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Alternative splicing generates distinct mRNA variants and is essential for development, homeostasis, and renewal. Proteins of the serine/arginine (SR)-rich splicing factor family are major splicing regulators that are broadly required for organ development as well as cell and organism viability. However, how these proteins support adult organ function remains largely unknown. Here, we used the continuously growing mouse incisor as a model to dissect the functions of the prototypical SR family protein SRSF1 during tissue homeostasis and renewal. We identified an SRSF1-governed alternative splicing network that is specifically required for dental proliferation and survival of progenitors but dispensable for the viability of differentiated cells. We also observed a similar progenitor-specific role of SRSF1 in the small intestinal epithelium, indicating a conserved function of SRSF1 across adult epithelial tissues. Thus, our findings define a regulatory mechanism by which SRSF1 specifically controls progenitor-specific alternative splicing events to support adult tissuehomeostasis and renewal.

Taste stem/progenitor cells from posterior mouse tongues have been used to generate taste bud organoids. However, the inaccessible location of taste receptor cells is observed in conventional organoids. In this study, we established a suspension-culture method to fine-tune taste bud organoids by apicobasal polarity alteration to form the accessible localization of taste receptor cells. Compared to conventional Matrigel-embedded organoids, suspension-cultured organoids showed comparable differentiation and renewal rates to those of taste buds in vivo and exhibited functional taste receptor cells and cycling progenitor cells. Accessible taste receptor cells enabled the direct application of calcium imaging to evaluate the taste response. Moreover, suspension-cultured organoids can be genetically altered. Suspension-cultured taste bud organoids harmoniously integrated with the recipient lingual epithelium, maintaining the taste receptor cells and gustatory innervation capacity. We propose that suspension-cultured organoids may provide an efficient model for taste research, including taste bud development, regeneration, and transplantation.

Additional file 1: Fig. S1. Transcriptomic comparison between ameloblastomas (AMs) and odontogenic keratocysts (OKCs). Fig. S2. Histopathological validation for the AM and OKC samples. Fig. S3. Validation for the mRNA expression of selected parameters from RNA-sequencing. Fig. S4. Cytotoxicity of verapamil. Fig. S5. Ca2+ influx increased in CACNA1C-overexpressed AM cells. Fig. S6. The cell proliferation strongly associated with the Cav1.2 in AM tumoroid. Fig. S7. Cav1.2 maintained Wnt/β-catenin signaling activity in AM tumoroid.

Objective: The vibration device is one of the most commonly used warm-up devices not only for healthy athletes but also for healthy individuals....

Purpose To study the epidemiology of myopia in school-aged children in Tianjin and the relationship between visual acuity-based screening and refraction-based screening. Method This school-based prospective cohort study was performed on children from 42 elementary schools and 17 middle schools in Tianjin, China. Totally 14,551 children, ages ranging from 5 to 16 years, were included in this study. Uncorrected visual acuity (UCVA) was determined by logarithmic tumbling E chart. Non-cycloplegic photorefraction was examined by the Spot (v2.1.4) photoscreener. The relationship between the UCVA and refractive error was investigated for different age groups. Results The overall prevalence of myopia at this school based screen is 78.2%, ranged from 10% at age of 5 to 95% at age of 16. The most dramatic increase in prevalence is from age of 6 (14.8%) to age of 7 (38.5%). The overall prevalence of high myopia is 2.5%. UCVA is found corresponding to spherical equivalent refraction (SER) in a manner of normal distribution and is significantly affected by age. When using UCVA to estimate the prevalence of myopia, the overall sensitivity and specificity are 0.824 and 0.820, respectively. Age-dependent optimal cutoff points and 95% confident intervals of such estimation are reported. Conclusions Myopia is heavily affecting school-aged children in Tianjin, China. The refraction screening is preferable for myopia screening, whereas the UCVA screening results need to be interpreted in an age-dependent manner for myopia estimation.

