Optimization of acoustic feature extraction from dysarthric speech

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2010.Cataloged from PDF version of thesis.Includes bibliographical references (p. 171-180).Dysarthria is a motor speech disorder characterized by weak or uncoordinated movements of the speech musculature. While unfamiliar listeners struggle to understand speakers with severe dysarthria, familiar listeners are often able to comprehend with high accuracy. This observation implies that although the speech produced by an individual with dysarthria may appear distorted and unintelligible to the untrained listener, there must be a set of consistent acoustic cues that the familiar communication partner is able to interpret. While dysarthric speech has been characterized both acoustically and perceptually, most accounts tend to compare dysarthric productions to those of healthy controls rather than identify the set of reliable and consistently controlled segmental cues. This work aimed to elucidate possible recognition strategies used by familiar listeners by optimizing a model of human speech recognition, Stevens' Lexical Access from Features (LAFF) framework, for ten individual speakers with dysarthria (SWDs). The LAFF model is rooted in distinctive feature theory, with acoustic landmarks indicating changes in the manner of articulation. The acoustic correlates manifested around landmarks provide the identity to articulator-free (manner) and articulator-bound (place) features.(cont.) SWDs created weaker consonantal landmarks, likely due to an inability to form complete closures in the vocal tract and to fully release consonantal constrictions. Identification of speaker-optimized acoustic correlate sets improved discrimination of each speaker's productions, evidenced by increased sensitivity and specificity. While there was overlap between the types of correlates identified for healthy and dysarthric speakers, using the optimal sets of correlates identified for SWDs adversely impaired discrimination of healthy speech. These results suggest that the combinations of correlates suggested for SWDs were specific to the individual and different from the segmental cues used by healthy individuals. Application of the LAFF model to dysarthric speech has potential clinical utility as a diagnostic tool, highlighting the fine-grain components of speech production that require intervention and quantifying the degree of impairment.by Thomas M. DiCicco, Jr.Ph.D

BRCA1 is an essential regulator of heart function and survival following myocardial infarction

The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer but its role in protecting other tissues from DNA damage has not been explored. Here we show a new role for BRCA1 as a gatekeeper of cardiac function and survival. In mice, loss of BRCA1 in cardiomyocytes results in adverse cardiac remodelling, poor ventricular function and higher mortality in response to ischaemic or genotoxic stress. Mechanistically, loss of cardiomyocyte BRCA1 results in impaired DNA double-strand break repair and activated p53-mediated pro-apoptotic signalling culminating in increased cardiomyocyte apoptosis, whereas deletion of the p53 gene rescues BRCA1-deficient mice from cardiac failure. In human adult and fetal cardiac tissues, ischaemia induces double-strand breaks and upregulates BRCA1 expression. These data reveal BRCA1 as a novel and essential adaptive response molecule shielding cardiomyocytes from DNA damage, apoptosis and heart dysfunction. BRCA1 mutation carriers, in addition to risk of breast and ovarian cancer, may be at a previously unrecognized risk of cardiac failure

Attenuation of doxorubicin-induced cardiotoxicity by mdivi-1: a mitochondrial division/mitophagy inhibitor

Doxorubicin is one of the most effective anti-cancer agents. However, its use is associated with adverse cardiac effects, including cardiomyopathy and progressive heart failure. Given the multiple beneficial effects of the mitochondrial division inhibitor (mdivi-1) in a variety of pathological conditions including heart failure and ischaemia and reperfusion injury, we investigated the effects of mdivi-1 on doxorubicin-induced cardiac dysfunction in naïve and stressed conditions using Langendorff perfused heart models and a model of oxidative stress was used to assess the effects of drug treatments on the mitochondrial depolarisation and hypercontracture of cardiac myocytes. Western blot analysis was used to measure the levels of p-Akt and p-Erk 1/2 and flow cytometry analysis was used to measure the levels p-Drp1 and p-p53 upon drug treatment. The HL60 leukaemia cell line was used to evaluate the effects of pharmacological inhibition of mitochondrial division on the cytotoxicity of doxorubicin in a cancer cell line. Doxorubicin caused a significant impairment of cardiac function and increased the infarct size to risk ratio in both naïve conditions and during ischaemia/reperfusion injury. Interestingly, co-treatment of doxorubicin with mdivi-1 attenuated these detrimental effects of doxorubicin. Doxorubicin also caused a reduction in the time taken to depolarisation and hypercontracture of cardiac myocytes, which were reversed with mdivi-1. Finally, doxorubicin caused a significant elevation in the levels of signalling proteins p-Akt, p-Erk 1/2, p-Drp1 and p-p53. Co-incubation of mdivi-1 with doxorubicin did not reduce the cytotoxicity of doxorubicin against HL-60 cells. These data suggest that the inhibition of mitochondrial fission protects the heart against doxorubicin-induced cardiac injury and identify mitochondrial fission as a new therapeutic target in ameliorating doxorubicin-induced cardiotoxicity without affecting its anti-cancer properties

