Perception of Children's Productions of /l/: Acoustic Correlates and Effects of Listener Experience.

INTRODUCTION: The aim of the current study was to examine the effect of listeners' experience with child speech and phonetic training on perceptual judgment of children's word-initial /l/ productions. The acoustic correlates of acceptable and misarticulated productions of /l/ and their relation to listeners' experience with child speech were explored. METHODS: Three listener groups listened to children's word-initial /l/ productions embedded in monosyllabic words and judged the "/l/-likeness" of the productions using a Visual Analog Scale (VAS). Three listener groups included (a) speech-language pathologists with at least 10 years of experience (SLP group), (b) graduate students in speech-language pathology (GS group), and (c) naïve listeners with no clinical phonetics experience (NL group). Acoustic correlates (both static and dynamic measures) of listeners' perception of /l/ sounds were also investigated. RESULTS: While mean VAS ratings did not differ significantly by listener group, the SLP group used a wider range of the VAS than the GS and NL groups. Correlational analysis between the static measure (F2-F1 values) and mean listener ratings showed that listeners tend to perceive sounds with the highest F2-F1 values more as /j/ than /l/, while those with the lowest F2-F1 value were perceived more as /w/ than /l/, especially for sounds that are in between phonemic categories. Listener ratings were not highly correlated with dynamic measures. CONCLUSION: These results suggest that experienced listeners use the VAS more continuously than less experienced listeners to indicate perception of subphonemic features of children's productions of /l/, and that their ratings correlate with acoustic measures. Furthermore, listeners with experience with child speech and phonetic training are more sensitive to subphonemic features of children's productions of /l/, especially for misarticulated productions. This supports the clinical use of VAS for perceptual judgments of children's /l/ productions.

SLPI in periodontal Ligament is not sleepy during biophysical force-induced tooth movement.

AIM: We aimed to identify a key molecule that maintains periodontal tissue homeostasis during biophysical force-induced tooth movement (BTM) by orchestrating alveolar bone (AB) remodelling. MATERIALS AND METHODS: Differential display-PCR was performed to identify key molecules for BTM in rats. To investigate the localization and expression of the identified molecules, immunofluorescence, real-time RT-PCR and Western blotting were performed in rats and human periodontal ligament (PDL) cells. Functional test and micro-CT analysis were performed to examine the in vivo effects of the identified molecules on BTM. RESULTS: Secretory leucocyte peptidase inhibitor (SLPI) in the PDL was revealed as a key molecule for BTM-induced AB remodelling. SLPI was enhanced in the PDL under both compression and tension, and downregulated by an adenyl cyclases inhibitor. SLPI induced osteoblastogenic genes including runt-related transcription factor 2 (Runx2) and synergistically augmented tension-induced Runx2 expression. SLPI augmented mineralization in PDL cells. SLPI induced osteoclastogenic genes including receptor activator of nuclear factor kappa-Β ligand (RANKL) and synergistically augmented the compression-induced RANKL and macrophage colony-stimulating factor (MCSF) expression. Finally, the in vivo SLPI application into the AB significantly augmented BTM. CONCLUSIONS: SLPI or its inhibitors might serve as a biological target molecule for therapeutic interventions to modulate BTM.

Acoustic Characteristics of Rhotic Vowel Productions of Young Children.

