DDX58(RIG-I)-related disease is associated with tissue-specific interferon pathway activation.

BACKGROUND: Singleton-Merten syndrome (SGMRT) is a rare immunogenetic disorder that variably features juvenile open-angle glaucoma (JOAG), psoriasiform skin rash, aortic calcifications and skeletal and dental dysplasia. Few families have been described and the genotypic and phenotypic spectrum is poorly defined, with variants in DDX58 (DExD/H-box helicase 58) being one of two identified causes, classified as SGMRT2. METHODS: Families underwent deep systemic phenotyping and exome sequencing. Functional characterisation with in vitro luciferase assays and in vivo interferon signature using bulk and single cell RNA sequencing was performed. RESULTS: We have identified a novel DDX58 variant c.1529A>T p.(Glu510Val) that segregates with disease in two families with SGMRT2. Patients in these families have widely variable phenotypic features and different ethnic background, with some being severely affected by systemic features and others solely with glaucoma. JOAG was present in all individuals affected with the syndrome. Furthermore, detailed evaluation of skin rash in one patient revealed sparse inflammatory infiltrates in a unique distribution. Functional analysis showed that the DDX58 variant is a dominant gain-of-function activator of interferon pathways in the absence of exogenous RNA ligands. Single cell RNA sequencing of patient lesional skin revealed a cellular activation of interferon-stimulated gene expression in keratinocytes and fibroblasts but not in neighbouring healthy skin. CONCLUSIONS: These results expand the genotypic spectrum of DDX58-associated disease, provide the first detailed description of ocular and dermatological phenotypes, expand our understanding of the molecular pathogenesis of this condition and provide a platform for testing response to therapy.

Sandwich Integration Technique for the Pressure Sensor Detection of Occlusal Force In Vitro.

Bite force measurement is an important parameter when checking the function and integrity of the masticatory system, whereas it is currently very difficult to measure bite force during functional movement. Hence, the purpose of this study is to explore the potential technique and device for the measurement and intervention of the continuous bite forces on functional and dynamic occlusal condition. A portable biosensor by sandwich technique was designed, and the validity, reliability, and sensitivity were determined by mechanical pressure loading tests; meanwhile, the pressure signal is acquired by, and transmitted to, voltage changes by the electrical measurements of the sensors. The result is that, when the mechanical stress detection device is thicker than 3.5 mm, it shows relatively ideal mechanical properties; however, when the thickness is less than 3.0 mm, there is a risk of cracking. Mechanical stress changing and voltage variation had a regularity and positive relationship in this study. The mechanical stress-measuring device made by medical and industrial cross has a good application prospect for the measurement of bite force during function.

Recent progress in the development of upconversion nanomaterials in bioimaging and disease treatment.

Multifunctional lanthanide-based upconversion nanoparticles (UCNPs), which feature efficiently convert low-energy photons into high-energy photons, have attracted considerable attention in the domain of materials science and biomedical applications. Due to their unique photophysical properties, including light-emitting stability, excellent upconversion luminescence efficiency, low autofluorescence, and high detection sensitivity, and high penetration depth in samples, UCNPs have been widely applied in biomedical applications, such as biosensing, imaging and theranostics. In this review, we briefly introduced the major components of UCNPs and the luminescence mechanism. Then, we compared several common design synthesis strategies and presented their advantages and disadvantages. Several examples of the functionalization of UCNPs were given. Next, we detailed their biological applications in bioimaging and disease treatment, particularly drug delivery and photodynamic therapy, including antibacterial photodynamic therapy. Finally, the future practical applications in materials science and biomedical fields, as well as the remaining challenges to UCNPs application, were described. This review provides useful practical information and insights for the research on and application of UCNPs in the field of cancer.

[Relationship between occupational noise exposure and hypertension in male steel workers].

