ABSTRACT
Embodied cognition explores the intricate interaction between the brain, body, and the surrounding environment. The advancement of mobile devices, such as immersive interactive computing and wireless electroencephalogram (EEG) devices, has presented new challenges and opportunities for studying embodied cognition. To address how mobile technology within immersive hybrid settings affects embodied cognition, we propose a target detection multitask incorporating mixed body movement interference and an environmental distraction light signal. We aim to investigate human embodied cognition in immersive projector-based augmented reality (IPAR) scenarios using wireless EEG technology. We recruited and engaged fifteen participants in four multitasking conditions: standing without distraction (SND), walking without distraction (WND), standing with distraction (SD), and walking with distraction (WD). We pre-processed the EEG data using Independent Component Analysis (ICA) to isolate brain sources and K-means clustering to categorize Independent Components (ICs). Following that, we conducted time-frequency and correlation analyses to identify neural dynamics changes associated with multitasking. Our findings reveal a decline in behavioral performance during multitasking activities. We also observed decreases in alpha and beta power in the frontal and motor cortex during standing target search tasks, decreases in theta power, and increases in alpha power in the occipital lobe during multitasking. We also noted perturbations in theta band power during distraction tasks. Notably, physical movement induced more significant fluctuations in the frontal and motor cortex than distractions from social environment light signals. Particularly in scenarios involving walking and multitasking, there was a noticeable reduction in beta suppression. Our study underscores the importance of brain-body collaboration in multitasking scenarios, where the simultaneous engagement of the body and brain in complex tasks highlights the dynamic nature of cognitive processes within the framework of embodied cognition. Furthermore, integrating immersive augmented reality technology into embodied cognition research enhances our understanding of the interplay between the body, environment, and cognitive functions, with profound implications for advancing human-computer interaction and elucidating cognitive dynamics in multitasking.
ABSTRACT
Craniometaphyseal dysplasia (CMD), a rare craniotubular disorder, occurs in an autosomal dominant (AD) or autosomal recessive (AR) form. CMD is characterized by hyperostosis of craniofacial bones and flaring metaphyses of long bones. Many patients with CMD suffer from neurological symptoms. To date, the pathogenesis of CMD is not fully understood. Treatment is limited to decompression surgery. Here, we report a knock in (KI) mouse model for AR CMD carrying a R239Q mutation in CX43. Cx43KI/KI mice replicate many features of AR CMD in craniofacial and long bones. In contrast to Cx43+/+ littermates, Cx43KI/KI mice exhibit periosteal bone deposition and increased osteoclast (OC) numbers in the endosteum of long bones, leading to an expanded bone marrow cavity and increased cortical bone thickness. Although formation of Cx43+/+ and Cx43KI/KI resting OCs are comparable, on bone chips the actively resorbing Cx43KI/KI OCs resorb less bone. Cortical bones of Cx43KI/KI mice have an increase in degenerating osteocytes and empty lacunae. Osteocyte dendrite formation is decreased with reduced expression levels of Fgf23, Sost, Tnf-α, IL-1ß, Esr1, Esr2, and a lower Rankl/Opg ratio. Female Cx43KI/KI mice display a more severe phenotype. Sexual dimorphism in bone becomes more evident as mice age. Our data show that the CX43R239Q mutation results in mislocalization of CX43 protein and impairment of gap junction and hemichannel activity. Different from CX43 ablation mouse models, the CX43R239Q mutation leads to the AR CMD-like phenotype in Cx43KI/KI mice not only by loss-of-function but also via a not yet revealed dominant function.
ABSTRACT
Currently, over 500 rare genetic bone disorders are identified. These diseases are often accompanied by dental abnormalities, which are sometimes the first clue for an early diagnosis. However, not many dentists are sufficiently familiar with phenotypic abnormalities and treatment approaches when they encounter patients with rare diseases. Such patients often need dental treatment but have difficulties in finding a dentist who can treat them appropriately. Herein we focus on major dental phenotypes and summarize their potential causes and mechanisms, if known. We discuss representative diseases, dental treatments, and their effect on the oral health of patients and on oral health-related quality of life. This review can serve as a starting point for dentists to contribute to early diagnosis and further investigate the best treatment options for patients with rare disorders, with the goal of optimizing treatment outcomes.