AIMS: This study examined the acoustic characteristics of perceptually acceptable rhotic vowels produced by young children with and without speech sound disorders (SSDs). Productions were analyzed in relation to the overall rhotic proficiency level of each child, as determined by rhotic vowel and consonant accuracy. The effect of the surrounding phonetic contexts on acoustic realization of rhotic vowels was also examined. METHODS: Participants included 18 children aged 2-6 years with and without SSD, grouped by overall rhotic sound proficiency (high rhotic proficiency: ≥70% correct rhotic consonants and vowels; intermediate rhotic proficiency: ≤30% correct rhotic consonants, but ≥70% correct rhotic vowels; low rhotic proficiency: ≤30% correct rhotic consonants and vowels). Target sounds included stressed and unstressed rhotic monophthongs ([ɝ] and [ɚ], respectively) and 4 rhotic diphthongs that differ by pre-rhotic vowel type (/ɪ͡ɚ/, /ɛ͡ɚ/, /ɔ͡ɚ/, /ɑ͡ɚ/). F3 and F3-F2 measures were compared across groups and contexts. RESULTS: No significant differences in F3 and F3-F2 by rhotic sound proficiency group were found in rhotic vowels produced by children with above 70% rhotic vowel accuracy, regardless of their proficiency with rhotic consonants. Acoustic patterns differed by phonetic contexts, but the effect varied by rhotic sound proficiency group. CONCLUSION: Results showed that once children learn to produce rhotic vowels, they show a comparable degree of rhoticity as those produced by children with high rhotic vowel and consonant accuracy. Results also suggest that rhotic sounds develop earlier in certain phonetic contexts than in others (e.g., [ɝ] before [ɚ]; /ɪ͡ɚ/ and /ɑ͡ɚ/ before /ɔ͡ɚ/).

Vowel acoustic characteristics of Southern American English variation in Louisiana.

This study examined acoustic characteristics of vowels produced by speakers from Louisiana, one of the states in the Southern English dialect region. First, how Louisiana vowels differ from or are similar to the reported patterns of Southern dialect were examined. Then, within-dialect differences across regions in Louisiana were examined. Thirty-four female adult monolingual speakers of American English from Louisiana, ranging in age from 18 to 23, produced English monosyllabic words containing 11 vowels /i, ɪ, e, ɛ, æ, ʌ, u, ʊ, o, ɔ, ɑ/. The first two formant frequencies at the midpoint of the vowel nucleus, direction, and amount of formant changes across three different time points (20, 50, and 80%), and vowel duration were compared to previously reported data on Southern vowels. Overall, Louisiana vowels showed patterns consistent with previously reported characteristics of Southern vowels that reflect ongoing changes in the Southern dialect (no evidence of acoustic reversal of tense-lax pairs, more specifically no peripheralization of front vowels). Some dialect-specific patterns were also observed (a relatively lesser degree of formant changes and slightly shorter vowel duration). These patterns were consistent across different regions within Louisiana.

Neuroprotective and Anti-Inflammatory Effects of Low-Moderate Dose Ionizing Radiation in Models of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia. The neuropathological features of AD include amyloid-ß (Aß) deposition and hyperphosphorylated tau accumulation. Although several clinical trials have been conducted to identify a cure for AD, no effective drug or treatment has been identified thus far. Recently, the potential use of non-pharmacological interventions to prevent or treat AD has gained attention. Low-dose ionizing radiation (LDIR) is a non-pharmacological intervention which is currently being evaluated in clinical trials for AD patients. However, the mechanisms underlying the therapeutic effects of LDIR therapy have not yet been established. In this study, we examined the effect of LDIR on Aß accumulation and Aß-mediated pathology. To investigate the short-term effects of low-moderate dose ionizing radiation (LMDIR), a total of 9 Gy (1.8 Gy per fraction for five times) were radiated to 4-month-old 5XFAD mice, an Aß-overexpressing transgenic mouse model of AD, and then sacrificed at 4 days after last exposure to LMDIR. Comparing sham-exposed and LMDIR-exposed 5XFAD mice indicated that short-term exposure to LMDIR did not affect Aß accumulation in the brain, but significantly ameliorated synaptic degeneration, neuronal loss, and neuroinflammation in the hippocampal formation and cerebral cortex. In addition, a direct neuroprotective effect was confirmed in SH-SY5Y neuronal cells treated with Aß1-42 (2 µM) after single irradiation (1 Gy). In BV-2 microglial cells exposed to Aß and/or LMDIR, LMDIR therapy significantly inhibited the production of pro-inflammatory molecules and activation of the nuclear factor-kappa B (NF-κB) pathway. These results indicate that LMDIR directly ameliorated neurodegeneration and neuroinflammation in vivo and in vitro. Collectively, our findings suggest that the therapeutic benefits of LMDIR in AD may be mediated by its neuroprotective and anti-inflammatory effects.

