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BackgroundOne of the most common symptoms of speech deficits in individuals with Parkinson's disease (PD) is significantly reduced vocal loudness and pitch range. The present study investigated whether abnormal vocalizations in individuals with PD are related to sensory processing of voice auditory feedback. Perturbations in loudness or pitch of voice auditory feedback are known to elicit short latency, compensatory responses in voice amplitude or fundamental frequency.Methodology/Principal FindingsTwelve individuals with Parkinson's disease and 13 age- and sex- matched healthy control subjects sustained a vowel sound (/α/) and received unexpected, brief (200 ms) perturbations in voice loudness (±3 or 6 dB) or pitch (±100 cents) auditory feedback. Results showed that, while all subjects produced compensatory responses in their voice amplitude or fundamental frequency, individuals with PD exhibited larger response magnitudes than the control subjects. Furthermore, for loudness-shifted feedback, upward stimuli resulted in shorter response latencies than downward stimuli in the control subjects but not in individuals with PD.Conclusions/SignificanceThe larger response magnitudes in individuals with PD compared with the control subjects suggest that processing of voice auditory feedback is abnormal in PD. Although the precise mechanisms of the voice feedback processing are unknown, results of this study suggest that abnormal voice control in individuals with PD may be related to dysfunctional mechanisms of error detection or correction in sensory feedback processing.

We present UV broadband photometry and optical emission-line measurements for a sample of 32 Brightest Cluster Galaxies (BCGs) in clusters of the Representative XMM-Newton Cluster Structure Survey (REXCESS) with z = 0.06 − 0.18. The REXCESS clusters, chosen to study scaling relations in clusters of galaxies, have X-ray measurements of high quality. The trends of star formation and BCG colors with BCG and host properties can be investigated with this sample. The UV photometry comes from the XMM Optical Monitor, supplemented by existing archival GALEX photometry. We detected Hα and forbidden line emission in 7 (22%) of these BCGs, in optical spectra obtained using the SOAR Goodman Spectrograph. All of these emission-line BCGs occupy clusters classified as cool cores based on the central cooling time in the cluster core, for an emission-line incidence rate of 70% for BCGs in REXCESS cool core clusters. Significant correlations between the Hα equivalent widths, excess UV production in the BCG, and the presence of dense, X-ray bright intracluster gas with a short cooling time are seen, including the fact that all of the Hα emitters inhabit systems with short central cooling times and high central ICM densities. Estimates of the star formation rates based on Hα and UV excesses are consistent with each other in these 7 systems, ranging from 0.1 − 8 solar masses per year. The incidence of emission-line BCGs in the REXCESS sample is intermediate, somewhat lower than in other X-ray selected samples (∼ 35%), and somewhat higher than but statistically consistent with optically selected, slightly lower redshift BCG samples (∼ 10 − 15%). The UV-optical colors (UVW1-R ∼ 4.7 ± 0.3) of REXCESS BCGs without strong optical emission lines are consistent with those predicted from templates and observations of ellipticals dominated by old stellar populations. We see no trend in UV-optical colors with optical luminosity, R − K color, X-ray temperature, redshift, or offset between X-ray centroid and X-ray peak ( w ). The lack of such trends in these massive galaxies, particularly the ones lacking emission lines, suggests that the proportion of UV-emitting (200-300 nm) stars is insensitive to galaxy mass, cluster mass, cluster relaxation, and recent evolution, over the range of this sample.

Several studies have shown sensorimotor deficits in speech processing in individuals with idiopathic Parkinson's disease (PD). The underlying neural mechanisms, however, remain poorly understood. In the present event-related potential (ERP) study, 18 individuals with PD and 18 healthy controls were exposed to frequency-altered feedback (FAF) while producing a sustained vowel and listening to the playback of their own voice. Behavioral results revealed that individuals with PD produced significantly larger vocal compensation for pitch feedback errors than healthy controls, and exhibited a significant positive correlation between the magnitude of their vocal responses and the variability of their unaltered vocal pitch. At the cortical level, larger P2 responses were observed for individuals with PD compared with healthy controls during active vocalization due to left-lateralized enhanced activity in the superior and inferior frontal gyrus, premotor cortex, inferior parietal lobule, and superior temporal gyrus. These two groups did not differ, however, when they passively listened to the playback of their own voice. Individuals with PD also exhibited larger P2 responses during active vocalization when compared with passive listening due to enhanced activity in the inferior frontal gyrus, precental gyrus, postcentral gyrus, and middle temporal gyrus. This enhancement effect, however, was not observed for healthy controls. These findings provide neural evidence for the abnormal auditory-vocal integration for voice control in individuals with PD, which may be caused by their deficits in the detection and correction of errors in voice auditory feedback. Hum Brain Mapp 37:4248-4261, 2016. © 2016 Wiley Periodicals, Inc.

