A Phonetic model of English intonation

This thesis proposes a phonetic model of English intonation which is a system for linking the phonological and F₀, descriptions of an utterance.It is argued that such a model should take the form of a rigorously defined formal system which does not require any human intuition or expertise to operate. It is also argued that this model should be capable of both analysis (F₀ to phonology) and synthesis (phonology to F₀). Existing phonetic models are reviewed and it is shown that none meet the specification for the type of formal model required.A new phonetic model is presented that has three levels of description: the F₀ level, the intermediate level and the phonological level. The intermediate level uses the three basic elements of rise,fall and connection to model F₀ contours. A mathematical equation is specified for each of these elements so that a continuous lb contour can be created from a sequence of elements. The phonological system uses H and L to describe high and low pitch accents, C to describe connection elements and B to describe the rises that occur at phrase boundaries. A fully specified grammar is described which links the intermediate and F₀ levels. A grammar is specified for linking the phonological and intermediate levels, but this is only partly complete due to problems with the phonological level of description.A computer implementation of the model is described. Most of the implementation work concentrated on the relationship between the intermediate level and the F₀ level. Results are given showing that the computer analysis system labels F₀ contours quite accurately, but is significantly worse than a human labeller. It is shown that the synthesis system produces artificial F₀ contours that are very similar to naturally occurring F₀ contoursThe thesis concludes with some indications of further work and ideas on how the computer implementation of the model could be of practical benefit in speech synthesis and recognition

Hyper-efficient model-independent Bayesian method for the analysis of pulsar timing data

A new model independent method is presented for the analysis of pulsar timing data and the estimation of the spectral properties of an isotropic gravitational wave background (GWB). We show that by rephrasing the likelihood we are able to eliminate the most costly aspects of computation normally associated with this type of data analysis. When applied to the International Pulsar Timing Array Mock Data Challenge data sets this results in speedups of approximately 2 to 3 orders of magnitude compared to established methods. We present three applications of the new likelihood. In the low signal to noise regime we sample directly from the power spectrum coefficients of the GWB signal realization. In the high signal to noise regime, where the data can support a large number of coefficients, we sample from the joint probability density of the power spectrum coefficients for the individual pulsars and the GWB signal realization. Critically in both these cases we need make no assumptions about the form of the power spectrum of the GWB, or the individual pulsars. Finally we present a method for characterizing the spatial correlation between pulsars on the sky, making no assumptions about the form of that correlation, and therefore providing the only truly general Bayesian method of confirming a GWB detection from pulsar timing data.Comment: 9 pages, 4 figure

Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone

Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) is a dominantly inherited degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. VCP (p97 in mouse, TER94 in Drosophila melanogaster and CDC48 in Saccharomyces cerevisiae) is a highly conserved AAA+-ATPase that regulates a wide array of cellular processes. The mechanism of IBMPFD pathogenesis is unknown. Towards elucidating the pathogenic mechanism we have developed and characterized transgenic mice with ubiquitous expression of wild-type and disease-causing versions of human VCP/p97. Here, we report that mice expressing VCP/p97 harboring the mutations R155H or A232E develop pathology that is limited to muscle, brain and bone, recapitulating the spectrum of disease in humans with IBMPFD. The mice exhibit progressive muscle weakness and pathological examination of muscle shows classic characteristics of inclusion body myopathy including rimmed vacuoles and TDP-43 pathology. The mice exhibit abnormalities in behavioral testing and pathological examination of the brain shows widespread TDP-43 pathology. Furthermore, radiological examination of the skeleton reveals that mutant mice develop severe osteopenia accompanied by focal lytic and sclerotic lesions in vertebrae and femur. In vitro studies indicate that mutant VCP causes inappropriate activation of the NF-κB signaling cascade, which could contribute to the mechanism of pathogenesis in multiple tissues including muscle, bone and brai

Study of the magnetite to maghemite transition using microwave permittivity and permeability measurements

The microwave cavity perturbation (MCP) technique is used to identify the transition from magnetite (Fe3O4) to the meta-stable form of maghemite (γ-Fe2O3). In this study Fe3O4 was annealed at temperatures from 60 to 300 °C to vary the oxidation. Subsequent to annealing, the complex permittivity and magnetic permeability of the iron oxide powders were measured. The transition to γ-Fe2O3 was corroborated with x-ray diffraction (XRD), x-ray photoelectron spectroscopy (XPS) and vibrating sample magnetometry (VSM). XRD, XPS and VSM implied that the starting powder was consistent with Fe3O4 and the powders annealed at more than 200 °C were transitioning to γ-Fe2O3. The MCP measurements gave large differences in both complex permittivity and magnetic permeability of the two phases in the frequency range of 2.5–10.2 GHz. Magnetic permeability decreased with annealing temperature, though magnetic losses showed frequency dependent behaviour. Complex permittivity measurements showed a large decrease in both dielectric constant and losses at all measurement frequencies, as well as a prominent loss peak centred around the phase transition temperatures. We interpret the loss peak as being a consequence of field effects due to an intermediate multi-phase mixture. Additionally, almost no frequency dependence was observed. The reduction in complex permittivity implies that the $\text{Fe}_{\text{oct}}^{2+}$ cations in the lattice provide a significant contribution to polarization at microwave frequencies and the effects of $\text{Fe}_{\text{oct}}^{3+}$ are nominal in comparison. The change in loss can be explained as a combination of the differences in the effective conductivity of the two phases (i.e. Fe3O4 exhibits electron-hopping conduction whereas the presence of vacancies in γ-Fe2O3 nullifies this). This shows that the non-invasive MCP measurements serve as a highly sensitive and versatile method for looking at this phase transition in iron and potentially the effects of oxidation states on the polarization in other iron oxides

