Age-related mitophagy regulates orthodontic tooth movement by affecting PDLSCs mitochondrial function and RANKL/OPG.

A thorough comprehension of age-related variances in orthodontic tooth movement (OTM) and bone remodeling response to mechanical force holds significant implications for enhancing orthodontic treatment. Mitophagy plays a crucial role in bone metabolism and various age-related diseases. However, the impact of mitophagy on the bone remodeling process during OTM remains elusive. Using adolescent (6 weeks old) and adult (12 months old) rats, we established OTM models and observed that orthodontic force increased the expression of the mitophagy proteins PTEN-induced putative kinase 1 (PINK1) and Parkin, as well as the number of tartrate-resistant acid phosphatase-positive osteoclasts and osteocalcin-positive osteoblasts. These biological changes were found to be age-related. In vitro, compression force loading promoted PINK1/Parkin-dependent mitophagy in periodontal ligament stem cells (PDLSCs) derived from adolescents (12-16 years old) and adults (25-35 years old). Furthermore, adult PDLSCs exhibited lower levels of mitophagy, impaired mitochondrial function, and a decreased ratio of RANKL/OPG compared to young PDLSCs after compression. Transfection of siRNA confirmed that inhibition of mitophagy in PDLSC resulted in decreased mitochondrial function and reduced RANKL/OPG ratio. Application of mitophagy inducer Urolithin A enhanced bone remodeling and accelerated OTM in rats, while the mitophagy inhibitor Mdivi-1 had the opposite effect. These findings indicate that force-stimulated PDLSC mitophagy contributes to alveolar bone remodeling during OTM, and age-related impairment of mitophagy negatively impacts the PDLSC response to mechanical stimulus. Our findings enhance the understanding of mitochondrial mechanotransduction and offer new targets to tackle current clinical challenges in orthodontic therapy.

Combination of sequencing batch reactor activated sludge process with sludge lysis using thermophilic bacterial community for minimizing excess sludge.

Sludge reduction is a major challenge in biological wastewater treatment. Hydrolytic enzymes secreted by thermophilic bacteria can lyse sludge and thus achieve sludge reduction, and the indigenous thermophilic community in sludge can lyse sludge more effectively. In this study, the feasibility of combining a sludge lysis reactor based on thermophilic bacteria community (LTBC reactor, 75 °C) with a conventional sequencing batch activated sludge reactor (SBR) for sludge reduction (i.e., LTBC-SBR process) was systematically investigated first time. The effect of lysed sludge returning to the biochemical tank on pollutant removal efficiency, sludge flocculation, sludge settling, and microbial community and function of the LTBC-SBR process was studied. In the LTBC1-SBR process, a sludge growth rate of 0.71 g TSS/day was observed when the lysed sludge reflux ratio (LRR) was 1, and the sludge generation was reduced by 81.5% compared to the conventional SBR reactor. In the LTBC1-SBR process, the removal efficiencies of chemical oxygen demand and total nitrogen were 94.0% and 80.5%, respectively. There was no significant difference in the sludge volume index from the SBR to the LTBC1-SBR stage, however, the effluent suspended solids concentration increased from 35.2 ± 2.1 mg/L to 80.1 ± 5.3 mg/L. This was attributed to the reflux of sludge lysate. In addition, the changes in extracellular polymers content and composition resulted in poor sludge flocculation performance. Heterotrophic bacteria associated with Actinobacteria and Patescibacteria enriched in LTBC1-SBR with relative abundance of 28.51 ± 1.25% and 20.01 ± 1.21%, respectively, which decomposed the macromolecules in the refluxed lysed sludge and contributed to the sludge reduction. Furthermore, due to the inhibition of nitrite-oxidizing bacteria, the nitrite concentration in the effluent of the LTBC1-SBR system reached 4.7 ± 1.1 mg/L, and part of the denitrification process was achieved by short-cut nitrification and simultaneous denitrification. These results indicate that in-situ sludge reduction technology based on lyse sludge lysing by thermophilic community has considerable potential to be widely used in wastewater treatment.

Biomechanical effects of clear aligners with different thicknesses and gingival-margin morphology for appliance design optimization.