OBJECTIVE: To analyze the effect of occupational noise exposure on hypertension in male steel workers. METHODS: The general information, noise exposure and blood pressure were collected through questionnaires and physical examinations. Chi-square test was used to investigate the prevalence of hypertension under different cumulative noise exposure, and the effect of noise exposure and other factors on hypertension was analyzed by the restrictive cubic spline(RCS) combined with multivariatenon-condition Logistic regression model. RESULTS: The prevalence of hypertension in noise exposure group was higher than that in noise non-exposure group(P<0. 001). After adjusting for multiple factors, the restricted cubic spline model showed a dose-response relationship between cumulative noise exposure(CNE) and hypertension(overall correlation χ~2=75. 76, P<0. 001, and nonlinear χ~2=24. 17, P<0. 001). Compared with the steel workers exposure to lowest dose, the risk of hypertension of steel workers exposure to 82-94 and 95-107 dB(A) in group was 1. 81(95%CI 1. 31-2. 52) times and 2. 60(95%CI 1. 84-3. 68) times. CONCLUSION: There is a non-linear dose-response relationship between cumulative noise exposure and hypertension.

Highly Thermally Conductive Polyimide Composites via Constructing 3D Networks.

Easy and high efficient methods are in great demand to obtain polyimide (PI) composites with high thermal conductivity in the electronic packaging field. In this work, PI/boron nitride (BN) composites with high thermal conductivity are easily fabricated. Tightly connected and well-arranged BN platelets construct effective 3D thermally conductive networks in the PI matrix upon hot pressing, after BN platelets are coated on the surface of PI granules by the help of a kind of PI adhesive. The thermal conductivity of the PI/BN composites reaches as high as 4.47 W mK-1 at a low BN loading of 20 vol%, showing an enhancement of 2099%, compared to pure PI. Such enhancement of the thermal conductivity is the highest compared with the results in the open literature. Our work is a good example that utilized the sufficient physical connection (aggregates) of thermally conductive fillers to significantly promote the thermal conductivity of polymer composites.

Comparisons of Therapeutic Efficacy and Safety of Solifenacin versus Tolterodine in Patients with Overactive Bladder: A Meta-Analysis.

OBJECTIVES: This meta-analysis was to assess solifenacin and tolterodine in patients with overactive bladder. METHODS: We searched PubMed, the Cochrane Library, EMBASE, CNKI, Wanfang, and ClinicalTrials.gov databases for randomized controlled trials (RCTs). The efficacy endpoint was daily micturition frequency, daily urgency episodes, daily incontinence episodes, and micturition volume per voiding. The safety endpoint was the incidence of the rate of major bleeding, intracranial bleeding, and gastrointestinal bleeding. RESULTS: Seven RCTs met the inclusion criteria and 1,318 patients were included. The meta-analysis showed that, compared with tolterodine, solifenacin was associated with similar daily micturition frequency, daily urgency episodes, daily incontinence episode, and micturition volume per voiding at 8 and 12 weeks of follow-up. Moreover, no significant difference was obtained in the incidence of dry mouth between solifenacin and tolterodine at 8 and 12 weeks of follow-up. However, tolterodine decreased the constipation rate at 12 weeks compared with solifenacin. CONCLUSION: Solifenacin and tolterodine yielded similar results on daily micturition frequency, daily urgency episodes, daily incontinence episodes, micturition volume per voiding, and the incidence of dry mouth. However, tolterodine can decrease the constipation rate at 12 weeks compared with solifenacin.

Preparation of the Sodium Alginate-g-(Polyacrylic Acid-co-Allyltrimethylammonium Chloride) Polyampholytic Superabsorbent Polymer and Its Dye Adsorption Property.

A polyampholytic superabsorbent polymer (PASAP), sodium alginate-g-(polyacrylic acid-co-allyltrimethylammonium chloride) (SA-g-(PAA-co-PTM)), was prepared by free-radical graft copolymerization and characterized. The polymer exhibited pH-dependent swelling behaviors with extremely high swelling ratios, and was saline tolerant. The dye adsorption properties of SA-g-(PAA-co-PTM) were investigated using methylene blue (MB) as a cationic dye model. It was found that its dye adsorption capacity was significantly affected by the TM content in PASAP and pH of dye solution. The dye adsorption kinetics and isotherm obey the pseudo-second-order kinetic model and the Langmuir isotherm model, respectively, and the adsorption process is chemisorption in nature. In addition, SA-g-(PAA-co-PTM) exhibited high MB adsorption capacities in a wide pH range and reusability in at least five adsorption-desorption cycles, indicating its great application potentials as the adsorbent for dye removals from effluents.