The TRPC6 inhibitor, larixyl acetate, is effective in protecting against traumatic brain injury-induced systemic endothelial dysfunction

BACKGROUND: The incidence of traumatic brain injuries (TBIs) is on the rise in the USA. Concussions, or mild TBIs without skull fracture, account for about 75% of all TBIs. Mild TBIs (mTBIs) lead to memory and cognitive deficits, headaches, intraocular pressure rises, axonal degeneration, neuroinflammation, and an array of cerebrovascular dysfunctions, including increased vascular permeability and decreased cerebral blood flow. It has been recently reported that besides vascular dysfunction in the cerebral circulation, mTBI may also cause a significant impairment of endothelial function in the systemic circulation, at least within mesenteric microvessels. In this study, we investigated whether mTBI affects endothelial function in aortas and determined the contribution of transient receptor potential canonical (TRPC) channels to modulating mTBI-associated endothelial dysfunction. METHODS: We used a model of closed-head mTBI in C57BL/6, 129S, 129S-C57BL/6-F2 mice, and 129S-TRPC1 and 129S-C57BL/6-TRPC6 knockout mice to determine the effect of mTBI on endothelial function in mouse aortas employing ex vivo isometric tension measurements. Aortic tissue was also analyzed using immunofluorescence and qRT-PCR for TRPC6 expression following mTBI. RESULTS: We show that in various strains of mice, mTBI induces a pronounced and long-lasting endothelial dysfunction in the aorta. Ablation of TRPC6 protects mice from mTBI-associated aortic endothelial dysfunction, while TRPC1 ablation does not impact brain injury-induced endothelial impairment in the aorta. Consistent with a role of TRPC6 activation following mTBI, we observed improved endothelial function in wild type control mice subjected to mTBI following 7-day in vivo treatment with larixyl acetate, an inhibitor of TRPC6 channels. Conversely, in vitro treatment with the pro-inflammatory endotoxin lipopolysaccharide, which activates endothelial TRPC6 in a Toll-like receptor type 4 (TLR4)-dependent manner, worsened aortic endothelial dysfunction in wild type mice. Lipopolysaccharide treatment in vitro failed to elicit endothelial dysfunction in TRPC6 knockout mice. No change in endothelial TRPC6 expression was observed 7 days following TBI. CONCLUSIONS: These data suggest that TRPC6 activation may be critical for inducing endothelial dysfunction following closed-head mTBI and that pharmacological inhibition of the channel may be a feasible therapeutic strategy for preventing mTBI-associated systemic endothelial dysfunction

Medieval Irish Chronicles Reveal Persistent Volcanic Forcing of Severe Winter Cold Events, 431–1649 CE

Explosive volcanism resulting in stratospheric injection of sulfate aerosol is a major driver of regional to global climatic variability on interannual and longer timescales. However, much of our knowledge of the climatic impact of volcanism derives from the limited number of eruptions that have occurred in the modern period during which meteorological instrumental records are available. We present a uniquely long historical record of severe short-term cold events from Irish chronicles, 431–1649 CE, and test the association between cold event occurrence and explosive volcanism. Thirty eight (79%) of 48 volcanic events identified in the sulfate deposition record of the Greenland Ice Sheet Project 2 ice-core correspond to 37 (54%) of 69 cold events in this 1219 year period. We show this association to be statistically significant at the 99.7% confidence level, revealing both the consistency of response to explosive volcanism for Ireland's climatically sensitive Northeast Atlantic location and the large proportional contribution of volcanism to historic cold event frequencies here. Our results expose, moreover, the extent to which volcanism has impacted winter-season climate for the region, and can help to further resolve the complex spatial patterns of Northern Hemisphere winter-season cooling versus warming after major eruptions.Earth and Planetary Science

Deep Brain Stimulation for Parkinson's Disease with Early Motor Complications:A UK Cost-Effectiveness Analysis

