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.

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].

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.

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.

Acoustic and Articulatory Characteristics of English Semivowels /ɹ, l, w/ Produced by Adult Second-Language Speakers.

PURPOSE: This study presents the results of acoustic and kinematic analyses of word-initial semivowels (/ɹ, l, w/) produced by second-language (L2) speakers of English whose native language is Korean. In addition, the relationship of acoustic and kinematic measures to the ratings of foreign accent was examined by correlation analyses. METHOD: Eleven L2 speakers and 10 native speakers (first language [L1]) of English read The Caterpillar passage. Acoustic and kinematic data were simultaneously recorded using an electromagnetic articulography system. In addition to speaking rate, two acoustic measures (ratio of third-formant [F3] frequency to second-formant [F2] frequency and duration of steady states of F2) and two kinematic measures (lip aperture and duration of lingual maximum hold) were obtained from individual target sounds. To examine the degree of contrast among the three sounds, acoustic and kinematic Euclidean distances were computed on the F2-F3 and x-y planes, respectively. RESULTS: Compared with L1 speakers, L2 speakers exhibited a significantly slower speaking rate. For the three semivowels, L2 speakers showed a reduced F3/F2 ratio during constriction, increased lip aperture, and reduced acoustic Euclidean distances among semivowels. Additionally, perceptual ratings of foreign accent were significantly correlated with three measures: duration of steady F2, acoustic Euclidean distance, and kinematic Euclidean distance. CONCLUSIONS: The findings provide acoustic and kinematic evidence for challenges that L2 speakers experience in the production of English semivowels, especially /ɹ/ and /w/. The robust and consistent finding of reduced contrasts among semivowels and their correlations with perceptual accent ratings suggests using sound contrasts as a potentially effective approach to accent modification paradigms.

Acoustic Characteristics of Pre- and Post-vocalic /l/: Patterns from One Southern White Vernacular English.

This study examined acoustic characteristics of the phoneme /l/ produced by young female and male adult speakers of Southern White Vernacular English (SWVE) from Louisiana. F1, F2, and F2-F1 values extracted at the /l/ midpoint were analyzed by word position (pre- vs. post-vocalic) and vowel contexts (/i, ɪ/ vs. /ɔ, a/). Descriptive analysis showed that SWVE /l/ exhibited characteristics of the dark /l/ variant. The formant patterns of /l/, however, differed significantly by word position and vowel context, with pre-vocalic /l/ showing significantly higher F2-F1 values than post-vocalic /l/, and /l/ in the high front vowel context showing significantly higher F2-F1 values than those in the low back vowel context. Individual variation in the effects of word position and vowel contexts on /l/ pattern was also observed. Overall, the findings of the current study showed a gradient nature of SWVE /l/ variants whose F2-F1 patterns generally fell into the range of the dark /l/ variant, while varying by word position and vowel context.

Optimal concentration of mesenchymal stem cells for fracture healing in a rat model with long bone fracture.

BACKGROUND: There is still no consensus on which concentration of mesenchymal stem cells (MSCs) to use for promoting fracture healing in a rat model of long bone fracture. AIM: To assess the optimal concentration of MSCs for promoting fracture healing in a rat model. METHODS: Wistar rats were divided into four groups according to MSC concentrations: Normal saline (C), 2.5 × 106 (L), 5.0 × 106 (M), and 10.0 × 106 (H) groups. The MSCs were injected directly into the fracture site. The rats were sacrificed at 2 and 6 wk post-fracture. New bone formation [bone volume (BV) and percentage BV (PBV)] was evaluated using micro-computed tomography (CT). Histological analysis was performed to evaluate fracture healing score. The protein expression of factors related to MSC migration [stromal cell-derived factor 1 (SDF-1), transforming growth factor-beta 1 (TGF-ß1)] and angiogenesis [vascular endothelial growth factor (VEGF)] was evaluated using western blot analysis. The expression of cytokines associated with osteogenesis [bone morphogenetic protein-2 (BMP-2), TGF-ß1 and VEGF] was evaluated using real-time polymerase chain reaction. RESULTS: Micro-CT showed that BV and PBV was significantly increased in groups M and H compared to that in group C at 6 wk post-fracture (P = 0.040, P = 0.009; P = 0.004, P = 0.001, respectively). Significantly more cartilaginous tissue and immature bone were formed in groups M and H than in group C at 2 and 6 wk post-fracture (P = 0.018, P = 0.010; P = 0.032, P = 0.050, respectively). At 2 wk post-fracture, SDF-1, TGF-ß1 and VEGF expression were significantly higher in groups M and H than in group L (P = 0.031, P = 0.014; P < 0.001, P < 0.001; P = 0.025, P < 0.001, respectively). BMP-2 and VEGF expression were significantly higher in groups M and H than in group C at 6 wk post-fracture (P = 0.037, P = 0.038; P = 0.021, P = 0.010). Compared to group L, TGF-ß1 expression was significantly higher in groups H (P = 0.016). There were no significant differences in expression levels of chemokines related to MSC migration, angiogenesis and cytokines associated with osteogenesis between M and H groups at 2 and 6 wk post-fracture. CONCLUSION: The administration of at least 5.0 × 106 MSCs was optimal to promote fracture healing in a rat model of long bone fractures.