Salmon protein gel enhancement for dysphagia diets: Konjac glucomannan and composite emulsions as texture modifiers.

The growing prevalence of dysphagia among the aging population presents a significant challenge. Many highly nutritious foods, like salmon, are often unsuitable for the elderly due to their firm texture when heated. To address this concern, a combination of salmon myofibrillar protein (SMP), Konjac glucomannan (KGM), and different emulsion fillers-such as oil droplets, octenyl succinic anhydride (OSA)-modified potato starch emulsion, and high methoxylated pectin (HMP) emulsions-was selected to enhance the network of salmon protein gels with the aims to create potential applications as dysphagia-friendly foods. The International Dysphagia Dietary Standardization Initiative (IDDSI) test indicated that all gel samples were classified as level 5. The OSA-SMP-KGM gel exhibited notably higher cohesiveness (P < 0.05), reduced adhesion, and enhanced mouthfeel. The OSA-SMP-KGM gel exhibited a smooth surface and excellent water retention (92.4 %), rendering it suitable for individuals with swallowing difficulties, particularly those prone to experiencing dry mouth. The yield stress of OSA-SMP-KGM gel was 594.14 Pa and stable structure was maintained during chewing and swallowing (γe/γv = 62.5). This study serves as a valuable reference for developing salmon-based products that are not only highly nutritious but also fulfill the criteria for a desirable swallowing texture.

Epidemiological Features of Infectious Diseases in Children and Adolescents: A Population-Based Observational Study in Shandong Province, China, 2013-2017.

BACKGROUND: The arrival of the big-data era provides us with a chance to elaborate the spectrum and epidemiological characteristics of infectious diseases in children and adolescents aged 0-18 years in the pre-COVID-19 pandemic era. METHODS: We collected data on infectious diseases in 891,981 participants from the Cheeloo Lifespan Electronic Health Research Data-library. The incidence density of each infection was calculated and stratified by age and region. The annual percentage change (APC) in incidence was estimated by logarithmic linear regression. RESULTS: A total of 18,183 cases of 78 infections were diagnosed, with an overall incidence density of 626.33 per 100,000 person-years (PY). Of these, 6825 cases of 50 non-notifiable infectious diseases were identified. Children aged 1-3 years had the highest incidence of infections. The overall incidence revealed a significant increasing trend from 2013 to 2017 (APC = 36.9%, p < 0.05). Hand, foot, and mouth disease, pneumonia, and influenza were the three most common diseases. The incidence of pneumonia, rubella, scarlet fever, zoster, molluscum contagiosum, and syphilis increased significantly during the study period (all p < 0.05). Taian, Binzhou, and Weihai had the highest incidence of all other cities. The incidence of gastrointestinal infections increased markedly in the eastern coastal regions. CONCLUSIONS: More stress should be placed on a number of non-notifiable infectious diseases with a high burden and a significant increasing trend. Age-based and regional targeting efforts are needed to prevent and contain infectious diseases among children and adolescents.

Primary cilia mediate skeletogenic BMP and Hedgehog signaling in heterotopic ossification.