International audienceBackground: Parkinson’s disease (PD) is a debilitating illness associated with considerable impairment of quality of life and substantial costs to health care systems. Deep brain stimulation (DBS) is an established surgical treatment option for some patients with advanced PD. The EARLYSTIM trial has recently demonstrated its clinical benefit also in patients with early motor complications. We sought to evaluate the cost-effectiveness of DBS, compared to best medical therapy (BMT), among PD patients with early onset of motor complications, from a United Kingdom (UK) payer perspective.Methods: We developed a Markov model to represent the progression of PD as rated using the Unified Parkinson's Disease Rating Scale (UPDRS) over time in patients with early PD. Evidence sources were a systematic review of clinical evidence; data from the EARLYSTIM study; and a UK Clinical Practice Research Datalink (CPRD) dataset including DBS patients. A mapping algorithm was developed to generate utility values based on UPDRS data for each intervention. The cost-effectiveness was expressed as the incremental cost per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were undertaken to explore the effect of parameter uncertainty.Results: Over a 15-year time horizon, DBS was predicted to lead to additional mean cost per patient of £26,799 compared with BMT (£73,077/patient versus £46,278/patient) and an additional mean 1.35 QALYs (6.69 QALYs versus 5.35 QALYs), resulting in an incremental cost-effectiveness ratio of £19,887 per QALY gained with a 99% probability of DBS being cost-effective at a threshold of £30,000/QALY. One-way sensitivity analyses suggested that the results were not significantly impacted by plausible changes in the input parameter values.Conclusion: These results indicate that DBS is a cost-effective intervention in PD patients with early motor complications when compared with existing interventions, offering additional health benefits at acceptable incremental cost. This supports the extended use of DBS among patients with early onset of motor complications

Plasma biomarkers of neurodegeneration in mild cognitive impairment with Lewy bodies

BACKGROUND: Blood biomarkers of Alzheimer's disease (AD) may allow for the early detection of AD pathology in mild cognitive impairment (MCI) due to AD (MCI-AD) and as a co-pathology in MCI with Lewy bodies (MCI-LB). However not all cases of MCI-LB will feature AD pathology. Disease-general biomarkers of neurodegeneration, such as glial fibrillary acidic protein (GFAP) or neurofilament light (NfL), may therefore provide a useful supplement to AD biomarkers. We aimed to compare the relative utility of plasma Aβ42/40, p-tau181, GFAP and NfL in differentiating MCI-AD and MCI-LB from cognitively healthy older adults, and from one another. METHODS: Plasma samples were analysed for 172 participants (31 healthy controls, 48 MCI-AD, 28 possible MCI-LB and 65 probable MCI-LB) at baseline, and a subset (n = 55) who provided repeated samples after ≥1 year. Samples were analysed with a Simoa 4-plex assay for Aβ42, Aβ40, GFAP and NfL, and incorporated previously-collected p-tau181 from this same cohort. RESULTS: Probable MCI-LB had elevated GFAP (p < 0.001) and NfL (p = 0.012) relative to controls, but not significantly lower Aβ42/40 (p = 0.06). GFAP and p-tau181 were higher in MCI-AD than MCI-LB. GFAP discriminated all MCI subgroups, from controls (AUC of 0.75), but no plasma-based marker effectively differentiated MCI-AD from MCI-LB. NfL correlated with disease severity and increased with MCI progression over time (p = 0.011). CONCLUSION: Markers of AD and astrocytosis/neurodegeneration are elevated in MCI-LB. GFAP offered similar utility to p-tau181 in distinguishing MCI overall, and its subgroups, from healthy controls

A microbial role in the construction of Mono Lake carbonate chimneys?

Lacustrine carbonate chimneys are striking, metre‐scale constructions. If these were bioinfluenced constructions, they could be priority targets in the search for early and extraterrestrial microbial life. However, there are questions over whether such chimneys are built on a geobiological framework or are solely abiotic geomorphological features produced by mixing of lake and spring waters. Here, we use correlative microscopy to show that microbes were living around Pleistocene Mono Lake carbonate chimneys during their growth. A plausible interpretation, in line with some recent works by others on other lacustrine carbonates, is that benthic cyanobacteria and their associated extracellular organic material (EOM) formed tubular biofilms around rising sublacustrine spring vent waters, binding calcium ions and trapping and binding detrital silicate sediment. Decay of these biofilms would locally have increased calcium and carbonate ion activity, inducing calcite precipitation on and around the biofilms. Early manganese carbonate mineralisation was directly associated with cell walls, potentially related to microbial activity though the precise mechanism remains to be elucidated. Much of the calcite crystal growth was likely abiotic, and no strong evidence for either authigenic silicate growth or a clay mineral precursor framework was observed. Nevertheless, it seems likely that the biofilms provided initial sites for calcite nucleation and encouraged the primary organised crystal growth. We suggest that the nano‐, micro‐ and macroscale fabrics of these Pleistocene Mono Lake chimneys were affected by the presence of centimetre‐thick tubular and vertically stacked calcifying microbial mats. Such carbonate chimneys represent a promising macroscale target in the exploration for ancient or extraterrestrial life