Low-Dose Ionizing Radiation Modulates Microglia Phenotypes in the Models of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia. AD involves major pathologies such as amyloid-ß (Aß) plaques and neurofibrillary tangles in the brain. During the progression of AD, microglia can be polarized from anti-inflammatory M2 to pro-inflammatory M1 phenotype. The activation of triggering receptor expressed on myeloid cells 2 (TREM2) may result in microglia phenotype switching from M1 to M2, which finally attenuated Aß deposition and memory loss in AD. Low-dose ionizing radiation (LDIR) is known to ameliorate Aß pathology and cognitive deficits in AD; however, the therapeutic mechanisms of LDIR against AD-related pathology have been little studied. First, we reconfirm that LDIR (two Gy per fraction for five times)-treated six-month 5XFAD mice exhibited (1) the reduction of Aß deposition, as reflected by thioflavins S staining, and (2) the improvement of cognitive deficits, as revealed by Morris water maze test, compared to sham-exposed 5XFAD mice. To elucidate the mechanisms of LDIR-induced inhibition of Aß accumulation and memory loss in AD, we examined whether LDIR regulates the microglial phenotype through the examination of levels of M1 and M2 cytokines in 5XFAD mice. In addition, we investigated the direct effects of LDIR on lipopolysaccharide (LPS)-induced production and secretion of M1/M2 cytokines in the BV-2 microglial cells. In the LPS- and LDIR-treated BV-2 cells, the M2 phenotypic marker CD206 was significantly increased, compared with LPS- and sham-treated BV-2 cells. Finally, the effect of LDIR on M2 polarization was confirmed by detection of increased expression of TREM2 in LPS-induced BV2 cells. These results suggest that LDIR directly induced phenotype switching from M1 to M2 in the brain with AD. Taken together, our results indicated that LDIR modulates LPS- and Aß-induced neuroinflammation by promoting M2 polarization via TREM2 expression, and has beneficial effects in the AD-related pathology such as Aß deposition and memory loss.

Effect of Aging on Taurine Transporter (TauT) Expression in the Mouse Brain Cortex.

Taurine content in an older brain is decreased compared to a younger brain and is associated with cognitive deficits. It is not yet known whether the decrease in taurine content is associated with decreased expression of taurine inflow mediating transporters during the aging process. In this study, we investigated whether aging affects taurine transporter and glycine transporter 1 expression in the brain cortex of the mouse. Taurine and glycine transporter expression was compared in the brain cortex of C57BL/6 mice at different ages (2, 12, and 24 months) and to age-matched NLRP3 inflammasome knockout mice. In wild type mice, taurine transporter (TauT) expression in the brain cortex of 12- or 24-month-old mice did not significantly differ from TauT expression in 2-month-old mice. Moreover, TauT expression in the brain cortex of 12- or 24-month-old mice did not significantly differ from age-matched NLRP3 KO mice. This result indirectly suggests that TauT expression may be not affected by aging or age-induced inflammation. In addition, glycine transporter expression was similar to the TauT expression pattern. In conclusion, aging and age-related inflammation might not significantly affect taurine and glycine transporter expression in aged mice. Thus, the decrease of taurine content in an older brain, which is associated with cognitive deficits, may not be significantly related to altered taurine and glycine transporter expression.

Pharmacological Stimulation of Nurr1 Promotes Cell Cycle Progression in Adult Hippocampal Neural Stem Cells.

