The ACE inhibitor captopril inhibits ACN-1 to control dauer formation and aging.

The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in Caenorhabditis elegans, Drosophila and rodents, but its mechanism is not well defined. Here, we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril-hypersensitive mutants. We identified a missense mutation that causes a partial loss of function of the daf-2 receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in C. elegans by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of acn-1 via captopril or RNA interference promoted dauer larvae formation, suggesting that acn-1 is a daf gene. Captopril-mediated lifespan extension was abrogated by daf-16(lf) and daf-12(lf) mutations. Our results indicate that captopril and acn-1 influence lifespan by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control.

The ACE-inhibitor drug captopril inhibits ACN-1 to control dauer formation and aging.

The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in C. elegans , Drosophila , and rodents, but its mechanism is not well defined. Here we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril hypersensitive mutants. We identified a missense mutation that causes a partial loss-of-function of the daf-2 receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in C. elegans by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of acn-1 via captopril or RNAi promoted dauer larvae formation, suggesting acn-1 is a daf gene. Captopril-mediated lifespan extension xwas abrogated by daf-16(lf) and daf-12(lf) mutations. Our results indicate that captopril and acn-1 control aging by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control. Summary Statement: Captopril and acn-1 control aging. By demonstrating they regulate dauer formation and interact with daf genes, including a new DAF-2(A261V) mutant corresponding to a human disease variant, we clarified the mechanism.

Zebrafish Model-Based Assessment of Indoxyl Sulfate-Induced Oxidative Stress and Its Impact on Renal and Cardiac Development.

Kidney disease patients may have concurrent chronic kidney disease-associated mineral bone disorder and hypertension. Cardiovascular disease (CVD) and neuropathy occur due to kidney failure-induced accumulation of uremic toxins in the body. Indoxyl sulfate (IS), a product of indole metabolism in the liver, is produced from tryptophan by the intestinal flora and is ultimately excreted through the kidneys. Hemodialysis helps renal failure patients eliminate many nephrotoxins, except for IS, which leads to a poor prognosis. Although the impacts of IS on cardiac and renal development have been well documented using mouse and rat models, other model organisms, such as zebrafish, have rarely been studied. The zebrafish genome shares at least 70% similarity with the human genome; therefore, zebrafish are ideal model organisms for studying vertebrate development, including renal development. In this study, we aimed to investigate the impact of IS on the development of zebrafish embryos, especially cardiac and renal development. At 24 h postfertilization (hpf), zebrafish were exposed to IS at concentrations ranging from 2.5 to 10 mM. IS reduced survival and the hatching rate, caused cardiac edema, increased mortality, and shortened the body length of zebrafish embryos. In addition, IS decreased heart rates and renal function. IS affected zebrafish development via the ROS and MAPK pathways, which subsequently led to inflammation in the embryos. The results suggest that IS interferes with cardiac and renal development in zebrafish embryos, providing new evidence about the toxicity of IS to aquatic organisms and new insights for the assessment of human health risks. Accordingly, we suggest that zebrafish studies can ideally complement mouse model studies to allow the simultaneous and comprehensive investigation of the physiological impacts of uremic endotheliotoxins, such as IS, on cardiac and renal development.

Tongue Postures and Tongue Centers: A Study of Acoustic-Articulatory Correspondences Across Different Head Angles.

Recent research on body and head positions has shown that postural changes may induce varying degrees of changes on acoustic speech signals and articulatory gestures. While the preservation of formant profiles across different postures is suitably accounted for by the two-tube model and perturbation theory, it remains unclear whether it is resulted from the accommodation of tongue postures. Specifically, whether the tongue accommodates the changes in head angle to maintain the target acoustics is yet to be determined. The present study examines vowel acoustics and their correspondence with the articulatory maneuvers of the tongue, including both tongue postures and movements of the tongue center, across different head angles. The results show that vowel acoustics, including pitch and formants, are largely unaffected by upward or downward tilting of the head. These preserved acoustics may be attributed to the lingual gestures that compensate for the effects of gravity. Our results also reveal that the tongue postures in response to head movements appear to be vowel-dependent, and the tongue center may serve as an underlying drive that covariates with the head angle changes. These results imply a close relationship between vowel acoustics and tongue postures as well as a target-oriented strategy for different head angles.

Temporal binding and agency under startle.

