Synthetic voice design and implementation.

The limitations of speech output technology emphasise the need for exploratory psychological research to maximise the effectiveness of speech as a display medium in human-computer interaction. Stage 1 of this study reviewed speech implementation research, focusing on general issues for tasks, users and environments. An analysis of design issues was conducted, related to the differing methodologies for synthesised and digitised message production. A selection of ergonomic guidelines were developed to enhance effective speech interface design. Stage 2 addressed the negative reactions of users to synthetic speech in spite of elegant dialogue structure and appropriate functional assignment. Synthetic speech interfaces have been consistently rejected by their users in a wide variety of application domains because of their poor quality. Indeed the literature repeatedly emphasises quality as being the most important contributor to implementation acceptance. In order to investigate this, a converging operations approach was adopted. This consisted of a series of five experiments (and associated pilot studies) which homed in on the specific characteristics of synthetic speech that determine the listeners varying perceptions of its qualities, and how these might be manipulated to improve its aesthetics. A flexible and reliable ratings interface was designed to display DECtalk speech variations and record listeners perceptions. In experiment one, 40 participants used this to evaluate synthetic speech variations on a wide range of perceptual scales. Factor analysis revealed two main factors: "listenability" accounting for 44.7% of the variance and correlating with the DECtalk "smoothness" parameter to . 57 (p<0.005) and "richness" to . 53 (p<0.005); "assurance" accounting for 12.6% of the variance and correlating with "average pitch" to . 42 (p<0.005) and "head size" to. 42 (p<0.005). Complimentary experiments were then required in order to address appropriate voice design for enhanced listenability and assurance perceptions. With a standard male voice set, 20 participants rated enhanced smoothness and attenuated richness as contributing significantly to speech listenability (p<0.001). Experiment three using a female voice set yielded comparable results, suggesting that further refinements of the technique were necessary in order to develop an effective methodology for speech quality optimization. At this stage it became essential to focus directly on the parameter modifications that are associated with the the aesthetically pleasing characteristics of synthetic speech. If a reliable technique could be developed to enhance perceived speech quality, then synthesis systems based on the commonly used DECtalk model might assume some of their considerable yet unfulfilled potential. In experiment four, 20 subjects rated a wide range of voices modified across the two main parameters associated with perceived listenability, smoothness and richness. The results clearly revealed a linear relationship between enhanced smoothness and attenuated richness and significant improvements in perceived listenability (p<0.001 in both cases). Planned comparisons conducted were between the different levels of the parameters and revealed significant listenability enhancements as smoothness was increased, and a similar pattern as richness decreased. Statistical analysis also revealed a significant interaction between the two parameters (p<0.001) and a more comprehensive picture was constructed. In order to expand the focus of and enhance the generality of the research, it was now necessary to assess the effects of synthetic speech modifications whilst subjects were undertaking a more realistic task. Passively rating the voices independent of processing for meaning is arguably an artificial task which rarely, if ever, would occur in 'real-world' settings. In order to investigate perceived quality in a more realistic task scenario, experiment five introduced two levels of information processing load. The purpose of this experiment was firstly to see if a comprehension load modified the pattern of listenability enhancements, and secondly to see if that pattern differed between high and and low load. Techniques for introducing cognitive load were investigated and comprehension load was selected as the most appropriate method in this case. A pilot study distinguished two levels of comprehension load from a set of 150 true/false sentences and these were recorded across the full range of parameter modifications. Twenty subjects then rated the voices using the established listenability scales as before but also performing the additional task of processing each spoken stimuli for meaning and determining the authenticity of the statements. Results indicated that listenability enhancements did indeed occur at both levels of processing although at the higher level variations in the pattern occured. A significant difference was revealed between optimal parameter modifications for conditions of high and low cognitive load (p<0.05). The results showed that subjects perceived the synthetic voices in the high cognitive load condition to be significantly less listenable than those same voices in the low cognitive load condition. The analysis also revealed that this effect was independent of the number of errors made. This result may be of general value because conclusions drawn from this findings are independent of any particular parameter modifications that may be exclusively available to DECtalk users. Overall, the study presents a detailed analysis of the research domain combined with a systematic experimental program of synthetic speech quality assessment. The experiments reported establish a reliable and replicable procedure for optimising the aesthetically pleasing characteristics of DECtalk speech, but the implications of the research extend beyond the boundaries of a particular synthesiser. Results from the experimental program lead to a number of conclusions, the most salient being that not only does the synthetic speech designer have to overcome the general rejection of synthetic voices based on their poor quality by sophisticated customisation of synthetic voice parameters, but that he or she needs to take into account the cognitive load of the task being undertaken. The interaction between cognitive load and optimal settings for synthesis requires direct consideration if synthetic speech systems are going to realise and maximise their potential in human computer interaction

Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice

Obesity is closely associated with the metabolic syndrome, a combination of disorders including insulin resistance, diabetes, dyslipidemia, and hypertension. A role for local glucocorticoid reamplification in obesity and the metabolic syndrome has been suggested. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active cortisol from inactive 11-keto forms, and aP2-HSD1 mice with relative transgenic overexpression of this enzyme in fat cells develop visceral obesity with insulin resistance and dyslipidemia. Here we report that aP2-HSD1 mice also have high arterial blood pressure (BP). The mice have increased sensitivity to dietary salt and increased plasma levels of angiotensinogen, angiotensin II, and aldosterone. This hypertension is abolished by selective angiotensin II receptor AT-1 antagonist at a low dose that does not affect BP in non-Tg littermates. These findings suggest that activation of the circulating renin-angiotensin system (RAS) develops in aP2-HSD1 mice. The long-term hypertension is further reflected by an appreciable hypertrophy and hyperplasia of the distal tubule epithelium of the nephron, resembling salt-sensitive or angiotensin II–mediated hypertension. Taken together, our findings suggest that overexpression of 11β-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS. The potential role of adipose 11β-HSD1 in mediating critical features of the metabolic syndrome extends beyond obesity and metabolic complications to include the most central cardiovascular feature of this disorder

Global trends in aquatic animal tracking with acoustic telemetry

Acoustic telemetry (AT) is a rapidly evolving technique used to track the movements of aquatic animals. As the capacity of AT research expands it is important to optimize its relevance to management while still pursuing key ecological questions. A global review of AT literature revealed region-specific research priorities underscoring the breadth of how AT is applied, but collectively demonstrated a lack of management-driven objectives, particularly relating to fisheries, climate change, and protection of species. In addition to the need for more research with direct pertinence to management, AT research should prioritize ongoing efforts to create collaborative opportunities, establish long-term and ecosystem-based monitoring, and utilize technological advancements to bolster aquatic policy and ecological understanding worldwide

On the Incommensurate Phase of Pure and Doped Spin-Peierls System CuGeO_3

Phases and phase transitions in pure and doped spin-Peierls system CuGeO_3 are considered on the basis of a Landau-theory. In particular we discuss the critical behaviour, the soliton width and the low temperature specific heat of the incommensurate phase. We show, that dilution leads always to the destruction of long range order in this phase, which is replaced by an algebraic decay of correlations if the disorder is weak.Comment: 4 pages revtex, no figure

Efficacy and pharmacokinetic/pharmacodynamic evaluation of the Aurora kinase A inhibitor MLN8237 against preclinical models of pediatric cancer

To gain a greater understanding of the potential of the Aurora kinase A inhibitor MLN8237 in the treatment of pediatric malignancies. The activity of MLN8237 was evaluated against 28 neuroblastoma and Ewing sarcoma cell lines, and its in vivo efficacy was studied over a range of doses against 12 pediatric tumor xenograft models. Pharmacokinetic, pharmacodynamic, and genomic studies were undertaken. In vitro neuroblastoma cell lines were generally more sensitive to MLN8237 than Ewing sarcoma lines. MLN8237 demonstrated significant activity in vivo against solid tumor models at the maximum tolerated dose (MTD); however, only 2 of 6 neuroblastoma models had objective responses at 0.25MTD. In contrast, MLN8237 induced objective responses at its MTD and at 0.5MTD in three ALL models and in two out of three at 0.25MTD. Pharmacokinetic studies at 0.5MTD demonstrated a T (max) of 0.5 h, C (max) of 24.8 mu M, AUC((0-24)) of 60.3 mu M h, and 12 h trough level of 1.2 mu M. Mitotic indices increased 6-12 h after MLN8237 administration. AURKA copy number variation was frequent in xenografts, and expression was highly correlated with copy number. Objective responses were more frequent in tumors with decreased AURKA copy number (5/8) compared to those with increased gene copy number (2/14). This report confirms the significant activity against both solid tumor and ALL xenografts at the MTD, with a steep dose response. These data support clinical development of MLN8237 in childhood cancer. Because of the steep dose-response relationship, such studies should target achieving trough levels of 1 mu M or higher for sustained periods of treatment