Subject(s)
Bone Diseases , Rare Diseases , Humans , Quality of LifeABSTRACT
Wireless electroencephalography (EEG) systems have been attracting increasing attention in recent times. Both the number of articles discussing wireless EEG and their proportion relative to general EEG publications have increased over years. These trends indicate that wireless EEG systems could be more accessible to researchers and the research community has recognized the potential of wireless EEG systems. To explore the development and diverse applications of wireless EEG systems, this review highlights the trends in wearable and wireless EEG systems over the past decade and compares the specifications and research applications of the major wireless systems marketed by 16 companies. For each product, five parameters (number of channels, sampling rate, cost, battery life, and resolution) were assessed for comparison. Currently, these wearable and portable wireless EEG systems have three main application areas: consumer, clinical, and research. To address this multitude of options, the article also discussed the thought process to find a suitable device that meets personalization and use cases specificities. These investigations suggest that low-price and convenience are key factors for consumer applications, wireless EEG systems with FDA or CE-certification may be more suitable for clinical settings, and devices that provide raw EEG data with high-density channels are important for laboratory research. This article presents an overview of the current state of the wireless EEG systems specifications and possible applications and serves as a guide point as it is expected that more influential and novel research will cyclically promote the development of such EEG systems.
Subject(s)
Wearable Electronic Devices , Wireless Technology , Humans , Electroencephalography , Electrodes , AttentionABSTRACT
Dental pain invokes the sympathetic nervous system, which can be measured by electrodermal activity (EDA). In the dental clinic, accurate quantification of pain is needed because it could enable optimized drug-dose treatments, thereby potentially reducing drug addiction. However, a confounding factor is that during pain there is also lingering residual stress, hence, both contribute to the EDA response. Therefore, we investigated whether EDA can differentiate stress from pain during dental examination. The use of electrical pulp test (EPT) is an ideal approach to tease out the dynamics of stress and mimic pain with lingering residual stress. Once the electrical sensation is felt and reaches a critical current threshold, the subject removes the probe from their tooth, hence, this stage of data represents largely EPT stimulus and the residual stress-induced EDA response is smaller. EPT was performed on necrotic and vital teeth in fifty-one subjects. We defined four different data groups of reactions based on each individual's EPT intensity level expectation based on the visual analog scale (VAS) of their baseline trial, as follows: mild stress, mild stress + EPT, strong stress, and strong stress + EPT. EDA-derived features exhibited significant difference between residual lingering stress + EPT groups and stress groups. We obtained 84.6% accuracy with 76.2% sensitivity and 86.8% specificity with multilayer perceptron in differentiating between pure-stress groups vs. stress + EPT groups. Moreover, EPT induced much greater EDA amplitude and faster response than stress. Our finding suggests that our machine learning approach can discriminate between stress and EPT stimulation in EDA signals.
Subject(s)
Galvanic Skin Response , Pain , Humans , Dental Clinics , Sympathetic Nervous System/physiology , Machine LearningABSTRACT
AIMS: To explore whether electrodermal activity (EDA) can serve as a complementary tool for pulpal diagnosis (Aim 1) and an objective metric to assess dental pain before and after local anaesthesia (Aim 2). METHODOLOGY: A total of 53 subjects (189 teeth) and 14 subjects (14 teeth) were recruited for Aim 1 and Aim 2, respectively. We recorded EDA using commercially available devices, PowerLab and Galvanic Skin Response (GSR) Amplifier, in conjunction with cold and electric pulp testing (EPT). Participants rated their level of sensation on a 0-10 visual analogue scale (VAS) after each test. We recorded EPT-stimulated EDA activity before and after the administration of local anaesthesia for participants who required root canal treatment (RCT) due to painful pulpitis. The raw data were converted to the time-varying index of sympathetic activity (TVSymp), a sensitive and specific parameter of EDA. Statistical analysis was performed using Python 3.6 and its Scikit-post hoc library. RESULTS: Electrodermal activity was upregulated by the stimuli of cold and EPT testing in the normal pulp. TVSymp signals were significantly increased in vital pulp compared to necrotic pulp by both cold test and EPT. Teeth that exhibited intensive sensitivity to cold with or without lingering pain had increased peak numbers of TVSymp than teeth with mild sensation to cold. Pre- and post-anaesthesia EDA activity and VAS scores were recorded in patients with painful pulpitis. Post-anaesthesia EDA signals were significantly lower compared to pre-anaesthesia levels. Approximately 71% of patients (10 of 14 patients) experienced no pain during treatment and reported VAS score of 0 or 1. The majority of patients (10 of 14) showed a reduction of TVSymp after the administration of anaesthesia. Two of three patients who experienced increased pain during RCT (post-treatment VAS > pre-treatment VAS) exhibited increased post-anaesthesia TVSymp. CONCLUSIONS: Our data show promising results for using EDA in pulpal diagnosis and for assessing dental pain. Whilst our testing was limited to subjects who had adequate communication skills, our future goal is to be able to use this technology to aid in the endodontic diagnosis of patients who have limited communication ability.