Acoustic characteristics of Korean-English bilingual speakers' /l/ and the relationship to their foreign accent ratings.

PURPOSE: The current study examined acoustic characteristics of English /l/ produced by Korean speakers who speak English as their second language (KE). Comparisons were made to patterns of their Korean /l/ and English /l/ produced by monolingual speakers of American English (AE). Vowel context and word position effects on acoustic differences among the three /l/ sounds were examined in relation to the degree of foreign accentedness of KE speakers. METHODS: Korean and English word-initial and -final /l/ in two vowel contexts (high front vs. low back) were produced by 12 KE female adult speakers in a carrier phrase. A comparison group of 10 AE speakers produced English /l/. F1 and F2 values of each /l/ production were extracted at the /l/ midpoint and were compared to each other. Euclidean distances across the productions were also examined in relation to the degrees of foreign accentedness of KE speakers. RESULTS: KE speakers' English /l/ showed significantly lower F2-F1 values than their Korean /l/ across word position and vowel context but significantly higher F2-F1 values than AE speakers' English word-initial /l/. Euclidean distance between KE speakers' English and Korean /l/, and KE and AE speakers' English /l/ correlated significantly with KE speakers' degree of foreign accentedness across word position and vowel context. CONCLUSION: Results indicate that the influence of Korean on KE speakers' English /l/ productions varied by word position and vowel context, as well as the degree of their foreign accentedness ratings. This finding suggests the context-dependent nature of /l/ productions and highlights the need for considering a speakers' degree of foreign accent when exploring English /l/ patterns of KE speakers.

Formant Trajectory Patterns of American English /l/ Produced by Adults and Children.

Purpose Most acoustic and articulatory studies on /l/ have focused on either duration, formant frequencies, or tongue shape during the constriction interval. Only a limited set of data exists for the transition characteristics of /l/ to and from surrounding vowels. The aim of this study was to examine second formant (F2) transition characteristics of /l/ produced by young children and adults. This was to better understand articulatory behaviors in the production of /l/ and potential clinical applications of these data to typical and delayed /l/ development. Method Participants included 17 children with typically developing speech between the ages of 2 and 5 years, and 10 female adult speakers of Southern American English. Each subject produced single words containing pre- and postvocalic /l/ in two vowel contexts (/i, ɪ/ and /ɔ, ɑ/). F2 transitions, out of and into /l/ constriction intervals from the adjacent vowels, were analyzed for perceptually acceptable /l/ productions. The F2 transition extent, duration, and rate, as well as F2 loci data, were compared across age groups by vowel context for both pre- and postvocalic /l/. Results F2 transitions of adults' /l/ showed a great similarity across and within speakers. Those of young children showed greater variability, but became increasingly similar to those of adults with age. The F2 loci data seemed consistent with greater coarticulation among children than adults. This conclusion, however, must be regarded as preliminary due to the possible influence of different vocal tract size across ages and variability in the data. Conclusions The results suggest that adult patterns can serve as a reliable reference to which children's /l/ productions can be evaluated. The articulatory configurations associated with the /l/ constriction interval and the vocal tract movements into and out of that interval may provide insight into the underlying difficulties related to misarticulated /l/.

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/).

Cross-Linguistic Perceptual Categorization of the Three Corner Vowels: Effects of Listener Language and Talker Age.