Nuclear receptor related-1 (Nurr1) protein performs a crucial role in hippocampal neural stem cell (hNSC) development as well as cognitive functions. We previously demonstrated that the pharmacological stimulation of Nurr1 by amodiaquine (AQ) promotes spatial memory by enhancing adult hippocampal neurogenesis. However, the role of Nurr1 in the cell cycle regulation of the adult hippocampus has not been investigated. This study aimed to examine changes in the cell cycle-related molecules involved in adult hippocampal neurogenesis induced by Nurr1 pharmacological stimulation. Fluorescence-activated cell sorting (FACS) analysis showed that AQ improved the progression of cell cycle from G0/G1 to S phase in a dose-dependent manner, and MEK1 or PI3K inhibitors attenuated this progression. In addition, AQ treatment increased the expression of cell proliferation markers MCM5 and PCNA, and transcription factor E2F1. Furthermore, pharmacological stimulation of Nurr1 by AQ increased the expression levels of positive cell cycle regulators such as cyclin A and cyclin-dependent kinases (CDK) 2. In contrast, levels of CDK inhibitors p27KIP1 and p57KIP2 were reduced upon treatment with AQ. Similar to the in vitro results, RT-qPCR analysis of AQ-administered mice brains revealed an increase in the levels of markers of cell cycle progression, PCNA, MCM5, and Cdc25a. Finally, AQ administration resulted in decreased p27KIP1 and increased CDK2 levels in the dentate gyrus of the mouse hippocampus, as quantified immunohistochemically. Our results demonstrate that the pharmacological stimulation of Nurr1 in adult hNSCs by AQ promotes the cell cycle by modulating cell cycle-related molecules.

Ghrelin protects adult rat hippocampal neural stem cells from excessive autophagy during oxygen-glucose deprivation.

Ghrelin functions as a neuroprotective agent and saves neurons from various insults include ischemic injury. However, it remains to be elucidated whether ghrelin protects neuronal cells against ischemic injury-induced excessive autophagy. Autophagy is required for the maintenance of neural stem cell homeostasis. However, regarding autophagic cell death, it is commonly assumed that excessive autophagy leads to self-elimination of mammalian cells. The purpose of this study was to investigate the potential neuroprotection effects of ghrelin from excessive autophagy in adult rat hippocampal neural stem cells (NSCs). Oxygen-Glucose Deprivation (OGD) strongly induces autophagy in adult rat hippocampal NSCs. Ghrelin treatment inhibited OGD-induced cell death of adult rat hippocampal NSCs assessed by cell-counting-kit-8 assay. Ghrelin also suppressed OGD-induced excessive autophagy activity. The protective effect of ghrelin was accompanied by an increased expression levels of Bcl-2, p-62 and decreased expression level of LC3-II, Beclin-1 by Western blot. Furthermore, ghrelin reduced autophagosome formation and number of GFP-LC3 transfected puncta. In conclusion, our data suggest that ghrelin protects adult rat hippocampal NSCs from excessive autophagy in experimental stroke (oxygen-glucose deprivation) model. Regulating autophagic activity may be a potential optimizing target for promoting adult rat hippocampal NSCs based therapy for stroke.

Digital panoramic radiographs are useful for diagnosis of osteoporosis in Korean postmenopausal women.

OBJECTIVE: The purpose of this study was to determine whether digital panoramic radiographs could be used for the diagnosis of osteoporosis through evaluation of the radiographs based on the correlation with bone mineral density (BMD). METHODS: One hundred and ninety-four post-menopausal women were selected from participants who had participated in the Dong-gu study. Panoramic radiographic indices measured are mental index (MI), mandibular cortical index (MCI) and simple visual estimation (SVE). BMD at the lumbar spine and proximal femur was measured by dual-energy X-ray absorptiometry (DXA). The Pearson's correlation test was performed to analyse the correlation between MI and age and BMD at the lumbar spine, femoral neck and total hip. Multiple linear regression analysis was performed to analyse the association of MI, MCI and SVE with BMD after adjusting for age, height and weight. To determine the optimal cut-off point of MI for the diagnosis of osteoporosis, the receiver operating characteristic analysis was performed. RESULTS: The MI was positively correlated with BMDs: lumbar spine: r = 0.36, femoral neck: r = 0.59 and total hip: r = 0.58 (p < 0.001). As age increased, MI decreased (r = -0.46). BMD at the lumbar spine and total hip were significantly lower in participants with reduction of mandibular width, thinning and resorption of mandibular cortex by the MI, SVE and MCI, respectively. The optimal cut-off value of MI for the diagnosis of spinal osteoporosis was 2.22 mm. CONCLUSION: Thickness and morphological changes of mandibular inferior cortical bone are associated with BMD, independent of age, height and weight. These results suggest that MI, MCI and SVE may be useful indices for the diagnosis of osteoporosis in a Korean population.