Subject(s)
Pulpitis , Humans , Pulpitis/diagnosis , Pulpitis/therapy , Galvanic Skin Response , Pain Measurement/methods , Pain/diagnosis , Pain/etiology , Dental PulpABSTRACT
Bio-signals are being increasingly used for the assessment of pathophysiological conditions including pain, stress, fatigue, and anxiety. For some approaches, a single signal is not sufficient to provide a comprehensive diagnosis; however, there is a growing consensus that multimodal approaches allow higher sensitivity and specificity. For instance, in visceral pain subjects, the autonomic activation can be inferred using electrodermal activity (EDA) and heart rate variability derived from the electrocardiogram (ECG), but including the muscle activation detected from the surface electromyogram (sEMG) can better differentiate the disease that causes the pain. There is no wearable device commercially capable of collecting these three signals simultaneously. This paper presents the validation of a novel multimodal low profile wearable data acquisition device for the simultaneous collection of EDA, ECG, and sEMG signals. The device was validated by comparing its performance to laboratory-scale reference devices. N = 20 healthy subjects were recruited to participate in a four-stage study that exposed them to an array of cognitive, orthostatic, and muscular stimuli, ensuring the device is sensitive to a range of stressors. Time and frequency domain analyses for all three signals showed significant similarities between our device and the reference devices. Correlation of sEMG metrics ranged from 0.81 to 0.95 and EDA/ECG metrics showed few instances of significant difference in trends between our device and the references. With only minor observed differences, we demonstrated the ability of our device to collect EDA, sEMG, and ECG signals. This device will enable future practical and impactful advances in the field of chronic pain and stress measurement and can confidently be implemented in related studies.
Subject(s)
Galvanic Skin Response , Wearable Electronic Devices , Humans , Electromyography , Electrocardiography , PainABSTRACT
BACKGROUND: Familial hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. HCM manifestations include left ventricular hypertrophy and heart failure, arrythmias, and sudden cardiac death. How dysregulated sarcomeric force production is sensed and leads to pathological remodeling remains poorly understood in HCM, thereby inhibiting the efficient development of new therapeutics. METHODS: Our discovery was based on insights from a severe phenotype of an individual with HCM and a second genetic alteration in a sarcomeric mechanosensing protein. We derived cardiomyocytes from patient-specific induced pluripotent stem cells and developed robust engineered heart tissues by seeding induced pluripotent stem cell-derived cardiomyocytes into a laser-cut scaffold possessing native cardiac fiber alignment to study human cardiac mechanobiology at both the cellular and tissue levels. Coupled with computational modeling for muscle contraction and rescue of disease phenotype by gene editing and pharmacological interventions, we have identified a new mechanotransduction pathway in HCM, shown to be essential in modulating the phenotypic expression of HCM in 5 families bearing distinct sarcomeric mutations. RESULTS: Enhanced actomyosin crossbridge formation caused by sarcomeric mutations in cardiac myosin heavy chain (MYH7) led to increased force generation, which, when coupled with slower twitch relaxation, destabilized the MLP (muscle LIM protein) stretch-sensing complex at the Z-disc. Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy. We demonstrate that the common muscle LIM protein-W4R variant is an important modifier, exacerbating the phenotypic expression of HCM, but alone may not be a disease-causing mutation. By mitigating enhanced actomyosin crossbridge formation through either genetic or pharmacological means, we alleviated stress at the Z-disc, preventing the development of hypertrophy associated with sarcomeric mutations. CONCLUSIONS: Our studies have uncovered a novel biomechanical mechanism through which dysregulated sarcomeric force production is sensed and leads to pathological signaling, remodeling, and hypertrophic responses. Together, these establish the foundation for developing innovative mechanism-based treatments for HCM that stabilize the Z-disc MLP-mechanosensory complex.