The present study examined the center and size of naïve adult listeners' vowel perceptual space (VPS) in relation to listener language (LL) and talker age (TA). Adult listeners of three different first languages, American English, Greek, and Korean, categorized and rated the goodness of different vowels produced by 2-year-olds and 5-year-olds and adult speakers of those languages, and speakers of Cantonese and Japanese. The center (i.e., mean first and second formant frequencies (F1 and F2)) and size (i.e., area in the F1/F2 space) of VPSs that were categorized either into /a/, /i/, or /u/ were calculated for each LL and TA group. All center and size calculations were weighted by the goodness rating of each stimulus. The F1 and F2 values of the vowel category (VC) centers differed significantly by LL and TA. These effects were qualitatively different for the three vowel categories: English listeners had different /a/ and /u/ centers than Greek and Korean listeners. The size of VPSs did not differ significantly by LL, but did differ by TA and VCs: Greek and Korean listeners had larger vowel spaces when perceiving vowels produced by 2-year-olds than by 5-year-olds or adults, and English listeners had larger vowel spaces for /a/ than /i/ or /u/. Findings indicate that vowel perceptual categories of listeners varied by the nature of their native vowel system, and were sensitive to TA.

Low serum 25-hydroxyvitamin D levels, tooth loss, and the prevalence of severe periodontitis in Koreans aged 50 years and older.

PURPOSE: Vitamin D deficiency may cause bone loss and increased inflammation, which are well-known symptoms of periodontal disease. This study investigated whether serum 25-hydroxyvitamin D (25(OH)D) levels are associated with periodontal disease status and tooth loss. METHODS: Cross-sectional data from 5,405 individuals aged ≥50 years (2,253 males and 3,152 females) were obtained from the 2008-2010 Dong-gu study, a prospective cohort study of risk factors for chronic diseases. Periodontal examinations were conducted to evaluate the number of remaining teeth, the periodontal probing depth (PPD), the clinical attachment level (CAL), and bleeding on probing. The percentages of sites with PPD ≥4 mm and CAL ≥4 mm were recorded for each participant. The severity of periodontitis was classified using the Centers for Disease Control and Prevention and the American Academy of Periodontology case definitions. Serum 25(OH)D levels were classified as reflecting severe deficiency, deficiency, insufficiency, or sufficiency. Multivariate linear regression analysis was performed to assess the associations of serum 25(OH)D levels with periodontal parameters and the number of remaining teeth after adjusting for confounders including age, smoking status, alcohol consumption status, month of blood collection, and physical activity. Multivariate logistic regression was used to evaluate the association between serum vitamin D levels and severe periodontitis. An overall statistical analysis and a stratified analysis by sex were performed. RESULTS: Overall, the rates of severe deficiency, deficiency, insufficiency, and sufficiency were 6.5%, 67.9%, 22.4%, and 3.2%, respectively. After adjustment for confounders, vitamin D levels were directly associated with the number of remaining teeth, an association that was significant in males, but not in females. Sufficient serum 25(OH)D was associated with a low frequency of severe periodontitis. CONCLUSIONS: This population-based cross-sectional study indicates that low serum 25(OH)D is significantly associated with tooth loss and severe periodontitis in Koreans aged 50 years and older.

Effect of a Er, Cr:YSGG laser and a Er:YAG laser treatment on oral biofilm-contaminated titanium.

OBJECTIVE: Implant surface decontamination is a challenging procedure for therapy of peri-implant disease. This study aimed to compare the effectiveness of decontamination on oral biofilm-contaminated titanium surfaces in Er:YAG laser, Er, Cr:YSGG laser, and plastic curette. METHODOLOGY: For oral biofilms formation, six participants wore an acrylic splint with eight titanium discs in the maxillary arch for 72 hours. A total of 48 contaminated discs were distributed among four groups: untreated control; decontamination with plastic curettes; Er, Cr:YSGG laser; and Er:YAG laser irradiation. Complete plaque removal was estimated using naked-eye and the time taken was recorded; the residual plaque area was measured and the morphological alteration of the specimen surface was observed by scanning electron microscopy. The total bacterial load and the viability of adherent bacteria were quantified by live or dead cell labeling with fluorescence microscopy. RESULTS: The mean treatment time significantly decreased based on the treatment used in the following order: Er:YAG, Er, Cr:YSGG laser, and plastic curettes (234.9±25.4 sec, 156.1±12.7 sec, and 126.4±18.6 sec, P=0.000). The mean RPA in the Er, Cr:YSGG laser group (7.0±2.5%) was lower than Er:YAG and plastic curettes groups (10.3±2.4%, 12.3±3.6%, p=0.023). The viable bacteria on the titanium surface after Er, Cr:YSGG laser irradiation was significantly lower compared to the decontamination with plastic curette (P=0.05) but it was not significantly different from the Er:YAG laser irradiation. CONCLUSION: We found that Er:YAG laser and Er, Cr:YSGG laser irradiation were effective methods for decontaminations without surface alterations.