Proteogenomic analysis of Inhibitor of Differentiation 4 (ID4) in basal-like breast cancer

Funder: National Health and Medical Research Council; doi: http://dx.doi.org/10.13039/501100000925Abstract: Background: Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC through unknown mechanisms. Methods: Here, we have defined unique molecular insights into the function of ID4 in BLBC and the related disease high-grade serous ovarian cancer (HGSOC), by combining RIME proteomic analysis, ChIP-seq mapping of genomic binding sites and RNA-seq. Results: These studies reveal novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins (γH2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage. Analysis of clinical samples demonstrates that ID4 is amplified and overexpressed at a higher frequency in BRCA1-mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair deficiency. Conclusions: These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOC

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P &lt; 0.001) and PARP inhibitor therapy (P &lt; 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P &lt; 0.018) and WEE1 inhibitor (P &lt; 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P &lt; 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Combination of the W boson polarization measurements in top quark decays using ATLAS and CMS data at root s=8 TeV

The combination of measurements of the W boson polarization in top quark decays performed by the ATLAS and CMS collaborations is presented. The measurements are based on proton-proton collision data produced at the LHC at a centre-of-mass energy of 8 TeV, and corresponding to an integrated luminosity of about 20 fb(-1)for each experiment. The measurements used events containing one lepton and having different jet multiplicities in the final state. The results are quoted as fractions of W bosons with longitudinal (F-0), left-handed (F-L), or right-handed (F-R) polarizations. The resulting combined measurements of the polarization fractions are F-0= 0.693 +/- 0.014 and F-L= 0.315 +/- 0.011. The fractionF(R)is calculated from the unitarity constraint to be F-R=-0.008 +/- 0.007. These results are in agreement with the standard model predictions at next-to-next-to-leading order in perturbative quantum chromodynamics and represent an improvement in precision of 25 (29)% for F-0(F-L) with respect to the most precise single measurement. A limit on anomalous right-handed vector (V-R), and left- and right-handed tensor (g(L), g(R)) tWb couplings is set while fixing all others to their standard model values. The allowed regions are [-0.11,0.16] for V-R, [-0.08,0.05] for g(L), and [-0.04,0.02] for g(R), at 95% confidence level. Limits on the corresponding Wilson coefficients are also derived.Peer reviewe

Measurement of hadronic event shapes in high-p T multijet final states at √s = 13 TeV with the ATLAS detector

A measurement of event-shape variables in proton-proton collisions at large momentum transfer is presented using data collected at s = 13 TeV with the ATLAS detector at the Large Hadron Collider. Six event-shape variables calculated using hadronic jets are studied in inclusive multijet events using data corresponding to an integrated luminosity of 139 fb−1. Measurements are performed in bins of jet multiplicity and in different ranges of the scalar sum of the transverse momenta of the two leading jets, reaching scales beyond 2 TeV. These measurements are compared with predictions from Monte Carlo event generators containing leading-order or next-to-leading order matrix elements matched to parton showers simulated to leading-logarithm accuracy. At low jet multiplicities, shape discrepancies between the measurements and the Monte Carlo predictions are observed. At high jet multiplicities, the shapes are better described but discrepancies in the normalisation are observed. [Figure not available: see fulltext.

A search for the dimuon decay of the Standard Model Higgs boson with the ATLAS detector

A search for the dimuon decay of the Standard Model (SM) Higgs boson is performed using data corresponding to an integrated luminosity of 139 fb(-1) collected with the ATLAS detector in Run 2 pp collisions at root s = 13 TeV at the Large Hadron Collider. The observed (expected) significance over the background-only hypothesis for a Higgs boson with a mass of 125.09 GeV is 2.0 sigma (1.7 sigma). The observed upper limit on the cross section times branching ratio for pp -&gt; H -&gt; mu mu is 2.2 times the SM prediction at 95% confidence level, while the expected limit on a H -&gt; mu mu signal assuming the absence (presence) of a SM signal is 1.1(2.0). The best-fit value of the signal strength parameter, defined as the ratio of the observed signal yield to the one expected in the SM, is mu = 1.2 +/- 0.6. (C) 2020 The Author(s). Published by Elsevier B.V