The purpose of this study was to explore vocal responses to pitch perturbation on the flat, rising, and falling contour made of sequences of level tones in Taiwanese Southern Min. Twenty-two native ...speakers produced nine disyllabic words (flat: high-high, mid-mid, and low-low tone sequences; rising: mid-high, low-high, and low-mid tone sequences; falling: high-mid, high-low, and mid-low tone sequences). Pitch-shift stimuli (200 ms) appeared at either 100 ms (the beginning of the first syllable) or 400 ms (the beginning of the second syllable) after vocal onset. The participants were asked to ignore the pitch perturbation that appeared via auditory feedback. We found their compensation decreased when both syllables had identical level tones (i.e., the flat contour) but was particularly large when the overall contour was falling. Furthermore, pitch compensation at 100 ms was smaller than at 400 ms for the falling contour, but not for the flat and rising contours. Our results suggest that less susceptibility to pitch perturbation in the initial speech planning process is conditioned by the velocity of overall pitch contour.
Purpose: Our audio--vocal system involves a negative feedback system that functions to correct for fundamental frequency (fsubscript 0) errors in production. Therefore, automatic and opposing ...responses appear when an unexpected change in voice pitch is present in auditory feedback. This study explores following responses to pitch perturbation in auditory feedback in tonal language speakers, which have been commonly overlooked or discarded by past research. We examine whether the number of response types (opposing vs. following) and their dynamic fsubscript 0 contours in tone word production vary as a function of instruction (involuntary "to ignore" vs. volitional "to compensate"). Method: Twenty-four native speakers of Taiwanese Southern Min (TSM) produced three disyllabic TSM words while receiving pitch perturbation through headphones. The three disyllabic words were "tsau"superscript 55-"im"subscript 55 ("out of tune"; HH), "kau"superscript 33-"uann"superscript 33 ("exchange"; MM), and "pan"superscript 11-"an"superscript 11 ("handle a case"; LL) that carry an identical high-, mid-, or low-level tone. The participants were instructed either "to ignore" or "to compensate" for the pitch shifts. Results: Results from a Bayesian Poisson regression show that the number of opposing and following responses were split nearly 50-50 for the "ignore" condition and 55%-35% for the "compensate" condition. The simulation results indicate that the speakers were able to switch between the feedback and the feedforward mode during the testing. On the other hand, fsubscript 0 contour analyses using generalized additive models show that pitch-increasing responses (i.e., oppose to downshifts or follow upshifts) were significantly larger than pitch-decreasing responses (i.e., oppose to upshifts or follow downshifts) for the MM and LL words, but not for the HH word. Conclusions: Our results provide support for the view that, for tone speakers, following responses are not uncommon. The magnitudes of pitch shift response trajectories have to do with the available pitch range for moving up or down in tone word production.
Auditory feedback plays an important role in regulating our vocal pitch. When pitch shifts suddenly appear in auditory feedback, the majority of the responses are opposing, correcting for the ...mismatch between perceived pitch and actual pitch. However, research has indicated that following responses to auditory perturbation could be common. This study attempts to explore the ways individual speakers would respond to pitch perturbation (using an opposing response or a following response) from trial to trial. Thirty-six native speakers of Mandarin produced the vowel /a/ while receiving perturbed pitch at a random time (500 ~ 700 ms) after vocal onset for a duration of 200 ms. Three blocks of 30 trials that differed in the pitch-shift stimulus direction were recorded in a randomized order: (a) the down-only condition where pitch was shifted downwards 250 cents; (b) the up-only condition where pitch was shifted upwards 250 cents; and (c) the random condition where downshifts and upshifts occurred randomly and were equally likely. The participants were instructed to ignore the pitch shifts. Results from the latent class analysis show that at the individual level across trials, 57% of participants were switchers, 28% were opposers, and 15% were followers. Our results support that speakers produce a mix of opposing and following responses when they respond to perturbed pitch. Specifically, the proportion of followers was conditional on the expectancy of pitch-shift stimulus direction: More followers were observed when the pitch-shift stimulus direction was predictable. Closer inspection of the levels of response consistency in different time phases shows that a particular mechanism (opposing or following) was initially implemented; the two mechanisms may alternate in the middle phase; and then finally, the pitch-shift response was featured as a particular mechanism near the end phase.