INTRODUCTION: The objectives of this study were to investigate the biomechanical effects of clear aligners (CAs) with various thermoplastic material thicknesses and gingival-margin designs for space closure in extraction treatment and to propose a computer-aided procedure to optimize CA design. METHODS: The radiologic and intraoral scanning technology, in vitro mechanical experiment, viscoelastic modeling, and finite element analysis (FEA) were integrated to establish an orthodontic simulation model. Twelve FEA models of CA were created, comprising combinations of 2 kinds of thicknesses (0.75 and 0.50 mm), 2 forms of gingival-margin shape (scalloped and straight), and 3 types of margin height (-2, 0, and 2 mm). In vitro testing was carried out to determine the actual properties of material thickness. RESULTS: A 0.75-mm-thick aligner resulted in greater periodontal ligament (PDL) stress than 0.50 mm, and there was no clear correlation between the control ability of tooth movement and the thickness. For different margin designs, PDL stress at -2 mm height was significantly lower than those with a higher border. Aligners with straight margins had higher stress than the scalloped aligners, whereas the differences were unnoticeable at 2 mm height. The optimized aligner with differential margin designs was recommended on the basis of biomechanical calculations, which facilitated the efficiency and control of tooth movement for multiple teeth. CONCLUSIONS: The effect of material thickness and margin design of CA on the force and movement differed in different teeth. Preferable CA designs of each tooth during different movement stages should be presented personalized under the guidance of precise biomechanics instead of pure morphologic analysis.

Down-Regulating the High Level of 17-Beta-Hydroxysteroid Dehydrogenase 13 Plays a Therapeutic Role for Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and there is no specific drug to treat it. Recent results showed that 17-beta-hydroxysteroid dehydrogenase type 13 (HSD17B13) is associated with liver diseases, but these conclusions are controversial. Here, we showed that HSD17B13 was more highly expressed in the livers of NAFLD patients, and high expression was induced in the livers of murine NAFLD models and cultural hepatocytes treated using various etiologies. The high HSD17B13 expression in the hepatocytes facilitated the progression of NAFLD by directly stabilizing the intracellular lipid drops and by indirectly activating hepatic stellate cells. When HSD17B13 was overexpressed in the liver, it aggravated liver steatosis and fibrosis in mice fed with a high-fat diet, while down-regulated the high expression of HSD17B13 by short hairpin RNAs produced a therapeutic effect in the NAFLD mice. We concluded that high HSD17B13 expression is a good target for the development of drugs to treat NAFLD.

TGF-ß isoforms inhibit hepatitis C virus propagation in transforming growth factor beta/SMAD protein signalling pathway dependent and independent manners.

Transforming growth factor beta (TGF-ß) plays an important role in the viral liver disease progression via controlling viral propagation and mediating inflammation-associated responses. However, the antiviral activities and mechanisms of TGF-ß isoforms, including TGF-ß1, TGF-ß2 and TGF-ß3, remain unclear. Here, we demonstrated that all of the three TGF-ß isoforms were increased in Huh7.5 cells infected by hepatitis C virus (HCV), but in turn, the elevated TGF-ß isoforms could inhibit HCV propagation with different potency in infectious HCV cell culture system. TGF-ß isoforms suppressed HCV propagation through interrupting several different stages in the whole HCV life cycle, including virus entry and intracellular replication, in TGF-ß/SMAD signalling pathway-dependent and TGF-ß/SMAD signalling pathway-independent manners. TGF-ß isoforms showed additional anti-HCV activities when combined with each other. However, the elevated TGF-ß1 and TGF-ß2, not TGF-ß3, could also induce liver fibrosis with a high expression of type I collagen alpha-1 and α-smooth muscle actin in LX-2 cells. Our results showed a new insight into TGF-ß isoforms in the HCV-related liver disease progression.

Rspo1-LGR4 axis in BMSCs protects bone against radiation-induced injury through the mTOR-dependent autophagy pathway.

While mesenchymal stem cells (MSCs) have been widely used to repair radiation-induced bone damage, the molecular mechanism underlying the effects of MSCs in the maintenance of bone homeostasis under radiation stress remains largely unknown. In this study, the role and mechanisms of R-spondin 1 (Rspo1)-leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) axis on the initiation of self-defense of bone mesenchymal stem cells (BMSCs) and maintenance of bone homeostasis under radiation stress were investigated. Interestingly, radiation increased levels of Rspo1 and LGR4 in BMSCs. siRNA knockdown of Rspo1 or LGR4 aggravated radiation-induced impairment of self-renewal ability and osteogenic differentiation potential of BMSCs. However, exogenous Rspo1 significantly attenuated radiation-induced depletion of BMSCs, and promoted the lineage shift towards osteoblasts. This alteration was associated with the reversal of mammalian target of rapamycin (mTOR) activation and autophagy decrement. Pharmacological and genetic blockade of autophagy attenuated the radio-protective effects of Rspo1, rendering BMSCs more vulnerable to radiation-induced injury. Then bone radiation injury was induced in C57BL6J mice to further determine the radio-protective effects of Rspo1. In mice, administration of Rspo1 recombinant protein alleviated radiation-induced bone loss. Our results uncover that Rspo1-LGR4-mTOR-autophagy axis are key mechanisms by which BMSCs initiate self-defense against radiation and maintain bone homeostasis. Targeting Rspo1-LGR4 may provide a novel strategy for the intervention of radiation-induced bone damage.