In this article, a half-bridge (HB) integrated phase-shifted full-bridge (PSFB) converter with a new center-tapped clamp circuit is proposed to achieve high efficiency in electric vehicle battery charging systems. The proposed converter has the benefits of HB integrated PSFB converters, such as the extended zero-voltage-switching range and the reduced conduction loss on the primary side. In addition, by using a new center-tapped clamp circuit, which consists of two diodes and one capacitor, the proposed converter can solve the drawbacks of conventional PSFB converters, such as the substantial circulating current, the severe voltage stress and switching loss in the secondary full-bridge rectifier, and a large output inductor. With these improvements, the efficiency is fairly increased, and the volume of the output inductor is reduced. In order to validate the feasibility of the proposed converter, a 3.3-kW prototype was built and tested.

We aimed to identify the association of hydration status with insulin resistance (IR) and body fat distribution. A total of 14 344 adults participated in the Korea National Health and Nutrition Examination Survey 2008–2010. We used urine specific gravity (USG) to indicate hydration status, and HOMA-IR (homoeostasis model assessment of IR) and trunk:leg fat ratio (TLR) as primary outcomes. In multivariate logistic regression, the OR per 0·01 increase in USG for high IR was 1·303 (95 % CI 1·185, 1·433;P< 0·001). In multivariate generalised additive model plots, increased USG showed a J-shaped association with logarithmic HOMA-IR, with the lowest Akaike’s information criterion score of USG 1·030. Moreover, increased USG was independently associated with increased trunk fat, decreased leg fat and increased TLR. In mediation analysis, the proportion of mediation effects of USG on TLR via IR was 0·193 (95 % CI 0·132, 0·285;P< 0·001), while the proportion of mediation effects of USG on IR via TLR was 0·130 (95 % CI 0·086, 0·188;P< 0·001). Increased USG, a sign of low hydration status and presumably high vasopressin, was associated with IR and poor fat distribution. Direct effect of low hydration status may be more dominant than indirect effect via IR or fat distribution. Further studies are necessary to confirm our findings.

In the forthcoming era of IoT, where everything will be connected, mobile devices will play a key role in providing data sharing and user-centric services between devices. In such a service environment, if a mobile application is vulnerable to security threats and exposed to malicious behavior, malware can spread to hundreds of millions of connected devices. In particular, it is important to isolate and respond quickly to malicious mobile code. This requires the prediction of malicious behavior. Currently, security risk assessment schemes based on the permission use the description of the application or user review, but these schemes mostly offer a subjective evaluation, which inevitably reduces accuracy. In this paper, we thus propose a scheme for assessing security risk of Android mobile applications by analyzing their application programming interfaces (APIs) using machine learning. The key idea of the proposed scheme is to extract the APIs from the execution code of the application with reverse engineering analysis, such that each API can be compared with the malicious API database built from the existing malware dataset. Instead of simply judging the applications as malicious or benign, our scheme shows their risk as a score. To do this quantitative evaluation, we use an ensemble of tree boosting machine learning algorithms. To prove the practicality of the proposed scheme, we experiment with a set of benign and malicious real world samples, and compare our results with existing schemes. Experimental results show better performance and accuracy than conventional schemes based on Naive Bayes and simple ensemble algorithms. Our proposed scheme is expected to significantly contribute in responding rapidly to ever-more-intelligent malware of the future.

Cultural heritage (CH) artifacts, such as ceramics and clothes, reflect the unique characteristics of ancient cultures and have the potential to be sustainably employed in modern design and entertainment. In particular, the shape of ceramics reflects regional and historical characteristics, so datafication is a promising avenue to preserve these assets for future generations. However, design is a specialized domain that requires significant human (expert and novice) labor. This often tedious process decreases the labeler’s motivation to complete the task, and data consistency varies with the experience and motivation of the labeler. To increase engagement, we developed an image labeling platform with graphical icon-based labeling methods and introduced gamification. The robust labeling methods with gamification increased novices’ engagement and decreased the workload of expert and novice labelers, but decreased data agreement between experts and novices, so we consider opportunities for gamification within the specialized cultural heritage domain.