Periodontal disease associated with blood glucose levels in urban Koreans aged 50 years and older: the Dong-gu study.

OBJECTIVE: To investigate the association of periodontal disease and the number of teeth present with the risk of prediabetes and diabetes as well as with blood glucose and HbA1c levels in adult Koreans. BACKGROUND: The relationship between periodontal disease and diabetes has not been fully elucidated. MATERIALS AND METHODS: Cross-sectional data from 5535 participants aged ≥50 years were obtained from 2008 to 2010. Periodontal status was measured as pocket depth (PD), clinical attachment loss (CAL) and bleeding on probing (BOP) recorded. The percentage of sites with a PD ≥4 mm, CAL ≥4 mm (CAL4) and BOP (BOP%) were recorded. Participants were divided into three groups according to PD4, CAL4 and BOP% measurements. Number of teeth present was divided into four groups. Participants were classified as normoglycaemic, prediabetic or diabetic based on HbA1c and fasting glucose levels. RESULTS: After full adjustment, the highest tertile of CAL4 (OR: 1.47, 95% CI: 1.18-2.02, p < 0.001), PD4 (OR: 1.58, 95% CI: 1.26-1.97, p < 0.001) and BOP% (OR: 1.37, 95% CI: 1.07-1.75, p = 0.012) had significantly increased odds of diabetes. The number of teeth present was inversely related to diabetes (p < 0.001) and prediabetes (p = 0.032) risk. Periodontal disease severity was positively associated with HbA1c and glucose levels. The number of teeth present was positively associated with HbA1c, but not glucose, levels. CONCLUSION: Periodontal disease and the number of teeth present are associated with an increased risk of diabetes and increased blood glucose and HbA1c levels in Koreans aged ≥50 years.

Relationship between periodontal disease and subclinical atherosclerosis: the Dong-gu study.

AIM: We assessed the association of periodontal disease and number of missing teeth with subclinical atherosclerosis in an adult Korean population. MATERIALS AND METHODS: Cross-sectional data from 5404 individuals aged ≥50 years were obtained from the 2008-2010 Dong-gu study. Periodontal examinations were conducted to determine the number of missing teeth, pocket depth (PD), clinical attachment loss (CAL), and bleeding on probing (BOP). The percentages of sites with PD ≥ 4 mm (PD 4%), CAL ≥ 4 mm (CAL 4%), and BOP (BOP%) were recorded for each participant. B-mode ultrasound was performed to determine common carotid artery intima-media thickness (CCA IMT) and the presence of carotid plaques. Multivariate linear regression models were used to assess the associations between periodontal parameters and CCA IMT and carotid plaque. RESULTS: Number of missing teeth was associated with increased CCA IMT, and BOP% was associated with increased CCA IMT in females only. This association was robust in never smokers. CONCLUSIONS: The number of missing teeth was associated with CCA IMT, and BOP% was associated with CCA IMT in females only. These associations were robust in never smokers. Our results suggest that tooth loss due to oral disease may play a role in subclinical carotid atherosclerosis.

The association between periodontal disease, tooth loss and bone mineral density in a Korean population.