Heterotopic ossification (HO), defined as the formation of extraskeletal bone in muscle and soft tissues, is a diverse pathological process caused by either genetic mutations or inciting trauma. Fibrodysplasia ossificans progressiva (FOP) is a genetic form of HO caused by mutations in the bone morphogenetic protein (BMP) type I receptor gene activin A receptor type 1 (ACVR1). These mutations make ACVR1 hypersensitive to BMP and responsive to activin A. Hedgehog (Hh) signaling also contributes to HO development. However, the exact pathophysiology of how skeletogenic cells contribute to endochondral ossification in FOP remains unknown. Here, we showed that the wild-type or FOP-mutant ACVR1 localized in the cilia of stem cells from human exfoliated deciduous teeth with key FOP signaling components, including activin A receptor type 2A/2B, SMAD family member 1/5, and FK506-binding protein 12kD. Cilia suppression by deletion of intraflagellar transport 88 or ADP ribosylation factor like GTPase 3 effectively inhibited pathological BMP and Hh signaling, subdued aberrant chondro-osteogenic differentiation in primary mouse or human FOP cells, and diminished in vivo extraskeletal ossification in Acvr1Q207D, Sox2-Cre; Acvr1R206H/+ FOP mice and in burn tenotomy-treated wild-type mice. Our results provide a rationale for early and localized suppression of cilia in affected tissues after injury as a therapeutic strategy against either genetic or acquired HO.

Microfluidics-assisted electrospinning of aligned nanofibers for modeling intestine barriers.

During electrospinning, the fibers deposited on the collector are usually randomly oriented in a disordered form. Researchers hope to generate periodic structures to expand the application of electrospinning, including improving the sensing properties of electronic and photonic devices, improving the mechanical properties of solid polymer composites and directional growth of human tissues. Here, we propose a technique to control the preparation of aligned foodborne nanofibers by placing dielectric polymers on microfluidic devices, which does not require the use of metal collectors. This study was conducted by introduced PEDOT:PSS polymer as a ground collector to prepare aligned foodborne nanofibers directly on the microfluidic platform. The fluidity of the electrolytic polymer collector makes it possible to shape the grounding collector according to the shape of the microcavity, thus forming a space adjustable nanofiber membrane with a controllable body. The simplicity of dismantling the collector also enables it extremely simple to obtain a complete electrospun fiber membrane without any additional steps. In addition, nanofibers can be easily stacked into a multi-layer structure with controllable hierarchical structures. The Caco-2 cells that grow on the device formed a compact intestinal epithelial layer that continuously expresses the tightly bound protein ZO-1. This intestinal barrier, which selectively filters small molecules, has a higher level of TEER, reproducing intestinal filtration functions similar to those of in vivo models. This method provides new opportunities for the design and manufacture of various tissue scaffolds, photonic and electronic sensors.

A Rapid, Visible, and Highly Sensitive Method for Recognizing and Distinguishing Invasive Fungal Infections via CCP-FRET Technology.

Invasive fungal infection (IFI) is one of the leading causes of death in the intensive care unit (ICU) due to its high morbidity and mortality among immunocompromised patients. Early diagnosis of IFI is typically infeasible because of the lack of clinical signs and symptoms. By virtue of the cationic conjugated polymer-based fluorescence resonance energy transfer (CCP-FRET) technology, we develop a rapid, visible, simple, and sensitive method for simultaneous detection and discrimination of three types of pathogens, including Candida albicans (C. albicans), Klebsiella pneumoniae (K. pneumoniae), and Cryptococcus neoformans (C. neoformans). The CCP-FRET system contains a CCP fluorescent probe and pathogen-specific DNA labeled with fluorescent dyes. These two components spontaneously self-assemble into the complex under electrostatic attraction, resulting in an efficient FRET from CCP to fluorescent dyes when irradiated with a 380 nm ultraviolet (UV) light. The CCP-FRET method can specifically identify the DNA molecules that are extracted from culture pathogen strains or blood samples via PCR and single base extension (SBE) reactions, without any cross-reactions on the DNA of nonspecific strains. In particular, the sensitivity of this method is down to 0.03125 ng, which is ten times higher than that of real-time PCR. We further evaluate its detection efficiency by testing 15 blood samples from neonatal patients who suffer from pathogen infections, in which some of them have undergone antipathogen treatments. Using the CCP-FRET method, 33.3% (5/15) of samples tested positive for C. albicans and/or K. pneumoniae infections, whereas no pathogen DNAs are recognized with real-time PCR, despite using the same primers. Interestingly, the CCP-FRET method can output unique fluorescent color as well as RGB patterns to different types of pathogen infections, by which the infection type can be conveniently determined. Collectively, the CCP-FRET method is a sensitive and reliable detection platform for rapid identification of fungal and bacterial multiple infections, holding great promise for uses in clinical testing.