Raistrickindole A, an Anti-HCV Oxazinoindole Alkaloid from Penicillium raistrickii IMB17-034.

Raistrickindole A (1), a new indole diketopiperazine alkaloid containing an unusual pyrazino[1',2':2,3][1,2]oxazino[6,5- b]indole tetraheterocyclic ring system, a new benzodiazepine derivative, raistrickin (2), and the known haenamindole (3) and sclerotigenin (4) were isolated from the marine-derived fungus Penicillium raistrickii IMB17-034. Their structures were elucidated by extensive spectroscopic analyses and TDDFT calculations of the NMR and ECD data. Compounds 1 and 2 showed inhibitory activities against the hepatitis C virus.

Transcriptome profiling analysis of the intoxication response in midgut tissue of Agrotis ipsilon larvae to Bacillus thuringiensis Vip3Aa protoxin.

Vip insecticidal proteins are produced by Bacillus thuringiensis (Bt) during its vegetative growth phase. In the present study, Vip3Aa11 and Vip3Aa39 proteins were investigated. These two proteins present 39 amino acid differential sites and they shared 95.06% amino acid sequence similarity. They are effective against some Lepidoptera insect larvae. In a previous study, using artificial diet bioassays, we estimated the LC50 of Vip3Aa11 and Vip3Aa39 strains against Agrotis ipsilon larvae were 73.41 µg/mL (with 95% confidence interval of 2.34-11.19) and 5.43 µg/mL (with 95% confidence interval of 43.20-115.03), respectively. To investigate the response of Agrotis ipsilon transcriptome in defending against Vip3Aa11 and Vip3Aa39 toxins, we performed high-throughput RNA-sequencing on cDNA generated from the midguts of Agrotis ipsilon larvae that consumed a control diet (CK-M-A), Vip3Aa11 (Vip3Aa11-M-A) and Vip3Aa39 (Vip3Aa39-M-A) proteins. We generated about 98.87 Gb bases in total on BGISEQ-500 sequencing platform. After assembling all samples together and filtering the abundance, we got 51,887 unigenes, the total length, average length, N50 and GC content of unigenes are 64,523,651 bp, 1243 bp, 2330 bp and 41.81% respectively. We revealed 558 midgut genes differential expressed in Vip3Aa11-M-A and 65 midgut genes differentially expressed in Vip3Aa39-M-A. The differentially expressed genes were enriched for serine proteases and potential Bt Vip toxin midgut receptor genes. Eleven serine proteases related genes and 13 Bt toxin potential receptor genes with differential expression were found. Based on transcriptome profiling, we focused on validation the sensitivity of these two Vip3Aa proteins to trypsin and their binding properties to Agrotis ipsilon midgut BBMV (Brush Border Membrane Vesicles). The results show that the sensitivity of the two proteins to trypsin is similar. Binding experiments revealed that both proteins can bind to Agrotis ipsilon midgut BBMV, and there is a competitive binding between them. This transcriptome dataset provided a comprehensive sequence resource of Agrotis ipsilon and provides a foundation for comparative studies with other species of insects.

miR-203 inhibits cell proliferation and promotes cisplatin induced cell death in tongue squamous cancer.

Oral squamous cell carcinoma (OSCC) is one of the most common types of the head and neck cancer. Chemo resistance of OSCC has been identified as a substantial therapeutic hurdle. In this study, we analyzed the role of miR-203 in the OSCC and its effects on cisplatin-induced cell death in an OSCC cell line, Tca8113. There was a significant decrease of miR-203 expression in OSCC samples, compared with the adjacent normal, non-cancerous tissue. After 3 days cisplatin treatment, the survived Tca8113 cells had a lower expression of miR-203 than that in the untreated control group. In contrast, PIK3CA showed an inverse expression in cancer and cisplatin survived Tca8113 cells. Transfection of Tca8113 cells with miR-203 mimics greatly reduced PIK3CA expression and Akt activation. Furthermore, miR-203 repressed PIK3CA expression through targeting the 3'UTR. Restoration of miR-203 not only suppressed cell proliferation, but also sensitized cells to cisplatin induced cell apoptosis. This effect was absent in cells that were simultaneously treated with PIK3CA RNAi. In summary, these findings suggest miR-203 plays an important role in cisplatin resistance in OSCC, and furthermore delivery of miR-203 analogs may serve as an adjuvant therapy for OSCC.