OBJECTIVE: We aimed to evaluate whether clinical attachment loss (CAL), a measure of the severity of periodontal disease or number of teeth present is associated with bone mineral density (BMD). METHODS: The study population consisted of 5383 people aged 50 years and older who participated in the Dong-gu Study. BMD at the lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. Oral examination included assessments of the number of teeth present and CAL. Number of teeth present was categorized into three equal categories. CAL values were divided into tertiles in terms of the percentage of sites with CAL ≥4 mm. Analysis of covariance was used to compare the adjusted means of BMD according to the tooth number and the tertiles of CAL. RESULTS: There was a significant association between the number of teeth present and BMD in men. Compared with men with 22 or more teeth, men with 10 and less teeth had lower BMD. CAL was significantly associated with lower BMD at the lumbar spine in women. CONCLUSION: Our data indicate that tooth loss and CAL were associated with low BMD. However, the magnitude of these associations was relatively small and the clinical significance was unclear.

Transcription-based and acoustic analyses of rhotic vowels produced by children with and without speech sound disorders: further analyses from the Memphis Vowel Project.

The acquisition of rhotic monophthongs (/ɝ/ and /ɚ/) and diphthongs (/ɪ͡ɚ, ɛ͡ɚ, ɔ͡ɚ and ɑ͡ɚ/) was examined in 3- and 4-year-old children with and without speech sound disorders (SSDs), using both transcription-based and acoustic analyses. African-American (AA) and European-American (EA) participants (n = 40) with and without SSD were selected from archival data collected as part of the Memphis Vowel Project. Dialect variation influenced rhotic vowels differently for EA and AA children, thus their data were reported separately. Transcription-based analyses showed wide variation in the accuracy of different rhotic vowels. The most frequent error pattern for children with SSD was Derhoticization to a Back Rounded Vowel (e.g. /ɝ/ → [ʊ]; /ɪ͡ɚ/ → [ɪ͡о]). Rhotic diphthong reduction errors were less frequent; however, Coalesence (/ɑ͡ɚ/ → [ɔ]) was often observed for /ɑ͡ɚ/. F2, F3 and F3-F2 spectral movement patterns revealed differences between productions transcribed as correct and incorrect.

Nitric oxide-induced apoptosis of human dental pulp cells is mediated by the mitochondria-dependent pathway.

Nitric oxide (NO) is recognized as a mediator and regulator of inflammatory responses. NO is produced by nitric oxide synthase (NOS), and NOS is abundantly expressed in the human dental pulp cells (HDPCs). NO produced by NOS can be cytotoxic at higher concentrations to HDPCs. However, the mechanism by which this cytotoxic pathway is activated in cells exposed to NO is not known. The purpose of this study was to elucidate the NO-induced cytotoxic mechanism in HDPCs. Sodium nitroprusside (SNP), a NO donor, reduced the viability of HDPCs in a dose- and time-dependent manner. We investigated the in vitro effects of nitric oxide on apoptosis of cultured HDPCs. Cells showed typical apoptotic morphology after exposure to SNP. Besides, the number of Annexin V positive cells was increased among the SNP-treated HDPCs. SNP enhanced the production of reactive oxygen species (ROS), and N-acetylcysteine (NAC) ameliorated the decrement of cell viability induced by SNP. However, a soluble guanylate cyclase inhibitor (ODQ) did not inhibited the decrement of cell viability induced by SNP. SNP increased cytochrome c release from the mitochondria to the cytosol and the ratio of Bax/Bcl-2 expression levels. Moreover, SNP-treated HDPCs elevated activities of caspase-3 and caspase-9. While pretreatment with inhibitors of caspase (z-VAD-fmk, z-DEVD-fmk) reversed the NO-induced apoptosis of HDPCs. From these results, it can be suggested that NO induces apoptosis of HDPCs through the mitochondria-dependent pathway mediated by ROS and Bcl-2 family, but not by the cyclic GMP pathway.

Genistein alleviates pulmonary fibrosis by inactivating lung fibroblasts.