Bleomycin: A novel osteogenesis inhibitor of dental follicle cells via a TGF-ß1/SMAD7/RUNX2 pathway.

BACKGROUND AND PURPOSE: Tooth eruption is a complicated process regulated by the dental follicles (DF). Our recent study discovered that tooth eruption was inhibited upon injection of bleomycin into DF. However, the mechanisms were unknown. EXPERIMENTAL APPROACH: Human dental follicle cells (hDFCs) were treated by bleomycin or exogenous TGF-ß1 or transfected by plasmids loading SMAD7 or shRNA targeting SMAD7, followed by osteogenesis induction assay and signalling analysis. Human fresh DF tissues and Wistar rats were used to further confirm bleomycin function. KEY RESULTS: Bleomycin decreased expression of RUNX2 and osteogenic genes in hDFCs, reducing osteogenic capacity. TGF-ß1 expression was up-regulated in bleomycin-treated hDFCs. The effects of exogenous TGF-ß1 were similar to those of bleomycin in hDFCs. Additionally, compared to SMAD2/3, SMAD7 expression increased more in bleomycin- or TGF-ß1-treated hDFCs. Overexpression of SMAD7 likewise significantly decreased RUNX2 expression and osteogenic capacity of hDFCs. Knockdown of SMAD7 markedly attenuated the inhibitory effects of bleomycin and TGF-ß1 on osteogenic capacity and RUNX2 expression of hDFCs. Most importantly, changes in TGF-ß1, SMAD7, and RUNX2 expressions were similar in the DF of rats and humans treated with bleomycin. CONCLUSION AND IMPLICATIONS: SMAD7 was a negative regulator of osteogenic differentiation in DFCs through suppressing RUNX2 expression. Bleomycin or TGF-ß1 inhibited osteogenic differentiation of DFCs via a TGF-ß1/SMAD7/RUNX2 pathway. Our findings might be beneficial for enhancing the osteogenic activity of DFCs or inhibiting the eruption of undesirable teeth.

Function of c-type cytochromes of Shewanella xiamenensis in enhanced anaerobic bioreduction of Cr(VI) by graphene oxide and graphene oxide/polyvinyl alcohol films.

Graphene-based materials have been demonstrated to facilitate electron extracellular transfer (EET) of Shewanella. In this study, compared to group lacking graphene oxide (GO)-based materials, GO films-added group and graphene oxide/polyvinyl alcohol (GO/PVA) film-added group delivered 2.67- and 3.13-fold increases in the Cr(VI) reduction by Shewanella xiamenensis, respectively. The whole reduction process could be divided into three stages, including microbial Cr(VI) reduction and GO reduction stage, microbial GO reduction stage and microbial Cr(VI) reduction mediated by reduced graphene oxide (rGO) stage. Moreover, gene analysis revealed that addition of GO and GO/PVA films stimulated overexpression of several c-type cytochrome (c-Cyts) genes, including mtrA, mtrB, mtrC, mtrD, mtrE, mtrF, omcA, petC and SO-4047. Specifically, appreciable Cr(VI) reduction by the strains that overexpressed mtrA, mtrB, mtrC, mtrD, mtrE, mtrF and omcA further confirmed that overexpression of c-Cyts genes indeed enhanced the efficiency of Cr(VI) reduction. Based on these results, the specific function of every c-Cyt was clearly found in Cr(VI) reduction by the induction of GO-based materials. Our finding has disclosed a synergetic mechanism stimulated by GO-based materials to enhance Cr(VI) bioreduction that was not only mediated through the modification of material but also upregulated the expression of functional genes.

Effects of bleomycin on tooth eruption: a novel potential application.