Subject(s)
Cardiomyopathy, Hypertrophic, Familial , Cardiomyopathy, Hypertrophic , Actomyosin/genetics , Humans , LIM Domain Proteins , Mechanotransduction, Cellular , Muscle Proteins , Mutation , Myocytes, CardiacABSTRACT
Cherubism (CBM), characterized by expansile jawbones with multilocular fibrocystic lesions, is caused by gain-of-function mutations in SH3 domain-binding protein 2 (SH3BP2; mouse orthologue Sh3bp2). Loss of jawbone and dental integrity significantly decrease the quality of life for affected children. Treatment for CBM is limited to multiple surgeries to correct facial deformities. Despite significant advances made with CBM knockin (KI) mouse models (Sh3bp2 KI/KI ), the activation mechanisms of CBM lesions remain unknown because mutant mice do not spontaneously develop expansile jawbones. We hypothesize that bony inflammation of an unknown cause triggers jawbone expansion in CBM. To introduce jawbone inflammation in a spatiotemporally controlled manner, we exposed pulp of the first right mandibular molar of 6-week-old Sh3bp2 +/+ , Sh3bp2 KI/+ , and Sh3bp2 KI/KI mice. Bacterial invasion from the exposed pulp into root canals led to apical periodontitis in wild-type and mutant mice. The pathogen-associated molecular patterns (PAMPs)-induced inflammation of alveolar bone resulted in jawbone expansion in Sh3bp2 KI/+ and Sh3bp2 KI/KI mice. CBM-like lesions developed exacerbated inflammation with increased neutrophil, macrophage, and osteoclast numbers. These lesions displayed excessive neutrophil extracellular traps (NETs) compared to Sh3bp2 +/+ mice. Expression levels of IL-1ß, IL-6, and TNF-α were increased in periapical lesions of Sh3bp2 +/+ , Sh3bp2 KI/+ , and Sh3bp2 KI/KI mice and also in plasma and the left untreated mandibles (with no pulp exposure) of Sh3bp2 KI/KI mice, suggesting a systemic upregulation. Ablation of Tlr2/4 signaling or depletion of neutrophils by Ly6G antibodies ameliorated jawbone expansion induced by PAMPs in Sh3bp2 KI/KI mice. In summary, successful induction of CBM-like lesions in jaws of CBM mice is important for studying initiating mechanisms of CBM and for testing potential therapies. Our findings further emphasize a critical role of host immunity in the development of apical periodontitis and the importance of maintaining oral health in CBM patients. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
ABSTRACT
Three-dimensional (3D)-printed guides have been used in endodontics to prepare a conservative access, locate calcified or missing canals, and perform precisive osteotomy in apicoectomy. Here, we present the treatment of a fusion tooth by combining 3D printing technology and endodontic intervention in a 10-year-old patient. The bifid crown of a maxillary right lateral incisor #7 had caused esthetic concerns and malocclusion. Clinical and radiographic examinations showed that #7 is fused with a supernumerary tooth with 2 independent root canals. The fusion involved the entire crown and the coronal and middle roots. Because of financial constraints, a multidisciplinary approach involving endodontic, orthodontic, and prosthodontic treatment was excluded. We hemisectioned the tooth intraorally with a 3D-printed guide, extracted the supernumerary tooth, and transplanted tooth #7 to a position with improved esthetics and occlusion. A 3D-printed tooth replica was used to prepare the recipient site for autotransplantation. At the 6-month follow-up, tooth #7 was diagnosed with pulp necrosis and asymptomatic apical periodontitis. Root canal treatment of tooth #7 was completed, and osseous healing was observed 8 months later. The patient had no clinical symptoms and was satisfied with the outcome 14 months after hemisection and transplantation. The open space between teeth #7 and #8 was closed without orthodontic treatment. We present an alternative option to treat a fusion tooth in young patients who do not opt for other treatment options because of their stage of development or for socio-economic reasons. Techniques in modern endodontics, such as cone-beam computed tomographic imaging and 3D printing, should be adapted when it is beneficial to patients.
Subject(s)
Root Canal Therapy , Tooth, Supernumerary , Child , Cone-Beam Computed Tomography , Humans , Incisor/diagnostic imaging , Incisor/surgery , Transplantation, AutologousABSTRACT
Differentiation of keratinocytes from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) has become an important tool for wound healing research and for studying skin diseases in instances where patient cells are not available. Several keratinocyte differentiation protocols using hiPSC colony fragments or embryoid bodies have been published with some requiring prolonged time for differentiation or extended use of reagent cocktails. In this study, we present a simplified method to efficiently generate large numbers of uniformly differentiated keratinocytes in less than 4 weeks from singularized hiPSCs with differentiation factors, retinoic acid and bone morphogenetic protein 4 (BMP4). Low seeding density of singularized iPSCs results in keratinocyte cultures with minimum cell death during differentiation and up to 96% homogeneity for keratin 14-positive cells and low percentage of keratinocyte maturation markers, comparable to early passage primary keratinocytes. hiPSC-derived keratinocytes remain in a proliferative state, can be maintained for prolonged periods of time, and can be terminally differentiated under high calcium conditions in the same way as primary human keratinocytes. Moreover, coculturing hiPSC-derived fibroblasts and keratinocytes consistently formed organotypic 3D skin equivalents. Therefore, keratinocytes generated by this method are a viable source of cells for downstream applications.