Nonalcoholic fatty liver disease (NAFLD) is recognized as the liver component of metabolic syndrome. The regulation of hepatic lipid should be emphasized to prevent accompanying illness. As ...AMP-activated protein kinase (AMPK) and sterol regulatory element binding protein (SREBP) regulate lipid metabolism, CD36 and fatty acid synthase (FAS) promote lipid uptake and lipogenesis respectively, while acetyl-CoA carboxylase (ACC) is an indicator of negative feedback. The increase of IRS-1 phosphorylation at the residue ser307 (p-ser307-IRS-1) and decrease of p-ser473-Akt (p-Akt) are viewed as the insulin resistance markers, and our previous reports suggested dipeptidyl peptidase-4 (DPP-4) mediates insulin resistance, the crucial factor of metabolic syndrome. Abelmoschus esculentus (AE) fruit is well-known for its antidiabetic utility. We had isolated several AE subfractions by successive steps, and found that F1 and F2 were especially valid in suppressing DPP-4 signaling. Since little is known if AE works on NAFLD, now we first attempt to investigate whether AE is useful to attenuate hepatic lipogenesis and lipid uptake in liver cells, along with improving the metabolic targets. We demonstrated that AE subfractions attenuated the hepatic lipid accumulation induced by free fatty acids. Treatment of AE alleviated FAS and returned the level of p-ser79-ACC (p-ACC). Although F1 was more effective on AMPK, F2 seemed more stable to attenuate SREBP-1. Moreover, as fatty acids stimulated the expression of CD36, F2 showed a superior effect to down-regulate the lipid uptake. Both AE subfractions reduced the generation of ROS, decreased the level of p-ser307-IRS-1, and restored the expression of p-Akt. Moreover, treatment of DPP-4 inhibitor linagliptin revealed that, AE could prevent the hepatic lipogenesis, oxidative burden, and the related insulin resistance via downregulating DPP-4. In conclusion, the present investigation revealed that AE, especially F2, is potential to be developed as adjuvant to prevent NAFLD.
The association of Alzheimer disease (AD) and Diabetes (DM) is less clear. Accumulation of beta amyloid (Aβ) and presence of hyperphosphorylated tau (p-tau) are hallmarks of AD, spreading in the ...region where insulin receptors are also found. Aβ exerts neuron toxicity, and could disturb insulin signaling of phosphatidylinositol 3-kinase (PI3K), glycogen synthase kinase (GSK)-3β and AMP-activated protein kinase (AMPK), but increase IRS-1-Ser307 phosphorylation which is viewed as insulin resistance marker. Previously we reported dipeptidyl peptidase-4 (DPP-4) mediate insulin resistance signals, and Abelmoschus esculentus (AE) subfractions F1 (rich in quercetin glucosides and triterpene ester) and F2 (containing large amount of polysaccharides) attenuate DPP-4-mediated apoptosis. In the present study, we aim to investigate if Aβ induce neuron death by regulating DPP-4 and insulin resistance signals, and the putative effect of F1 and F2. By MTT, microscopy, and Western blotting, we demonstrate treatment of appropriate doses of AE subfractions prevent Aβ-induced neuron apoptosis. F1 attenuate Aβ-induced caspase 3 expression especially at 25 μg/mL, while F2 attenuate caspase 3 activation even at the low dose of 1 μg/mL. Both AE subfractions decrease Aβ-enhanced DPP-4, but increase Aβ-reduced p-AMPK and p-PI3K. The activity analysis reveals that F2 is more valid than F1 to reduce DPP-4 activity. The inhibition of DPP-4 demonstrates it plays the pivotal role in Aβ-induced neuron apoptosis. Moreover, although both F1 and F2 are effective to inhibit p-IRS-1-Ser307, F2 takes advantage to reduce p-Tau while F1 is superior to enhance p-GSK-3β. This implies AE subfractions act on different targets, and could be developed respectively. In conclusion, we demonstrate AE is potential to prevent Aβ-induced neuron damage by regulating DPP-4 and the insulin resistance cascades. AE could be an adjuvant to protect neuron degenerative disease related to Aβ and insulin resistance.