In the current study we present evidence suggesting that PARP-1 regulates neurogenesis and its deficiency may result in schizophrenia-like behavioral deficits in mice. PARP-1 knockout neural stem cells exhibited a marked upregulation of embryonic stem cell phosphatase that can suppress the proliferative signaling of PI3K-Akt and ERK. The suppressed activity of Akt and ERK in the absence of PARP-1 results in the elevation of FOXO1 activity and its downstream target genes p21 and p27, leading to the inhibition of neural stem cell proliferation. Moreover, expression of neurogenic factors and neuronal differentiation were decreased in the PARP-1 knockout neural stem cells whereas glial differentiation was increased. In accordance with the in vitro data, PARP-1 knockout mice exhibited reduced brain weight with enlarged ventricle as well as decreased adult neurogenesis in the hippocampus. Interestingly, PARP-1 knockout mice exhibited schizophrenia-like symptoms such as anxiety, depression, social interaction deficits, cognitive impairments, and prepulse inhibition deficits. Taken together, our results suggest that PARP-1 regulates neurogenesis during development and in adult and its absence may lead to the schizophrenia-like behavioral abnormality in mice.

Asymmetric division of stem cells allows for maintenance of the cell population and differentiation for harmonious progress. Developing mouse incisors allows for examination of how the stem cell niche employs specific insights into essential phases. Microtubule-associated serine/threonine kinase family member 4 (Mast4) knockout (KO) mice showed abnormal incisor development with weak hardness as the apical bud was reduced and preameloblasts were shifted to the apical side, resulting in Amelogenesis Imperfecta. In addition, Mast4 KO incisors showed abnormal enamel maturation, and stem cell maintenance was inhibited as amelogenesis accelerated. Distal-Less Homeobox 3 (DLX3), known to be a critical factor Tricho-Dento-Osseous (TDO) syndrome, is considered to be responsible for Amelogenesis Imperfecta in humans. MAST4 directly binds to DLX3 and induces phosphorylation at three residues within the nuclear localization sites (NLS) that promote the nuclear translocation of DLX3. MAST4-mediated phosphorylation of DLX3 ultimately controls the transcription of DLX3 target genes, which are carbonic anhydrase and ion transporter genes involved in the pH regulation process during ameloblast maturation. Taken together, our data reveal a novel role of MAST4 as a critical regulator of ameloblast maturation, which controls DLX3 transcriptional activity.

Experience-dependent synaptic plasticity is important for learning and memory and regulated by the functions of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. Glucocorticoids have been shown to augment synaptic potentiation processes during stress, however the underlying mechanisms have not been fully described. In this study, we have investigated the role of the Adenylyl cyclases in glucocorticoid enhancement of synaptic potentiation. We report that stress-induced glucocorticoid secretion augments phosphorylation and postsynaptic localisation of GluA1. These effects were reproduced in adrenalectomised rats treated with a stress-equivalent dose of corticosterone; and blocked by pre-treatment with the glucocorticoid receptor (GR) antagonist RU-486. Selective pharmacological inhibition of adenylyl cyclase activity with SQ22536 ablated the glucocorticoid-induced increase in phosphorylated GluA1, and reversed glucocorticoid-dependent LTP enhancement. Glucocorticoid exposure also induced induce a rapid increase in translation of hippocampal adenylyl cyclases 1 and 8, indicating a further potential role in mediating the longer-term consequences of stress. These data support a key role for adenylyl cyclases in facilitating the modulatory actions of glucocorticoid hormones on AMPA receptor regulation of learning and memory; initially as an acute mediator of the hormonally induced stress increase in LTP, then potentially in mediating adaptive changes for subsequent stress effects.