Abscisic acid, H2O2 and nitric oxide interactions mediated cold-induced S-adenosylmethionine synthetase in Medicago sativa subsp. falcata that confers cold tolerance through up-regulating polyamine oxidation.

S-adenosylmethionine synthetase (SAMS) is the key enzyme catalysing the formation of S-adenosylmethionine (SAM), a precursor of polyamines and ethylene. To investigate the potential role of SAMS in cold tolerance, we isolated MfSAMS1 from the cold-tolerant germplasm Medicago sativa subsp. falcata and analysed the association of SAM-derived polyamines with cold tolerance. The expression of MfSAMS1 in leaves was greatly induced by cold, abscisic acid (ABA), H2O2 and nitric oxide (NO). Our data revealed that ABA, H2O2 and NO interactions mediated the cold-induced MfSAMS1 expression and cold acclimation in falcata. SAM, putrescine, spermidine and spermine levels, ethylene production and polyamine oxidation were sequentially altered in response to cold, indicating that SAMS-derived SAM is preferentially used in polyamine synthesis and homeostasis during cold acclimation. Antioxidant enzyme activities were also induced in response to cold and showed correlation with polyamine oxidation. Overexpression of MfSAMS1 in tobacco resulted in elevated SAM levels, but polyamine levels and ethylene production in the transgenic plants were not significantly changed. Compared to the wild type, transgenic plants had increased levels of apoplastic H2O2, higher transcript levels of genes involved in polyamine synthesis and oxidation, and higher activities of polyamine oxidation and antioxidant enzymes. The results showed that overexpression of MfSAMS1 promoted polyamine synthesis and oxidation, which in turn improved H2 O2 -induced antioxidant protection, as a result enhanced tolerance to freezing and chilling stress in transgenic plants. This is the first report demonstrating that SAMS plays an important role in plant tolerance to cold via up-regulating polyamine oxidation.

Modified Application of the Abdominal Re-Approximation Anchor Device in the Closure of Septic Open Abdomen in a Patient With Class III Obesity.

The Abdominal Re-Approximation Anchor (ABRA®) is a pivotal dynamic wound closure system utilized for achieving primary fascial closure in patients undergoing open abdomen surgeries. However, its efficacy can be hindered in patients with class III obesity due to anatomical complexities and compromised tissue characteristics. Here, we present the unique case of a 25-year-old woman with class III obesity (body mass index (BMI) ≥ 40 kg/m2) who required primary abdominal closure following complications of an ileostomy repair. Traditional placement of the ABRA device was not feasible due to thick subcutaneous tissue layers. Consequently, a modified application of ABRA was decided based on clinical judgment, whereby the ABRA button anchors were strategically placed internally under the subcutaneous tissue instead of externally on the skin surface. The patient completed six intraoperative tightenings of the ABRA device via this novel technique and was treated with washouts over the course of two months until complete resolution was achieved. The presented case demonstrates a successful modification of the ABRA wound closure device to suit an open abdomen patient with class III obesity.

The role of vitamins and nutrients in rosacea.

Rosacea is a common inflammatory skin condition displaying symptoms like flushing, erythema, papules, and pustules. Oral antibiotics, despite long-term adverse effects, are often used due to topical treatment limitations, underscoring the need for cost-effective choices like dietary modifications. Our review investigates the role of vitamins and minerals in rosacea, and provides evidence-based recommendations for supplementation and topical treatment of these nutrients for rosacea. An online search was performed on PubMed, Web of Science, Science Direct, Google Scholar, and ClinicalTrials.gov from 1998 to 2023. Included studies were summarized and assessed for quality and relevance in rosacea management. Varied outcomes emerged concerning the impact of essential vitamins and minerals on rosacea treatment. Vitamin A derivatives, specifically oral isotretinoin, demonstrated significant efficacy, with a 90% reduction in lesions, complete remission in 24% of patients, and marked improvement in 57% of patients. Vitamin B3 derivatives, such as topical 1-methylnicotinamide 0.25% and NADH 1%, improved symptoms in 76.4% (26/34) and 80% of patients, respectively. Outcomes for vitamin D, vitamin C, and zinc supplementation varied across studies. However, zinc sulfate solution 5% significantly reduced acne rosacea severity for patients with 40% and 60% exhibiting a moderate or good response, respectively. Omega-3 fatty acids showed significant improvement in alleviating xerophthalmia in 64% of patients with ocular rosacea. Vitamins and minerals hold potential in managing rosacea symptoms, offering a safe and cost-effective alternative or adjunctive treatment option. Currently, there are no established recommendations regarding their supplementation for rosacea. Studies assessing serum levels of vitamins and minerals in relation to rosacea are warranted, as this avenue holds potential for future advancements in the field.