Acquisition and Acoustic Patterns of Southern American English /l/ in Young Children.

Purpose The aim of the current study was to examine /l/ developmental patterns in young learners of Southern American English, especially in relation to the effect of word position and phonetic contexts. Method Eighteen children with typically developing speech, aged between 2 and 5 years, produced monosyllabic single words containing singleton /l/ in different word positions (pre- vs. postvocalic /l/) across different vowel contexts (high front vs. low back) and cluster /l/ in different consonant contexts (/pl, bl/ vs. /kl, gl/). Each production was analyzed for its accuracy and acoustic patterns as measured by the first two formant frequencies and their difference (F1, F2, and F2-F1). Results There was great individual variability in /l/ acquisition patterns, with some 2- and 3-year-olds reaching 100% accuracy for prevocalic /l/, while others were below 70%. Overall, accuracy of prevocalic /l/ was higher than that of postvocalic /l/. Acoustic patterns of pre- and postvocalic /l/ showed greater differences in younger children and less apparent differences in 5-year-olds. There were no statistically significant differences between the acoustic patterns of /l/ coded as perceptually acceptable and those coded as misarticulated. There was also no apparent effect of vowel and consonant contexts on /l/ patterns. Conclusion The accuracy patterns of this study suggest an earlier development of /l/, especially prevocalic /l/, than has been reported in previous studies. The differences in acoustic patterns between pre- and postvocalic /l/, which become less apparent with age, may suggest that children alter the way they articulate /l/ with age. No significant acoustic differences between acceptable and misarticulated /l/, especially postvocalic /l/, suggest a gradient nature of /l/ that is dialect specific. This suggests the need for careful consideration of a child's dialect/language background when studying /l/.

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.

The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer's Disease-related Pathogenesis.

Several studies have revealed that the transcription factor nuclear receptor related 1 (Nurr1) plays several roles not only in the regulation of gene expression related to dopamine synthesis, but also in alternative splicing, and miRNA targeting. Moreover, it regulates cognitive functions and protects against inflammation-induced neuronal death. In particular, the role of Nurr1 in the pathogenesis of Parkinson's disease (PD) has been well investigated; for example, it has been shown that it restores behavioral and histological impairments in PD models. Although many studies have evaluated the connection between Nurr1 and PD pathogenesis, the role of Nurr1 in Alzheimer's disease (AD) remain to be studied. There have been several studies describing Nurr1 protein expression in the AD brain. However, only a few studies have examined the role of Nurr1 in the context of AD. Therefore, in this review, we highlight the overall effects of Nurr1 under the neuropathologic conditions related to AD. Furthermore, we suggest the possibility of using Nurr1 as a therapeutic target for AD or other neurodegenerative disorders.

Inhibitory effect of C-X-C motif chemokine ligand 14 on the osteogenic differentiation of human periodontal ligament cells through transforming growth factor-beta1.

OBJECTIVE: This study aimed to determine the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) in pulpal and periodontal cells in vivo and in vitro, and investigate function of CXCL14 and its underlying mechanism in the proliferation and osteogenic differentiation of human periodontal ligament (hPDL) cells. METHODS: To determine the expression level of CXCL14 in adult rat oral tissues and in hPDL cells after application of biophysical forces, RT-PCR, western blot, and histological analyses were performed. The role of CXCL14 in proliferation and osteogenic differentiation of PDL cells was evaluated by measuring dehydrogenase activity and Alizarin red S staining. RESULTS: Strong immunoreactivity against CXCL14 was observed in the PDL tissues and pulpal cells of rat molar, and attenuated apparently by orthodontic biophysical forces. As seen in rat molar, highly expressed CXCL14 was observed in human dental pulp and hPDL cells, and attenuated obviously by biophysical tensile force. CXCL14 expression in hPDL cells was increased in incubation time-dependent manner. Proliferation of hPDL cells was inhibited dramatically by small interfering (si) RNA against CXCL14. Furthermore, dexamethasone-induced osteogenic mineralization was inhibited by recombinant human (rh) CXCL14, and augmented by CXCL14 siRNA. rhCXCL14 increased transforming growth factor-beta1 (TGF- ß1) in hPDL cells. Inhibition of the cell proliferation and osteogenic differentiation of hPDL cells by CXCL14 siRNA and rhCXCL14 were restored by rhTGF-ß1 and SB431542, respectively. CONCLUSION: These results suggest that CXCL14 may play roles as a growth factor and a negative regulator of osteogenic differentiation by increasing TGF-ß1 expression in hPDL cells.

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.

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.