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Lipopolysaccharide (LPS)-mediated activation of Toll-like receptors (TLRs) in hepatic macrophages and injury to hepatocytes are major contributors to the pathogenesis of alcoholic liver disease (ALD). However, the mechanisms by which TLR-dependent inflammatory responses and alcohol-induced hepatocellular damage coordinately lead to ALD are not completely understood. In this study, we found that mice deficient in IRAKM, a proximal Toll-like receptor pathway molecule typically associated with inhibition of TLR signaling, were actually protected from chronic ethanol-induced liver injury. In bone marrow derived macrophages challenged with low concentrations of LPS, which reflect the relevant pathophysiological levels of LPS in both alcoholic patients and ethanol-fed mice, the IRAKM Myddosome was preferentially formed. Further, the IRAKM Myddosome mediated the up-regulation of Mincle, a sensor for cell death. Mincle-deficient mice were also protected from ethanol-induced liver injury. The endogenous Mincle ligand, SAP130 is a danger signal released by damaged cells; culture of hepatocytes with ethanol increased the release of SAP130. Ex vivo studies in bone marrow derived macrophages suggested that the endogenous Mincle ligand, SAP130, and LPS synergistically activated inflammatory responses, including inflammasome activation. Conclusion: This study reveals a novel IRAKM-Mincle axis that contributes to the pathogenesis of ethanol-induced liver injury.

Metabolic acidosis can lead to inflammation, tissue damage, and cancer metastasis. Dietary acid load contributes to metabolic acidosis if endogenous acid–base balance is not properly regulated. Breast cancer survivors have reduced capacities to adjust their acid–base balance; yet, the associations between dietary acid load and inflammation and hyperglycemia have not been examined among them. We analyzed data collected from 3042 breast cancer survivors enrolled in the Women’s Healthy Eating and Living (WHEL) Study who had provided detailed dietary intakes and measurements of plasma C-reactive protein (CRP) and hemoglobin A1c (HbA1c). Using a cross-sectional design, we found positive associations between dietary acid load and plasma CRP and HbA1c. In the multivariable-adjusted models, compared to women with the lowest quartile, the intakes of dietary acid load among women with the highest quartile showed 30–33% increases of CRP and 6–9% increases of HbA1c. Our study is the first to demonstrate positive associations between dietary acid load and CRP and HbA1c in breast cancer survivors. Our study identifies a novel dietary factor that may lead to inflammation and hyperglycemia, both of which are strong risk factors for breast cancer recurrence and comorbidities.

Resistance to endocrine therapy agents has presented a clinical obstacle in the treatment of hormone-dependent breast cancer. Our laboratory has initiated a study of microRNA regulation of signaling pathways that may result in breast cancer progression on aromatase inhibitors (AI). Microarray analysis of hormone refractory cell lines identified 115 differentially regulated microRNAs, of which 49 microRNAs were believed to be hormone-responsive. A group of microRNAs were inversely expressed in the AI-resistant lines versus LTEDaro and tamoxifen-resistant. We focused our work on hsa-miR-128a which was hormone-responsive and selectively up-regulated in the letrozole-resistant cell lines. Human miR-128a was predicted to target the TGFβ signaling pathway and indeed sensitivity to TGFβ was compromised in the letrozole-resistant cells, as compared to parental MCF-7aro. Human miR-128a was shown to negatively target TGFβRI protein expression by binding to the 3’UTR region of the gene. Inhibition of endogenous miR-128a resulted in re-sensitization of the letrozole-resistant lines to TGFβ growth inhibitory effects. This data suggests that the hormone-responsive miR-128a can modulate TGFβ signaling and survival of the letrozole-resistant cell lines. To our knowledge, this is the first study to address the role of microRNA regulation as well as TGFβ signaling in AI-resistant breast cancer cell lines. We believe that in addition to estrogen-modulation of gene expression, hormone-regulated microRNAs may provide an additional level of post-transcriptional regulation of signaling pathways critically involved in breast cancer progression and AI-resistance.