Subject(s)
Cell Culture Techniques/methods , Cell Differentiation , Fibroblasts/cytology , Human Embryonic Stem Cells/cytology , Induced Pluripotent Stem Cells/cytology , Keratinocytes/cytology , Skin/cytology , Bone Morphogenetic Protein 4/metabolism , Cells, Cultured , Fibroblasts/metabolism , Human Embryonic Stem Cells/metabolism , Humans , Induced Pluripotent Stem Cells/metabolism , Keratinocytes/metabolism , Skin/metabolism , Tretinoin/metabolismABSTRACT
Previous claims of the number of color categories and corresponding basic color terms in modern Mandarin Chinese remain irreconcilable, mainly due to the shortage in objectively evaluating the basicness of color terms with statistical significance. Therefore the present study applied k-means cluster analysis to investigate native Mandarin Chinese speakers' color naming data of 330 color chips similar to those used in World Color Survey. Results confirmed that there are 11 basic color categories among modern Mandarin speakers in Taiwan, one corresponding to each basic color term. Results also showed that observers overwhelmingly agreed in their use of Mandarin color terms, including those that had yielded ambiguous results in previous studies (gray, brown, pink, and orange). There is significant cross-language similarity when comparing the distribution of color categories in the World Color Survey chart with American English and Japanese data. The motif analysis and group mutual information analysis suggest that Mandarin color terms used in Taiwan describe very similar categories and are, hence, similarly precise in communicating color information as those in Japanese and American English. These results show that three languages of fundamentally different cultures and histories have very similar basic color terms.
Subject(s)
Asian People , Classification , Color , Language , Adult , China , Cluster Analysis , Color Perception , Female , Humans , Male , United States , Young AdultABSTRACT
BACKGROUND: Chronic diseases are a leading cause of morbidity and mortality worldwide, and preventative screenings are the most effective way to reduce the risk of developing a chronic disease. However, many individuals do not take advantage of preventative screening services for chronic diseases, especially in rural areas. In this study, we investigated (1) the factors that affect people's willingness to participate in chronic disease screenings and (2) reasons why people have not undergone screening for a chronic disease in the past. METHODS: Study participants (aged 30-65 of years age; n = 204) included individuals from four areas in northern of Taiwan that are considered to have a high chronic disease risk. To identify factors that influence willingness to attend health screenings, data were collected by questionnaire. RESULTS: Over 50% of participants (58.33%; n = 119) indicated that they were unaware of community-based screenings for chronic diseases oï¬ered by Chang Gung Memorial Hospital, which is one of the top-rated medical centers in Taiwan. Factors that increase willingness to participate in health screenings for chronic diseases include: (1) the convenience of screening site locations; (2) affordability; and (3) other considerations related to healthcare providers and diagnostic facilities (e.g., reputation, degree of modernization, etc.). Conversely, factors that reduce willingness to participate in health screenings include: (1) a belief that one was currently healthy; (2) lack of time; (3) a belief that screening procedures were too complicated to understand; (4) physical pain or negative emotions such as fear, anxiety, embarrassment, pain, and discomfort and, (5) having had a negative experience during a previous health checkup. CONCLUSIONS: Our findings demonstrate that health attitudes, sociodemographic factors, and other motivating and preventative factors affect peoples' willingness to participate in health screenings. The motivating factors and barriers for people to participate in health screening for chronic diseases are very heterogeneous. However, understanding the barriers and motivating factors to health screening would mean that interventions with the purpose of decreasing people's health risks and reducing deaths and disabilities caused by a chronic illness could be implemented.