Users of mobile phone applications (apps) often have to wait for the pages of apps to load, a process that substantially affects user experience. Based on the Attentional Gate Model and Emotional ...Contagion Theory, this paper explores the effects of the urgency expressed by a spokes-character's movement in the loading page of a social app the app type on users' switching intention through two studies. In Study 1 (
= 173), the results demonstrated that for a hedonic-orientated app, a high-urgency (vs. low-urgency) spokes-character resulted in a lower switching intention, whereas the opposite occurred for a utilitarian-orientated app. We adopted a similar methodology in Study 2 (
= 182) and the results showed that perceived waiting time mediated the interaction effect demonstrated in Study 1. Specifically, for the hedonic-orientated (vs. utilitarian-orientated) social app, the high-urgency (vs. low-urgency) spokes-character made participants estimate a shorter perceived waiting time, which induces a lower user switching intention. This paper contributes to the literature on emotion, spokes-characters, and human-computer interaction, which extends an enhanced understanding of users' perception during loading process and informs the design of spokes-characters for the loading pages of apps.
Summary
Aim
It is now clear that insulin signaling has important roles in regulation of neuronal functions in the brain. Dysregulation of brain insulin signaling has been linked to neurodegenerative ...disease, particularly Alzheimer's disease (AD). In this regard, there is evidence that improvement of neuronal insulin signaling has neuroprotective activity against amyloid β (Aβ)‐induced neurotoxicity for patients with AD. Linagliptin is an inhibitor of dipeptidylpeptidase‐4 (DPP‐4), which improves impaired insulin secretion and insulin downstream signaling in the in peripheral tissues. However, whether the protective effects of linagliptin involved in Aβ‐mediated neurotoxicity have not yet been investigated.
Methods
In the present study, we evaluated the mechanisms by which linagliptin protects against Aβ‐induced impaired insulin signaling and cytotoxicity in cultured SK‐N‐MC human neuronal cells.
Results
Our results showed that Aβ impairs insulin signaling and causes cell death. However, linagliptin significantly protected against Aβ‐induced cytotoxicity, and prevented the activation of glycogen synthase kinase 3β (GSK3β) and tau hyperphosphorylation by restoring insulin downstream signaling. Furthermore, linagliptin alleviated Aβ‐induced mitochondrial dysfunction and intracellular ROS generation, which may be due to the activation of 5′ AMP‐activated protein kinase (AMPK)‐Sirt1 signaling. This upregulation of Sirt1 expression was also observed in diabetic patients with AD coadministration of linagliptin.
Conclusions
Taken together, our findings suggest linagliptin can restore the impaired insulin signaling caused by Aβ in neuronal cells, suggesting DPP‐4 inhibitors may have therapeutic potential for reducing Aβ‐induced impairment of insulin signaling and neurotoxicity in AD pathogenesis.