A Blueprint for Real-Time Functional Mapping via Human Intracranial Recordings

International audienceBACKGROUND: The surgical treatment of patients with intractable epilepsy is preceded by a pre-surgical evaluation period during which intracranial EEG recordings are performed to identify the epileptogenic network and provide a functional map of eloquent cerebral areas that need to be spared to minimize the risk of post-operative deficits. A growing body of research based on such invasive recordings indicates that cortical oscillations at various frequencies, especially in the gamma range (40 to 150 Hz), can provide efficient markers of task-related neural network activity. PRINCIPAL FINDINGS: Here we introduce a novel real-time investigation framework for mapping human brain functions based on online visualization of the spectral power of the ongoing intracranial activity. The results obtained with the first two implanted epilepsy patients who used the proposed online system illustrate its feasibility and utility both for clinical applications, as a complementary tool to electrical stimulation for presurgical mapping purposes, and for basic research, as an exploratory tool used to detect correlations between behavior and oscillatory power modulations. Furthermore, our findings suggest a putative role for high gamma oscillations in higher-order auditory processing involved in speech and music perception. CONCLUSION/SIGNIFICANCE: The proposed real-time setup is a promising tool for presurgical mapping, the investigation of functional brain dynamics, and possibly for neurofeedback training and brain computer interfaces

A meta-analysis of CAG (cytarabine, aclarubicin, G-CSF) regimen for the treatment of 1029 patients with acute myeloid leukemia and myelodysplastic syndrome

The regimen of cytarabine, aclarubicin and G-CSF (CAG) has been widely used in China and Japan for treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We searched literature on CAG between 1995 and 2010 and performed a meta-analysis to determine its overall efficacy using a random-effects or fixed-effects model. Thirty five trials with a total of 1029 AML (n = 814) and MDS (n = 215) patients were included for analysis. The CR rate of AML (57.9%) was significantly higher than that of MDS (45.7%) (p < 0.01). No difference in CR was noted between the new (56.7%) and relapsed/refractory AML (60.1%) (p > 0.05). The CR rate was also significantly higher in patients with favorable (64.5%) and intermediate (69.6%) karyotypes than those with unfavorable one (29.5%) (p < 0.05). Remarkably, the CR rate of CAG was significantly higher than those of non-CAG regimens (odds ratio 2.43). CAG regimen was well tolerated, with cardiotoxicity in 2.3% and early death in 5.2% of the cases. In conclusion, CAG regimen was an effective and safe regimen for the treatment of AML, and may be more effective than non-CAG regimens. Randomized controlled trials are strongly recommended to evaluate its efficacy and safety in comparison with the current standard treatment

Cardiomyocyte Specific Ablation of p53 Is Not Sufficient to Block Doxorubicin Induced Cardiac Fibrosis and Associated Cytoskeletal Changes

Doxorubicin (Dox) is an anthracycline used to effectively treat several forms of cancer. Unfortunately, the use of Dox is limited due to its association with cardiovascular complications which are manifested as acute and chronic cardiotoxicity. The pathophysiological mechanism of Dox induced cardiotoxicity appears to involve increased expression of the tumor suppressor protein p53 in cardiomyocytes, followed by cellular apoptosis. It is not known whether downregulation of p53 expression in cardiomyocytes would result in decreased rates of myocardial fibrosis which occurs in response to cardiomyocyte loss. Further, it is not known whether Dox can induce perivascular necrosis and associated fibrosis in the heart. In this study we measured the effects of acute Dox treatment on myocardial and perivascular apoptosis and fibrosis in a conditional knockout (CKO) mouse model system which harbours inactive p53 alleles specifically in cardiomyocytes. CKO mice treated with a single dose of Dox (20 mg/kg), did not display lower levels of myocardial apoptosis or reactive oxygen and nitrogen species (ROS/RNS) compared to control mice with intact p53 alleles. Interestingly, CKO mice also displayed higher levels of interstitial and perivascular fibrosis compared to controls 3 or 7 days after Dox treatment. Additionally, the decrease in levels of the microtubule protein α-tubulin, which occurs in response to Dox treatment, was not prevented in CKO mice. Overall, these results indicate that selective loss of p53 in cardiomyocytes is not sufficient to prevent Dox induced myocardial ROS/RNS generation, apoptosis, interstitial fibrosis and perivascular fibrosis. Further, these results support a role for p53 independent apoptotic pathways leading to Dox induced myocardial damage and highlight the importance of vascular lesions in Dox induced cardiotoxicity

High Throughput Screening for Small Molecule Enhancers of the Interferon Signaling Pathway to Drive Next-Generation Antiviral Drug Discovery