Pulmonary fibrosis is a serious lung disease that occurs predominantly in men. Genistein is an important natural soybeanderived phytoestrogen that affects various biological functions, such as cell migration and fibrosis. However, the antifibrotic effects of genistein on pulmonary fibrosis are largely unknown. The antifibrotic effects of genistein were evaluated using in vitro and in vivo models of lung fibrosis. Proteomic data were analyzed using nano-LC-ESI-MS/MS. Genistein significantly reduced transforming growth factor (TGF)-ß1-induced expression of collagen type I and α-smooth muscle actin (SMA) in MRC-5 cells and primary fibroblasts from patients with idiopathic pulmonary fibrosis (IPF). Genistein also reduced TGF-ß1-induced expression of p-Smad2/3 and p-p38 MAPK in fibroblast models. Comprehensive protein analysis confirmed that genistein exerted an anti-fibrotic effect by regulating various molecular mechanisms, such as unfolded protein response, epithelial mesenchymal transition (EMT), mammalian target of rapamycin complex 1 (mTORC1) signaling, cell death, and several metabolic pathways. Genistein was also found to decrease hydroxyproline levels in the lungs of BLM-treated mice. Genistein exerted an anti-fibrotic effect by preventing fibroblast activation, suggesting that genistein could be developed as a pharmacological agent for the prevention and treatment of pulmonary fibrosis. [BMB Reports 2024; 57(3): 143-148].

Therapeutic Potential of Traditional Oriental Medicines in Targeting Tau Pathology: Insights from Cell-free and Cell-based Screening.

BACKGROUND: Traditional Oriental Medicines (TOMs) formulated using a variety of medicinal plants have a low risk of side effects. In previous studies, five TOMs, namely Dangguijakyaksan, Hwanglyeonhaedoktang, Ukgansan, Palmijihwanghwan, and Jowiseungchungtang have been commonly used to treat patients with Alzheimer's disease. However, only a few studies have investigated the effects of these five TOMs on tau pathology. OBJECTIVE: This study aimed to examine the effect of five TOMs on various tau pathologies, including post-translational modifications, aggregation and deposition, tau-induced neurotoxicity, and tau-induced neuroinflammation. METHODS: Immunocytochemistry was used to investigate the hyperphosphorylation of tau induced by okadaic acid. In addition, the thioflavin T assay was used to assess the effects of the TOMs on the inhibition of tau K18 aggregation and the dissociation of tau K18 aggregates. Moreover, a water-soluble tetrazolium-1 assay and a quantitative reverse transcription polymerase chain reaction were used to evaluate the effects of the TOMs on tau-induced neurotoxicity and inflammatory cytokines in HT22 and BV2 cells, respectively. RESULTS: The five TOMs investigated in this study significantly reduced okadaic acid-induced tau hyperphosphorylation. Hwanglyeonhaedoktang inhibited the aggregation of tau and promoted the dissociation of tau aggregates. Dangguijakyaksan and Hwanglyeonhaedoktang attenuated tau-induced neurotoxicity in HT22 cells. In addition, Dangguijakyaksan, Hwanglyeonhaedoktang, Ukgansan, and Palmijihwanghwan reduced tauinduced pro-inflammatory cytokine levels in BV2 cells. CONCLUSION: Our results suggest that five TOMs are potential therapeutic candidates for tau pathology. In particular, Hwanglyeonhaedoktang showed the greatest efficacy among the five TOMs in cell-free and cell-based screening approaches. These findings suggest that Hwanglyeonhaedoktang is suitable for treating AD patients with tau pathology.

Taurine chloramine modulates the expression of adipokines through inhibition of the STAT-3 signaling pathway in differentiated human adipocytes.