Subject(s)
Chronic Disease/prevention & control , Health Behavior , Health Status , Mass Screening/psychology , Patient Acceptance of Health Care/statistics & numerical data , Adult , Aged , Female , Humans , Male , Mass Screening/methods , Middle Aged , Patient Participation/statistics & numerical data , Surveys and Questionnaires , TaiwanABSTRACT
Defects in bone resorption by osteoclasts result in numerous rare genetic bone disorders as well as in some common diseases such as osteoporosis or osteopetrosis. The use of hiPSC-differentiated osteoclasts opens new avenues in this research field by providing an unlimited cell source and overcoming obstacles such as unavailability of human specimens and suitable animal models. Generation of hiPSCs is well established but efficient differentiation of hiPSCs into osteoclasts has been challenging. Published hiPSC-osteoclast differentiation protocols use a hiPSC-OP9 co-culture system or hiPSC-derived embryoid bodies (EBs) with multiple cytokines. Our three-stage protocol consists of 1) EB mesoderm differentiation, 2) expansion of myelomonocytic cells and 3) maturation of hiPSC-osteoclasts. We generate uniformly-sized EBs by culturing Accutase-dissociated hiPSCs on Nunclon Sphera microplates and promote EB mesoderm differentiation in a cytokine cocktail for 4 days. For Stage 2, EBs are transferred to gelatin-coated plates and cultured with hM-CSF and hIL-3 to expand the myelomonocytic population. By supplementing with vitamin D, hTGFß, hM-CSF and hRANKL, cells collected at the end of Stage 2 are differentiated into mature osteoclasts (Stage 3). Compared to other techniques, our protocol does not require a co-culture system; induces EBs into mesoderm differentiation in a homogenous manner; uses less cytokines for differentiation; requires only a short time for osteoclast maturation and produces sufficient numbers of osteoclasts for subsequent molecular analyses. Graphic abstract.
ABSTRACT
Craniometaphyseal dysplasia (CMD), a rare genetic bone disorder, is characterized by lifelong progressive thickening of craniofacial bones and metaphyseal flaring of long bones. The autosomal dominant form of CMD is caused by mutations in the progressive ankylosis gene ANKH (mouse ortholog Ank), encoding a pyrophosphate (PPi) transporter. We previously reported reduced formation and function of osteoblasts and osteoclasts in a knockin (KI) mouse model for CMD (AnkKI/KI) and in CMD patients. We also showed rapid protein degradation of mutant ANK/ANKH. Mutant ANK protein displays reduced PPi transport, which may alter the inorganic phosphate (Pi) and PPi ratio, an important regulatory mechanism for bone mineralization. Here we investigate whether reducing dietary Pi intake can ameliorate the CMD-like skeletal phenotype by comparing male and female Ank+/+ and AnkKI/KI mice exposed to a low (0.3%) and normal (0.7%) Pi diet for 13 weeks from birth. Serum Pi and calcium (Ca) levels were not significantly changed by diet, whereas PTH and 25-hydroxy vitamin D (25-OHD) were decreased by low Pi diet but only in male Ank+/+ mice. Importantly, the 0.3% Pi diet significantly ameliorated mandibular hyperostosis in both sexes of AnkKI/KI mice. A tendency of decreased femoral trabeculation was observed in male and female Ank+/+ mice as well as in male AnkKI/KI mice fed with the 0.3% Pi diet. In contrast, in female AnkKI/KI mice the 0.3% Pi diet resulted in increased metaphyseal trabeculation. This was also the only group that showed increased bone formation rate. Low Pi diet led to increased osteoclast numbers and increased bone resorption in all mice. We conclude that lowering but not depleting dietary Pi delays the development of craniofacial hyperostosis in CMD mice without severely compromising serum levels of Pi, Ca, PTH, and 25-OHD. These findings may have implications for better clinical care of patients with CMD. © 2020 American Society for Bone and Mineral Research.
Subject(s)
Diet , Hyperostosis/therapy , Phosphates/administration & dosage , Animals , Bone Diseases, Developmental , Craniofacial Abnormalities , Disease Models, Animal , Female , Gene Knock-In Techniques , Humans , Hypertelorism , Male , Mice , Phosphate Transport Proteins/geneticsABSTRACT
Piezoelectric materials, a type of "smart" material that generates electricity while deforming and vice versa, have been used extensively for many important implantable medical devices such as sensors, transducers, and actuators. However, commonly utilized piezoelectric materials are either toxic or nondegradable. Thus, implanted devices employing these materials raise a significant concern in terms of safety issues and often require an invasive removal surgery, which can damage directly interfaced tissues/organs. Here, we present a strategy for materials processing, device assembly, and electronic integration to 1) create biodegradable and biocompatible piezoelectric PLLA [poly(l-lactic acid)] nanofibers with a highly controllable, efficient, and stable piezoelectric performance, and 2) demonstrate device applications of this nanomaterial, including a highly sensitive biodegradable pressure sensor for monitoring vital physiological pressures and a biodegradable ultrasonic transducer for blood-brain barrier opening that can be used to facilitate the delivery of drugs into the brain. These significant applications, which have not been achieved so far by conventional piezoelectric materials and bulk piezoelectric PLLA, demonstrate the PLLA nanofibers as a powerful material platform that offers a profound impact on various medical fields including drug delivery, tissue engineering, and implanted medical devices.