The lateral amygdala (LA) is a main sensory input site from the cortical and thalamic regions. In turn, LA glutamatergic pyramidal neurons strongly project to the basal amygdala (BA). Although it is well known that auditory fear conditioning involves synaptic potentiation in the LA, it is not clear whether the LA-BA synaptic transmission is modified upon auditory fear conditioning. Here we found that high-frequency stimulation ex vivo resulted in long-term potentiation (LTP) with a concomitant enhancement of neurotransmitter release at LA-BA synapses. Auditory fear conditioning also led to the presynaptic facilitation at LA-BA synapses. Meanwhile, AMPA/NMDA current ratio was not changed upon fear conditioning, excluding the involvement of postsynaptic mechanism. Notably, fear conditioning occluded electrically induced ex vivo LTP in the LA-BA pathway, indicating that the conditioning and electrically induced LTP share common mechanisms. Our findings suggest that the presynaptic potentiation of LA-BA synapses may be involved in fear conditioning.

This paper presents a combined framework for power distribution network expansion planning (DNEP) and energy storage systems (ESSs) allocation in active distribution networks (ADNs) hosting large amount of photovoltaic (PV) generations and loads. The proposed DNEP ensures the reliable operation of the targeted ADN with the objective of achieving its dispatchability while minimizing grid losses by determining the optimal grid expansion to connect new nodes, the reinforcement of existing lines, and the ESS allocation. The allocated ESSs compensate for the stochastic power flows caused by the stochastic loads and generation, allowing ADNs to follow a pre-defined power schedule at the grid connection point. The grid constraints are modeled by using a modified augmented relaxed optimal power flow (AR-OPF) model that convexifies the classical AC-OPF providing the global optimal and the exact solution of the OPF problem for radial networks. The DNEP problem’s complexity is handled by employing a sequential algorithm where new nodes are added one by one, following the priorities determined by the user. In each stage of the sequential planning, the Benders decomposition algorithm determines the optimal solution for investments and ADN operation iteratively. Moreover, the siting and sizing problems associated with the ESSs and line investment are solved separately to enhance the convergence speed. Simulations are conducted on a real 55-node Swiss ADN hosting sizeable stochastic photovoltaic generation.

Objectives The treatment of ameloblastoma, an odontogenic epithelial tumour destroying jawbone, mainly depends on radical destructive resections. Other therapeutic options are limited by the characteristics of ameloblastoma, such as high recurrence rates and resistance to radiation and chemotherapy, which implies possible existence of cancer stem cells (CSCs) in ameloblastoma. Here, we identified a putative CSC population in immortalized and primary human ameloblastoma cells and examined possible therapeutic reagents to reduce the CSC population. Methods We investigated subpopulations of AM‐1 cell line and human ameloblastoma cells using immunocytochemistry and flow cytometry and the effects of Wnt signalling activators on the 2‐ and 3‐dimensional cultured ameloblastoma cells using molecular biological analyses. Result Among heterogenous ameloblastoma cells, small‐sized and round‐shaped cells were found to be proliferative and expressed a marker of dental epithelial stem cells, SRY‐box 2 (Sox2). Exogenous activation of Wnt signalling using glycogen synthase kinase 3β inhibitors, lithium chloride (LiCl) and valproic acid (VPA), increased the cell size and decreased proliferation of cells and expression of Sox2 in 2 dimensionally cultured AM‐1 and human primary ameloblastoma cells. Furthermore, the growth of 3 dimensionally cultured AM‐1 cells as suspended or embedded in gel was suppressed by treatment with Wnt signalling activators, VPA and CHIR99021, or antibodies to sclerostin, an antagonist of Wnt signalling. Conclusion We suggest that Wnt signalling activators are potential drug candidates to suppress CSCs in ameloblastoma., Ameloblastoma, a benign tumour of the odontogenic epithelium, presents significant recurrence rates and resistance to radiotherapy and chemotherapy, which compel patients to undergo radical resections, potentially causing surgical morbidity. In this study, we found that the exogenous activation of Wnt signalling using antibody (α‐SOST antibody) or chemicals (LiCl, VPA or CHIR9902) increases β‐catenin (β‐cat) in ameloblastoma, leading to an increase in β‐cathigh and Sox2‐ cells and decrease in β‐catlow and Sox2+ cells, the putative cancer stem cells (CSCs). This change of sub‐population in ameloblastoma results in the suppression of spheroid‐forming activity and invasiveness. The results suggest that Wnt signalling activators may serve as potential drug candidates to suppress CSCs in ameloblastoma.