There are many kinds of potentially undesirable teeth. At present, surgical extraction is the most efficient way to eliminate these teeth, but it's very complex and invasive. In this study, we investigated the effects of bleomycin (BLM) on dental follicle and tooth eruption as a potential conservative therapy for undesirable teeth. Our data showed that local injection of 0.2 U/kg BLM had no significant effects on tooth eruption compared to the control group in Wistar rats. With higher dose of BLM (0.5 or 2 U/kg), the eruption of treated teeth was interrupted and their root formation failed until 4 weeks postnatal without significant systemic toxicity. Additionally, those effects were not depending on the toxicity of overdose evidenced by TUNEL assay. In summary, injecting BLM into dental follicle at an early stage could interrupt tooth development and eruption, and may prevent the potentially clinical problems resulting from undesirable teeth instead of surgical removal.

Universal existence of fluorescent carbon dots in beer and assessment of their potential toxicity.

Nanosized materials may produce adverse physiological effects or potential health risks due to their unique physical and chemical properties. Herein, the universal presence of fluorescent carbon dots (CDs) in commercial beers was confirmed through a systematic survey. The beer CDs were roughly spherically shaped in appearance and emitted bright blue fluorescence under ultraviolet light with quantum yields (QYs) ranging from 1.42% to 3.92%. Furthermore, digestion, biodistribution, and cytotoxicity assessments of CDs from Snow beer were conducted as an example. The CDs were significantly quenched during in vitro digestion. The dynamic distribution of CDs in mice showed that they easily accumulated in the intestine and liver, and more importantly, the beer CDs were found in the brain, which indicated that they were able to cross the blood-brain barrier. Acute toxicity of the beer CDs was evaluated using BALB/c mice, and the results revealed that the biochemical parameters of mice after administration of a single dose of 2 g kg-1 body weight were almost same as those of the control groups. Histological analysis showed no obvious organ damage in the tested mice. The in vitro results indicated that CDs dispersed onto both the cell membrane and the cytoplasm of MC3T3-E1 cells, alter the cell cycle progression, and caused cell apoptosis at high doses. This work reports the potential risk of CDs in beer and provides valuable information regarding CDs in food.

FEM analysis in excellent cushion characteristic of ostrich (Struthio camelus) toe pads.

African ostrich (Struthio camelus) is the largest and fastest extent bipedal animal. The ostrich mainly relies on the 3rd toe to support the entire body under high-speed motion. The short and severe impact concentrated on the limited area would produce tremendous momentary internal stress and strain, which may contribute to the phalanges disloaction, soft tissue damage and the like. The vibration and excessive negative acceleration caused by the ground reaction force also affect the stability of the touching process. Therefore, ostrich toe pads are required to have excellent cushion characteristics. However, current studies often explains the cushion properties by analyzing the macro-microscopic structure of the pad organism, and there is a paucity of research on its biomechanical behaviour. Consequently, from the perspective of multi-layer structure and biomaterial assembly, this study aims to explain the biomechanical characteristics of the ostrich toe pads by FEM (Finite Element Method) analysis. Based on results, we deem that the ostrich toe pad could absorb energy and reduce vibration effectively. Firstly, the multi-layer structure of the pads make the stress and strain decay from outside to inside. Secondly, the minimal response frequency of the pad is 164.22 Hz, making it effectively avoid resonance phenomenon. Finally, the composite material model has the best performance in decreasing the negative acceleration peak value, the impact force peak value and the maximal equivalent stress value at velocities of 0.669 m/s and 1.339 m/s. These results help to further understand the buffer mechanism of the ostrich toe pad, and also have important inter-species reference value for the pathogenesis of human foot soft tissue injury.

Study of the corrosion behavior of Aspergillus niger on 7075-T6 aluminum alloy in a high salinity environment.