Subject(s)
Absorbable Implants , Micro-Electrical-Mechanical Systems/instrumentation , Nanofibers/chemistry , Transducers , Drug Delivery Systems , Electricity , Electronics , Equipment Design , Monitoring, Physiologic/instrumentation , Pressure , Prostheses and Implants , Tissue Engineering , UltrasonicsABSTRACT
BACKGROUND: As the average age of the population continues to rise in the 21st century, chronic illnesses have become the most prominent threats to human health. Research has shown that early screenings for chronic diseases are an effective way of lowering incidence and mortality rates. However, low participation rates for health screening is one of the main challenges for preventive medicine. The objective of this study was to determine the primary drivers which: (1) first motivate people to participate in community-based health screening for chronic diseases; and (2) increase their willingness to continue to participate. METHODS: A total of 440 individuals between 30 and 75 years of age were invited to undergo a health screening and then complete an interview questionnaire. Screenings and interviews were conducted in four regions in northern Taiwan. The questionnaire was separated into three sections, which explored sociodemographic differences, drivers of willingness to participate, and willingness to continue to participate respectively. Raw data was analyzed using the statistical software package SPSS (SPSS Inc., Chicago, IL, USA). MAIN OUTCOME MEASURES: Effects of sociodemographic factors on health screening participation rate, drivers of willingness to participate, and willingness to continue to participate. RESULTS: Seventy-three percent of participants responded that they would be willing to continue to join in future health screenings. Notably, elderly people and married people were respectively more likely to participate in preventive health screening than were younger people and people who were single, divorced, separated, or widowed. Level of education was another key driver of willingness to participate in health screening for chronic diseases, as were the concern of relatives/friends and the provision of participation incentives. DISCUSSION: Some of our findings, such as the key drivers of willingness to continue to participate in health screening that we identified, were different from findings of many previous studies conducted in other countries. The current study also found that a higher percentage of participants would be willing to join a similar health screening in the future if the service design is considered in advance and is well-implemented.
Subject(s)
Chronic Disease/psychology , Community Health Centers/statistics & numerical data , Mass Screening/psychology , Mass Screening/statistics & numerical data , Motivation , Preventive Health Services/statistics & numerical data , Adult , Aged , Female , Humans , Male , Middle Aged , Surveys and Questionnaires , TaiwanABSTRACT
Mutations in the progressive ankylosis protein (NP_473368, human ANKH) cause craniometaphyseal dysplasia (CMD), characterized by progressive thickening of craniofacial bones and widened metaphyses in long bones. The pathogenesis of CMD remains largely unknown, and treatment for CMD is limited to surgical intervention. We have reported that knock-in mice (AnkKI/KI) carrying a F377del mutation in ANK (NM_020332, mouse ANK) replicate many features of CMD. Interestingly, ablation of the Ank gene in AnkKO/KO mice also leads to several CMD-like phenotypes. Mutations causing CMD led to decreased steady-state levels of ANK/ANKH protein due to rapid degradation. While wild type (wt) ANK was mostly associated with plasma membranes, endoplasmic reticulum (ER), Golgi apparatus and lysosomes, CMD-linked mutant ANK was aberrantly localized in cytoplasm. Inhibitors of proteasomal degradation significantly restored levels of overexpressed mutant ANK, whereas endogenous CMD-mutant ANK/ANKH levels were more strongly increased by inhibitors of lysosomal degradation. However, these inhibitors do not correct the mislocalization of mutant ANK. Co-expressing wt and CMD-mutant ANK in cells showed that CMD-mutant ANK does not negatively affect wt ANK expression and localization, and vice versa. In conclusion, our finding that CMD mutant ANK/ANKH protein is short-lived and mislocalized in cells may be part of the CMD pathogenesis.
