (grant number C18281/A19169) and the ESRC (grant number ES/N000498/1). C.M.T. is supported by a Wellcome Trust Career Re-entry Fellowship (grant number 104077/Z/14/Z).Peer reviewedPublisher PD

Harnessing Whole Genome Polygenic Risk Scores to Stratify Individuals Based on Cardiometabolic Risk Factors and Biomarkers at Age 10 in the Lifecourse - Brief Report

In this study, we investigated the capability of polygenic risk scores to stratify a cohort of young individuals into risk deciles based on 10 different cardiovascular traits and circulating biomarkers. METHODS: We first conducted large-scale genome-wide association studies using data on adults (mean age 56.5 years) enrolled in the UK Biobank study (n=393 193 to n=461 460). Traits and biomarkers analyzed were body mass index, systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein B, apolipoprotein A-I, C-reactive protein and vitamin D. Findings were then leveraged to build whole genome polygenic risk scores in participants from the Avon Longitudinal Study of Parents and Children (mean age, 9.9 years) which were used to stratify this cohort into deciles in turn and analyzed against their respective traits. RESULTS: For each of the 10 different traits assessed, we found strong evidence of an incremental trend across deciles (all P<0.0001). Large differences were identified when comparing top and bottom deciles; for example, using the apolipoprotein B polygenic risk scores there was a mean difference of 13.2 mg/dL for this established risk factor of coronary heart disease in later life. CONCLUSIONS: Although the use of polygenic prediction in a clinical setting may currently be premature, our findings suggest they are becoming increasingly powerful as a means of predicting complex trait variation at an early stage in the lifecourse

Prosody and Utterance Boundaries in American Sign Language Interpretation

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