In this study, the corrosion behavior of 7075-T6 aluminum alloy in a high salinity environment containing Aspergillus niger was investigated using high-performance liquid chromatography tandem mass spectrometry, gas chromatography, surface analysis and electrochemical measurement. Results demonstrated that uniform and localized corrosion rates of the alloy in the presence of A. niger were approximately 3.7 and 22.4 times, respectively, of that in the absence A. niger. This higher corrosion rate was attributed to accelerated anode and cathode reactions from the actions of A. niger biofilm. Additionally, organic acid corrosion caused by the presence of A. niger was confirmed to be the main cause for the corrosion of aluminum alloy.

Elevated ATF4 Expression in Odontogenic Keratocysts Epithelia: Potential Involvement in Tissue Hypoxia and Stromal M2 Macrophage Infiltration.

The aim of this study was to investigate the expression of the activating transcription factor 4 (ATF4) in odontogenic keratocysts (OKC), its association with hypoxia and M2-polarized macrophages infiltration, and its potential relationships with angiogenesis in OKC. The expression of ATF4, hypoxia-inducible factor 1α (HIF-1α), macrophage colony-stimulating factor (M-CSF), and receptor activator of nuclear factor κ-B ligand (RANKL) in OKC samples and normal oral mucosa (OM) was detected by immunohistochemistry. Meanwhile, microvessel density (MVD) was measured using antibody against CD31. M2-polarized macrophages were identified using double-staining for CD68+ and CD163+. The correlations of ATF4 with HIF-1α, M-CSF, and M2-polarized macrophages infiltration were determined by Spearman's rank correlation test and hierarchical clustering. Human immortalized oral epithelial cells (HIOECs) were used in in vitro experiments. Our data showed that the expression of HIF-1α, ATF4, and M-CSF was significantly upregulated in the epithelium of OKC when compared with the OM. The expression of ATF4 was positively correlated with that of HIF-1α, M-CSF, MVD, and M2-polarized macrophages infiltration. Elevated expression of ATF4 in the epithelial lining of OKC may facilitate the M2 macrophages infiltration in response to hypoxia, leading to the development of OKC.

Activin A amplifies dysregulated BMP signaling and induces chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP).

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP), is caused by mutations in the type I BMP receptor ACVR1 that lead to increased activation of the BMP-pSmad1/5/8 signaling pathway. Recent findings suggest that Activin A (Act A) promiscuously stimulates the bone morphogenetic protein (BMP) signaling pathway in vitro and mediates heterotopic ossification (HO) in mouse models of FOP, but primary data from FOP patient cells are lacking. OBJECTIVE: To examine BMP-pSmad1/5/8 pathway signaling and chondro-osseous differentiation in response to endogenous and exogenous Act A in primary connective tissue progenitor cells [CTPCs; also known as stem cells from human exfoliated deciduous teeth (SHED) cells] from patients with FOP. These cells express the common FOP mutation, ACVR1 (R206H). RESULTS: We found that Act A amplifies dysregulated BMP pathway signaling in human FOP primary CTPCs cells through the Smad1/5/8 pathway and induces chondro-osseous differentiation. Amplification of BMP-pSmad1/5/8 signaling was inhibited by Follistatin and by a neutralizing antibody to Activin A. The increased basal pSmad1/5/8 activity, as well as the hypoxia-induced stimulation of FOP CTPCs cells, were BMP4 and Act A independent. Importantly, either BMP4 or Act A stimulated pSmad1/5/8 pathway signaling but BMP4 signaling was not dependent on Activin A and vice versa. Circulating plasma levels of Act A or BMP4 are similar in controls compared to FOP patients, and suggest the potential for an autocrine or paracrine route for pathological signaling. CONCLUSIONS: The mutated FOP receptor [ACVR1 (R206H)] is hypersensitive to BMP4 and uniquely sensitive (compared to the wild type receptor) to Act A. Both canonical and non-canonical ligands have a synergistic effect on BMP-pSmad1/5/8 signaling in FOP CTPCs and may cooperate to alter the threshold for HO in FOP. Our findings in primary human FOP CTPCs have important implications for the design of clinical trials to inhibit dysregulated BMP pathway signaling in humans who have FOP.