Subject(s)
Bone Diseases, Developmental/etiology , Craniofacial Abnormalities/etiology , Hyperostosis/etiology , Hypertelorism/etiology , Phosphate Transport Proteins/metabolism , Animals , Bone Diseases, Developmental/genetics , Cells, Cultured , Craniofacial Abnormalities/genetics , Humans , Hyperostosis/genetics , Hypertelorism/genetics , Mice , Mutation , Phosphate Transport Proteins/genetics , Proteasome Endopeptidase Complex/metabolism , Protein Stability , Rats , Saccharomyces cerevisiae , UbiquitinationABSTRACT
We utilized a bone marrow stromal culture system to investigate changes in TGFß signaling in a mouse model for cherubism (Sh3bp2KI/KI). Interestingly, bone marrow cultures derived from cherubism mice not only displayed impaired osteoblast differentiation, but also had spontaneous osteoclast formation. PAI1, a target gene of TGFß signaling, was elevated 2-fold in cherubism CD11b-,CD45- cells compared to wild type cells, while the expression of BAMBI, an inhibitor of TGFß signaling, was down-regulated. We also discovered that treatment of cherubism cultures with antagonists of the TGFß signaling pathway could largely rescue osteoblast differentiation and markedly reduce spontaneous osteoclast formation. Treatment with the type I TGFß receptor small molecule inhibitor SB505124 increased osteoblast reporter gene Col1a1-2.3 expression 24-fold and increased the expression of osteoblast gene markers Osterix (Sp7) 25-fold, Bone Sialoprotein (BSP) 7-fold, Osteocalcin (Bglap1) 100-fold, and Dentin Matrix Protein 1 (DMP1) 35-fold. In contrast, SB505124 treatment resulted in a significant reductions in osteoclast number and size. Gene expression analyses for RANKL, a positive regulator of osteoclast formation was 2.5-fold higher in osteoblast cultures derived from Sh3bp2KI/KI mice compared to wild type cultures, whereas OPG, an inhibitor of RANKL was 5-fold lower. However, SB505124 treatment reduced RANKL almost back down to wild type levels, while increasing OPG expression. Our studies also implicate a role for TGFß ligands in the etiology of cherubism. Blocking of TGFß ligands with the monoclonal antibody 1D11 increased Col1a1-2.3 reporter expression 4-fold and 13-fold in cultures derived from Sh3bp2KI/+ and Sh3bp2KI/KI mice, respectively. Serum levels of latent TGFß1 were also 2-fold higher in SH3BP2KI/KI mice compared to wild type littermates. Taken together, these studies provide evidence that elevated levels of TGFß signaling may contribute to the disease phenotype of cherubism and a reduction in pathway activity may be an effective therapeutic approach to treat this rare disease.
Subject(s)
Benzodioxoles/therapeutic use , Cherubism/drug therapy , Cherubism/pathology , Imidazoles/therapeutic use , Pyridines/therapeutic use , Transforming Growth Factor beta/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/genetics , Animals , Benzodioxoles/pharmacology , Bone Marrow Cells/cytology , Bone Resorption , Cell Differentiation/genetics , Cells, Cultured , Disease Models, Animal , Femur/cytology , Genetic Markers/genetics , Imidazoles/pharmacology , Membrane Proteins/genetics , Mice , Molecular Targeted Therapy , Osteoblasts/cytology , Osteoclasts/cytology , Osteogenesis , Phenotype , Pyridines/pharmacology , RANK Ligand/genetics , Stromal Cells , Tibia/cytology , Transforming Growth Factor beta/physiologyABSTRACT
We identified osteoclast defects in craniometaphyseal dysplasia (CMD) using an easy-to-use protocol for differentiating osteoclasts from human induced pluripotent stem cells (hiPSCs). CMD is a rare genetic bone disorder, characterized by life-long progressive thickening of craniofacial bones and abnormal shape of long bones. hiPSCs from CMD patients with an in-frame deletion of Phe377 or Ser375 in ANKH are more refractory to in vitro osteoclast differentiation than control hiPSCs. To exclude differentiation effects due to genetic variability, we generated isogenic hiPSCs, which have identical genetic background except for the ANKH mutation. Isogenic hiPSCs with ANKH mutations formed fewer osteoclasts, resorbed less bone, expressed lower levels of osteoclast marker genes, and showed decreased protein levels of ANKH and vacuolar proton pump v-ATP6v0d2. This proof-of-concept study demonstrates that efficient and reproducible differentiation of isogenic hiPSCs into osteoclasts is possible and a promising tool for investigating mechanisms of CMD or other osteoclast-related disorders.