Forward models are a component of the motor system that predicts the sensory consequences of our actions. These models play several key roles in motor control and are hypothesized to underlie (among other things) the two phenomena under investigation in this experiment: The feeling of agency that we have over self-initiated actions (as opposed to reflexes), and "temporal binding", in which self-caused sensations are judged to have occurred earlier in time than they actually did. This experiment probes the connection between forward models and both of these phenomena using the "Startle" paradigm. In the Startle paradigm, a startlingly loud sound causes people to initiate a prepared action at a very short latency. It is hypothesized that the latency of a startle-initiated action is so short that normal cortical operations (including forward models) are circumvented. This experiment replicates the temporal-binding effect and simultaneously measures participants' sense of agency over their actions. The results show that both the temporal-binding effect and the sense of agency we have over our own actions is disrupted under the startle paradigm in line with the theory that these phenomena both rely on forward models. Furthermore, this experiment provides evidence in support of the claim that a startle-induced action is qualitatively different from other actions.

Articulatory Evidence for the Syllable-final Nasal Merging in Taiwan Mandarin.

Syllable-final nasals /n/ and /ŋ/ in Taiwan Mandarin have been reported to be undergoing merging. Perceptual studies have reported that the alleged merging is context-sensitive and the merging directions are vowel-dependent. These findings have been mostly attributed to dialectal and social factors. The current study uses ultrasonography to capture postures of the entire tongue during the production of syllable-final nasals. The results, though confirming previous findings that the merging directions of syllable-final nasals are vowel-dependent, are best accounted for by the biomechanics of the tongue, as supported by computational 3D model simulations. Furthermore, for some speakers, although nasals were merged in terms of tongue posture, the degrees of nasalization of the preceding vowel were contrastive, suggesting that the merging process may be incomplete.

Quantal biomechanical effects in speech postures of the lips.

The unique biomechanical and functional constraints on human speech make it a promising area for research investigating modular control of movement. The present article illustrates how a modular control approach to speech can provide insights relevant to understanding both motor control and observed variation across languages. We specifically explore the robust typological finding that languages produce different degrees of labial constriction using distinct muscle groupings and concomitantly distinct lip postures. Research has suggested that these lip postures exploit biomechanical regions of nonlinearity between neural activation and movement, also known as quantal regions, to allow movement goals to be realized despite variable activation signals. We present two sets of computer simulations showing that these labial postures can be generated under the assumption of modular control and that the corresponding modules are biomechanically robust: first to variation in the activation levels of participating muscles, and second to interference from surrounding muscles. These results provide support for the hypothesis that biomechanical robustness is an important factor in selecting the muscle groupings used for speech movements and provide insight into the neurological control of speech movements and how biomechanical and functional constraints govern the emergence of speech motor modules. We anticipate that future experimental work guided by biomechanical simulation results will provide new insights into the neural organization of speech movements.NEW & NOTEWORTHY This article provides additional evidence that speech motor control is organized in a modular fashion and that biomechanics constrain the kinds of motor modules that may emerge. It also suggests that speech can be a fruitful domain for the study of modularity and that a better understanding of speech motor modules will be useful for speech research. Finally, it suggests that biomechanical modeling can serve as a useful complement to experimental work when studying modularity.

On pharyngealized vowels in Northern Horpa: An acoustic and ultrasound study.

In the Northern Horpa (NH) language of Sichuan, vowels are divided between plain and pharyngealized sets, with the latter pronounced with auxiliary articulatory gestures involving more constriction in the vocal tract. The current study examines how the NH vocalic contrast is manifested in line with the process of pharyngealization both acoustically and articulatorily, based on freshly gathered data from two varieties of the language (i.e., Rtsangkhog and Yunasche). Along with formant analyses, ultrasound imaging was employed to capture the tongue postures and positions during vowel production. The results show that in contrast with plain vowels, pharyngealized vowels generally feature lower F2 values and higher F1 and F3 values. Mixed results for F2 and F3 suggest that the quality contrasts are vowel-dependent. Ultrasound images, on the other hand, reveal that the vocalic distinction is affected by different types of tongue movements, including retraction, backing, and double bunching, depending on the inherent tongue positions for each vowel. The two NH varieties investigated are found to display differential formant changes and different types of tongue displacements. The formant profiles along with ultrasound images support the view that the production of the NH phonologically marked vowels is characteristic of pharyngealization.

Sibilant Fricative Merging in Taiwan Mandarin: An Investigation of Tongue Postures using Ultrasound Imaging.