To examine the possible role of taurine chloramine (TauCl) in modulating the expression of adipokines in adipose tissue associated with obesity, we evaluated the effect of TauCl in human differentiated adipocytes in response to IL-1ß. To study the physiological effects of TauCl on adipokine expression, differentiated adipocytes were treated with IL-1ß in the presence or absence of TauCl at concentrations ranging from 200 to 600 µM for 7 days. Cell culture supernatants and total RNA were analyzed by ELISA and real-time PCR, respectively, to determine protein and mRNA levels of adipokines, including adiponectin, leptin, IL-6, and IL-8. Levels of proteins involved in relevant signaling pathways were investigated by western blotting. Stimulation with IL-1ß significantly decreased levels of adiponectin and leptin in adipocytes, but increased levels of IL-6 and IL-8 in a dose-dependent manner. Treatment with TauCl significantly reversed the modulation of adipokine expression by inhibiting STAT-3 signaling in IL-1ß-stimulated adipocytes, independent of MAPK signaling. TauCl treatment more significantly modulated the expression of adipokines in adipocytes stimulated with IL-1ß than that of non-stimulated adipocytes, suggesting that TauCl plays a significant role in modulating the expression of adipokines under inflammatory conditions. In conclusion, TauCl and other taurine derivatives that inhibit the STAT-3 signaling pathway can modulate expression of adipokines and thus may be useful as therapeutic agents for obesity-related diseases.

Ghrelin directly stimulates adult hippocampal neurogenesis: implications for learning and memory.

Adult hippocampal neurogenesis is important in mediating hippocampal-dependent learning and memory. Exogenous ghrelin is known to stimulate progenitor cell proliferation in the dentate gyrus of adult hippocampus. The aim of this study was to investigate the role of endogenous ghrelin in regulating the in vivo proliferation and differentiation of the newly generating cells in the adult hippocampus using ghrelin knockout (GKO) mice. Targeted deletion of ghrelin gene resulted in reduced numbers of progenitor cells in the subgranular zone (SGZ) of the hippocampus, while ghrelin treatment restored progenitor cell numbers to those of wild-type controls. We also found that not only the number of bromodeoxyuridine (BrdU)-positive cells but also the fraction of immature neurons and newly generated neurons were decreased in the GKO mice, which were increased by ghrelin replacement. Additionally, in the GKO mice, we observed impairment of memory performance in Y-maze task and novel object recognition test. However, these functional deficiencies were attenuated by ghrelin administration. These results suggest that ghrelin directly induces proliferation and differentiation of adult neural progenitor cells in the SGZ. Our data suggest ghrelin may be a plausible therapeutic potential to enhance learning and memory processes.

Effect of Speaker Age on Listener Perceptions of Word-Final /l/.

PURPOSE: This study investigated an effect of speaker age on listeners' perception of word-final /l/ produced by child and adult speakers of Southern White Vernacular English, a dialect that shows higher rates of word-final /l/ vocalization than other dialects of English. METHOD: Stimuli included children and adults' word-final /l/ embedded in monosyllabic words in two vowel contexts (/i, ɪ/ and /ɔ, ɑ/). A total of 25 monolingual adult listeners listened to each word and were asked to judge the /l/-likeness using a visual analog scale. Average listener ratings and three acoustic measures (F2 transition rate [F2 TR] and F2-F1 [Hz] values at 20% and 80% time points along the vowel-/l/ duration) were analyzed. RESULTS: Adult productions were rated more as correct /l/ than those of children in both vowel contexts, despite the similarity in their F2 TR and F2-F1 values at the 80% time point. Correlation between the acoustic measures and the average listener ratings were weak for all three measures for adults' productions. For children's productions, while the correlation with F2 TR values were weak, moderate significant correlations were found for F2-F1 values at the 20% and 80% time points. In terms of vowel context, word-final /l/ in the high front vowel context was rated more as /l/ than those in low back vowel context. CONCLUSIONS: Findings suggest that listeners are more likely to accept word-final /l/ as being correct when produced by adult speakers, regardless of their acoustic characteristics, but more likely to perceive an error when produced by a child and attend more to acoustic information for their perceptual judgment. This highlights the importance of considering children's dialectal background when judging word-final /l/, which is more likely to be vocalized in certain dialects and certain vowel contexts, and thus can be misjudged without such consideration.