A growing body of evidence suggests that disruption of the homeostasis of lipid metabolism affects the pathogenesis of Alzheimer＇s disease （AD）. In particular, dysregulation of cholesterol ...homeostasis in the brain has been reported to considerably increase the risk of developing AD. Thus, dysregulation of lipid homeostasis may increase the amyloid β （Aβ） levels by affecting amyloid precursor protein （APP） cleavage, which is the most important risk factor involved in the pathogenesis of AD. Previous research demonstrated that Aβ can trigger neuronal insulin resistance, which plays an important role in response to Aβ-induced neurotoxicity in AD. Epidemiological studies also suggested that statin use is associated with a decreased incidence of AD. Therefore, statins are believed to be a good candidate for conferring neuropro- tective effects against AD. Statins may play a beneficial role in reducing A~-induced neurotoxicity. Their effect involves a putative mechanism beyond its cholesterol-lowering effects in preventing A3-induced neurotoxicity. However, the underlying molecular mechanisms of the protective effect of statins have not been clearly determined in Aβ-induced neurotoxicity. Given that statins may provide benefits beyond the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A （HMG-CoA） reductase, these drugs may also improve the brain. Thus, statins may have beneficial effects on impaired insulin signaling by activating AMP-activated protein kinase （AMPK） in neuronal cells. They play a potential therapeutic role in targeting Aβ-mediated neurotoxicity.
Oncogenic activation of the Wnt/β‐catenin signaling pathway is common in hepatocellular carcinoma (HCC). Our recent studies have demonstrated that SRY (sex determining region Y)‐box 1 (SOX1) and ...secreted frizzled‐related proteins are concomitantly promoter‐hypermethylated, and this might lead to abnormal activation of the Wnt signaling pathway in HCC. SOX1 encodes a transcription factor involved in the regulation of embryonic development and cell fate determination. However, the expression and functional role of SOX1 in HCC remains unclear. In this study, we confirmed via quantitative methylation‐specific polymerase chain reaction that SOX1 was frequently downregulated through promoter hypermethylation in HCC cells and tissues. Overexpression of SOX1 by a constitutive or inducible approach could suppress cell proliferation, colony formation, and invasion ability in HCC cell lines, as well as tumor growth in nonobese diabetic/severe combined immunodeficiency mice. Conversely, knockdown of SOX1 by withdrawal of doxycycline could partially restore cell proliferation and colony formation in HCC cells. We used a T cell factor (TCF)‐responsive luciferase reporter assay and western blot analysis to prove that SOX1 could regulate TCF‐responsive transcriptional activity and inhibit the expression of Wnt downstream genes. Furthermore, we used glutathione S‐transferase pull‐down, co‐immunoprecipitation, and confocal microscopy to demonstrate that SOX1 could interact with β‐catenin but not with the β‐catenin/TCF complex. Moreover, restoration of the expression of SOX1 induces significant cellular senescence in Hep3B cells. Conclusion: Our data show that a developmental gene, SOX1, may function as a tumor suppressor by interfering with Wnt/β‐catenin signaling in the development of HCC. (HEPATOLOGY 2012;56:2142–2153)
Prolonged exposure to high levels of glucose and fatty acid (FFA) can induce tissue damage commonly referred to as glucolipotoxicity and is particularly harmful to pancreatic β‐cells. ...Glucolipotoxicity‐mediated β‐cell failure is a critical causal factor in the late stages of diabetes, which suggests that mechanisms that prevent or reverse β‐cell death may play a critical role in the treatment of the disease. Transcription factor PDX1 was recently reported to play a key role in maintaining β‐cell function and survival, and glucolipotoxicity can activate mammalian sterile 20‐like kinase 1 (Mst1), which, in turn, stimulates PDX1 degradation and causes dysfunction and apoptosis of β‐cells. Interestingly, previous research has demonstrated that increased glucagon‐like peptide‐1 (GLP‐1) signalling effectively protects β cells from glucolipotoxicity‐induced apoptosis. Unfortunately, few studies have examined the related mechanism in detail, especially the role in Mst1 and PDX1 regulation. In the present study, we investigate the toxic effect of high glucose and FFA levels on rat pancreatic RINm5F β‐cells and demonstrate that the GLP‐1 analogue liraglutide restores the expression of PDX1 by inactivating Mst1, thus ameliorating β‐cell impairments. In addition, liraglutide also upregulates mitophagy, which may help restore mitochondrial function and protect β‐cells from oxidative stress damage. Our study suggests that liraglutide may serve as a potential agent for developing new therapies to reduce glucolipotoxicity.
PDF