Most of current strategies for antiviral therapeutics target the virus specifically and directly, but an alternative approach to drug discovery might be to enhance the immune response to a broad range of viruses. Based on clinical observation in humans and successful genetic strategies in experimental models, we reasoned that an improved interferon (IFN) signaling system might better protect against viral infection. Here we aimed to identify small molecular weight compounds that might mimic this beneficial effect and improve antiviral defense. Accordingly, we developed a cell-based high-throughput screening (HTS) assay to identify small molecules that enhance the IFN signaling pathway components. The assay is based on a phenotypic screen for increased IFN-stimulated response element (ISRE) activity in a fully automated and robust format (Z′>0.7). Application of this assay system to a library of 2240 compounds (including 2160 already approved or approvable drugs) led to the identification of 64 compounds with significant ISRE activity. From these, we chose the anthracycline antibiotic, idarubicin, for further validation and mechanism based on activity in the sub-µM range. We found that idarubicin action to increase ISRE activity was manifest by other members of this drug class and was independent of cytotoxic or topoisomerase inhibitory effects as well as endogenous IFN signaling or production. We also observed that this compound conferred a consequent increase in IFN-stimulated gene (ISG) expression and a significant antiviral effect using a similar dose-range in a cell-culture system inoculated with encephalomyocarditis virus (EMCV). The antiviral effect was also found at compound concentrations below the ones observed for cytotoxicity. Taken together, our results provide proof of concept for using activators of components of the IFN signaling pathway to improve IFN efficacy and antiviral immune defense as well as a validated HTS approach to identify small molecules that might achieve this therapeutic benefit

Chemiluminescence assay for quinones based on generation of reactive oxygen species through the redox cycle of quinone.

A sensitive and selective chemiluminescence assay for the determination of quinones was developed. The method was based on generation of reactive oxygen species through the redox reaction between quinone and dithiothreitol as reductant, and then the generated reactive oxygen was detected by luminol chemiluminescence. The chemiluminescence was intense, long-lived, and proportional to quinone concentration. It is concluded that superoxide anion was involved in the proposed chemiluminescence reaction because the chemiluminescence intensity was decreased only in the presence of superoxide dismutase. Among the tested quinones, the chemiluminescence was observed from 9,10-phenanthrenequinone, 1,2-naphthoquinone, and 1,4-naphthoquinone, whereas it was not observed from 9,10-anthraquinone and 1,4-benzoquinone. The chemiluminescence property was greatly different according to the structure of quinones. The chemiluminescence was also observed for biologically important quinones such as ubiquinone. Therefore, a simple and rapid assay for ubiquinone in pharmaceutical preparation was developed based on the proposed chemiluminescence reaction. The detection limit (blank + 3SD) of ubiquinone was 0.05 microM (9 ng/assay) with an analysis time of 30 s per sample. The developed assay allowed the direct determination of ubiquinone in pharmaceutical preparation without any purification procedure

Attenuated Fatigue in Slow Twitch Skeletal Muscle during Isotonic Exercise in Rats with Chronic Heart Failure

During isometric contractions, slow twitch soleus muscles (SOL) from rats with chronic heart failure (chf) are more fatigable than those of sham animals. However, a muscle normally shortens during activity and fatigue development is highly task dependent. Therefore, we examined the development of skeletal muscle fatigue during shortening (isotonic) contractions in chf and sham-operated rats. Six weeks following coronary artery ligation, infarcted animals were classified as failing (chf) if left ventricle end diastolic pressure was >15mmHg. During isoflurane anaesthesia, SOL with intact blood supply was stimulated (1s on 1s off) at 30Hz for 15 min and allowed to shorten isotonically against a constant afterload. Muscle temperature was maintained at 37°C. In resting muscle, maximum isometric force (Fmax) and the concentrations of ATP and CrP were not different in the two groups. During stimulation, Fmax and the concentrations declined in parallel sham and chf. Fatigue, which was evident as reduced shortening during stimulation, was also not different in the two groups. The isometric force decline was fitted to a bi-exponential decay equation. Both time constants increased transiently and returned to initial values after approximately 200 s of the fatigue protocol. This resulted in a transient rise in baseline tension between stimulations, although this effect which was less prominent in chf than sham. Myosin light chain 2s phosphorylation declined in both groups after 100 s of isotonic contractions, and remained at this level throughout 15 min of stimulation. In spite of higher energy demand during isotonic than isometric contractions, both shortening capacity and rate of isometric force decline were as well or better preserved in fatigued SOL from chf rats than in sham. This observation is in striking contrast to previous reports which have employed isometric contractions to induce fatigue

Precision muon reconstruction in Double Chooz

We describe a muon track reconstruction algorithm for the reactor anti-neutrino experiment Double Chooz. The Double Chooz detector consists of two optically isolated volumes of the liquid scintillator viewed by PMTs, and an Outer Veto above these made of crossed scintillator strips. Muons are reconstructed by their Outer Veto hit positions along with timing information from the other two detector volumes. All muons are fit under the hypothesis that they are through-going and ultrarelativistic. If the energy depositions suggest that the muon may have stopped, the reconstruction fits also for this hypothesis and chooses between the two via the relative goodness-of-fit. In the ideal case of a through-going muon intersecting the center of the detector, the resolution is ~40mm in each transverse dimension. High quality muon reconstruction is an important tool for reducing the impact of the cosmogenic isotope background in Double Chooz. © 2014 Elsevier B.V