PURPOSE This study aimed to identify the factors influencing the interaction between mothers and preschool-age children and construct a structural equation model based on the factors identified. METHODS The data were collected from the mothers of children aged three to six years enrolled in kindergartens in Seoul, Gyeonggi, Chungbuk, and Jeonbuk. A total of 328 questionnaires were used for the analysis. Analysis was performed using SPSS 26.0 and AMOS 26.0 programs. RESULTS The child's self-regulation (β = .42, p < .001) had the most significant influence on the interaction between mothers and preschool children, followed by the mother's parenting stress (β = -.23, p =.008), social support (β = .17, p < .001), and the child's active temperament (β = .15, p < .001). The child's gender, emotional temperament, social temperament, and mother's education level had indirect influences. CONCLUSION These results suggest that interventions considering the child's temperament, mother's parenting stress, and social support are required to promote the interaction between preschool-age children and mothers.

Background and Objectives: The purpose of this study was to investigate the effects of microcurrent stimulation on pain, shoulder function, and grip strength in patients with rotator cuff repair. Materials and Methods: This randomized single-blind controlled trial was conducted on inpatients of the rehabilitation department, and included 28 patients who underwent rotator cuff repair. Participants were randomly assigned to the experimental group (n = 14), treated with microcurrent stimulation, and the control group (n = 14), treated with false microcurrent stimulation. The microcurrent stimulation administered to the experimental group underwent general physical therapy and microcurrent stimulation three times a week for 4 weeks. Results: Changes in pain, range of motion in shoulder, simple shoulder test, and grip strength were assessed before and after the intervention. Both groups showed a significant decrease in pain and shoulder function (t = 27.412, 22.079, 19.079, and 18.561, p &lt, 0.001), and grip strength showed a significant increase (t = −8.251 and −9.946, 0.001). The experimental group that underwent microcurrent stimulation exhibited a significant effect on pain, shoulder function, and grip strength compared with the control group that underwent false microcurrent stimulation (t = −2.17, −2.22, and 2.213, p = 0.039, 0.035, and 0.036). Conclusions: This study confirmed that microcurrent stimulation is effective for the treatment of rotator cuff repair patients.

Mesenchymal stromal cells (MSCs) differentiation into different lineages is precisely controlled by signaling pathways. Given that protein kinases play a crucial role in signal transduction, here we show that Microtubule Associated Serine/Threonine Kinase Family Member 4 (Mast4) serves as an important mediator of TGF-β and Wnt signal transduction in regulating chondro-osteogenic differentiation of MSCs. Suppression of Mast4 by TGF-β1 led to increased Sox9 stability by blocking Mast4-induced Sox9 serine 494 phosphorylation and subsequent proteasomal degradation, ultimately enhancing chondrogenesis of MSCs. On the other hand, Mast4 protein, which stability was enhanced by Wnt-mediated inhibition of GSK-3β and subsequent Smurf1 recruitment, promoted β-catenin nuclear localization and Runx2 activity, increasing osteogenesis of MSCs. Consistently, Mast4−/− mice demonstrated excessive cartilage synthesis, while exhibiting osteoporotic phenotype. Interestingly, Mast4 depletion in MSCs facilitated cartilage formation and regeneration in vivo. Altogether, our findings uncover essential roles of Mast4 in determining the fate of MSC development into cartilage or bone.