In Taiwan Mandarin, retroflex [ʂ] is allegedly merging with dental [s], reducing the traditional three-way contrast between sibilant fricatives (i.e., dental [s]-retroflex [ʂ]-alveopalatal [ɕ]) to a two-way contrast. Most of the literature on the observed merging focuses on the acoustic properties and perceptual identification of the sibilants, whereas much less attention has been drawn to the articulatory evidence accounting for the aforementioned sibilant merging. The current study employed ultrasound imaging techniques to uncover the tongue postures for the three sibilant fricatives [s, ʂ, ɕ] in Taiwan Mandarin occurring before vowels [a], [ɨ], and [o]. Results revealed varying classes of the [s-ʂ] merger: complete merging (overlap), no merging (non-overlap), and context-dependent merging (context-dependent overlap, which only occurred before [a]). The observed [s-ʂ] merger was also confirmed by the perceptual identification by trained phoneticians. Center of gravity (CoG), a reliable spectral moment of identifying different sibilant fricatives, was also measured to reflect the articulatory-acoustic correspondence. Results showed that the [s-ʂ] merger varies across speakers and may also be conditioned by vowel contexts and that articulatory mergers may not be entirely reflected in CoG values, suggesting that auxiliary articulatory gestures may be employed to maintain the acoustic contrast.

Ethyl Acetate Extract of Scindapsus cf. hederaceus Exerts the Inhibitory Bioactivity on Human Non-Small Cell Lung Cancer Cells through Modulating ER Stress.

Unfolded protein response (UPR) is a cytoprotective mechanism that alleviates the protein-folding burden in eukaryotic organisms. Moderate activation of UPR is required for maintaining endoplasmic reticulum (ER) homeostasis and profoundly contributes to tumorigenesis. Defects in UPR signaling are implicated in the attenuation of various malignant phenotypes including cell proliferation, migration, and invasion, as well as angiogenesis. This suggests UPR as a promising target in cancer therapy. The pharmacological effects of the plant Scindapsus cf. hederaceus on human cancer cell lines is not understood. In this study, we identified an ethyl acetate extract from Scindapsus cf. hederaceus (SH-EAE), which markedly altered the protein expression of UPR-related genes in human non-small cell lung cancer (NSCLC) cells. Treatment with the SH-EAE led to the dose-dependent suppression of colony forming ability of both H1299 and H460 cells, but not markedly in normal bronchial epithelial BEAS-2B cells. SH-EAE treatment also attenuated the migration and invasion ability of H1299 and H460 cells. Moreover, SH-EAE strikingly suppressed the protein expression of two ER stress sensors, including inositol requiring enzyme-1α (IRE-1α) and protein kinase R-like ER kinase (PERK), and antagonized the induction of C/EBP homologous protein (CHOP) expression by thapsigargin, an ER stress inducer. SH-EAE induced the formation of massive vacuoles which are probably derived from ER. Importantly, SH-EAE impaired the formation of intersegmental vessels (ISV) in zebrafish larvae, an index of angiogenesis, but had no apparent effect on the rate of larval development. Together, our findings demonstrate, for the first time, that the ability of SH-EAE specifically targets the two sensors of UPR, with significant anti-proliferation and anti-migration activities as a crude extract in human NSCLC cells. Our finding also indicates potential applications of SH-EAE in preventing UPR activation in response to Tg-induced ER stress. We suggest that SH-EAE attenuates UPR adaptive pathways for rendering the NSCLC cells intolerant to ER stress.

Pitch planning in English and Taiwanese Mandarin: evidence from startle-elicited responses.

Startling auditory stimulus (SAS) can trigger rapid release of pre-planned movement sequences and can effect a physiological perturbation of pitch level. An SAS-based paradigm was used to investigate planning of pitch profiles in English and Taiwanese Mandarin. Results show that startle-elicited pitch level is elevated, whereas pitch contours are preserved. These results support the view that pitch contours are pre-specified in speech plans, while absolute pitch level is not.

Speech function of the oropharyngeal isthmus: A modeling study.

A finite element method (FEM) based numerical model of upper airway structures (jaw, tongue, maxilla, soft palate) was implemented to observe interactions between the soft palate and tongue, and in particular to distinguish the contributions of individual muscles in producing speech-relevant constrictions of the oropharyngeal isthmus (OPI), or "uvular" region of the oral tract. Simulations revealed a sphincter-like general operation for the OPI, particularly with regard to the function of the palatoglossus muscle. Further, as has been observed with the lips, the OPI can be controlled by multiple distinct muscular mechanisms, each reliably producing a different sized opening and robust to activation noise, suggestive of a modular view of speech motor control. As off-midline structures of the OPI are difficult to observe during speech production, biomechanical simulation offers a promising approach to studying these structures.