The palliative role of lasers in the treatment of melanoma.

Melanoma, accounting for a significant proportion of skin cancer-related deaths, has variable survival outcomes based on the stage at diagnosis and treatment efficacy. Traditional treatments, while effective, pose risks of scarring and systemic side effects. Laser therapy offers an emerging non-surgical alternative, with CO2 lasers particularly showing promise in palliative care.A comprehensive search was conducted using PubMed, focusing on laser therapy for melanoma treatment. The search included studies on both stand-alone and adjunct laser therapies, with inclusion criteria requiring peer-reviewed articles detailing treatment outcomes for primary, recurrent, or metastatic melanoma.The literature shows that laser therapy for melanoma falls into four major types when categorized by laser medium: solid-state, diode, pulse-dye, and gas (CO2). Data on solid-state lasers for melanoma are limited and their use remains controversial. However, one study with high-energy pulsed neodymium lasers reported a 5-year survival of 82.9% with minimal adverse effects for primary melanoma. CO2 laser therapy has been effective for palliative treatment, with one study showing 54.8% of patients with recurrent melanoma surviving 5.4 years post-ablation. For metastatic melanoma, numerous studies have shown that CO2 laser therapy can provide symptomatic relief and disease control. Combination therapies using lasers and immune-based therapies have demonstrated enhanced outcomes and immune activation, highlighting the potential of laser therapies in melanoma management.While traditional treatments remain the standard for primary melanoma, laser therapies, particularly CO2 laser ablation, show substantial promise in palliative care for metastatic melanoma. Careful patient selection and assessment are crucial for achieving positive outcomes.

Hydrogen peroxide and nitric oxide mediated cold- and dehydration-induced myo-inositol phosphate synthase that confers multiple resistances to abiotic stresses.

myo-Inositol phosphate synthase (MIPS) is the key enzyme of myo-inositol synthesis, which is a central molecule required for cell metabolism and plant growth as a precursor to a large variety of compounds. A full-length fragment of MfMIPS1 cDNA was cloned from Medicago falcata that is more cold-tolerant than Medicago sativa. While MfMIPS1 transcript was induced in response to cold, dehydration and salt stress, MIPS transcript and myo-inositol were maintained longer and at a higher level in M. falcata than in M. sativa during cold acclimation at 5 °C. MfMIPS1 transcript was induced by hydrogen peroxide (H(2) O(2)) and nitric oxide (NO), but was not responsive to abscisic acid (ABA). Pharmacological experiments revealed that H(2) O(2) and NO are involved in the regulation of MfMIPS1 expression by cold and dehydration, but not by salt. Overexpression of MfMIPS1 in tobacco increased the MIPS activity and levels of myo-inositol, galactinol and raffinose, resulting in enhanced resistance to chilling, drought and salt stresses in transgenic tobacco plants. It is suggested that MfMIPS1 is induced by diverse environmental factors and confers resistance to various abiotic stresses.

Nitric oxide mediates cold- and dehydration-induced expression of a novel MfHyPRP that confers tolerance to abiotic stress.

Hybrid proline-rich proteins (HyPRPs) are cell wall-localized proteins, and are frequently responsive to environmental stresses. The coding sequence of a HyPRP cDNA was isolated from Medicago falcata, a forage crop that shows cold and drought tolerance. The predicted MfHyPRP contains a proline-rich domain at N-terminus after the signal peptide and a conserved eight-cysteine motif at the C-terminus. Higher level of MfHyPRP transcript was observed in leaves than in stems and roots under control conditions, while more MfHyPRP transcript was induced in leaves and stems than in roots after cold treatment. Levels of MfHyPRP transcript and MfHyPRP protein in leaves were induced by cold, dehydration, abscisic acid (ABA), hydrogen peroxide (H2 O2) and nitric oxide (NO), but not responsive to salt stress. The cold- or dehydration-induced expression of MfHyPRP was blocked by scavenger of NO, but not affected by inhibitor of ABA biosynthesis or scavenger of H2 O2. The results indicated that NO, but not ABA and H2 O2, was essential in the cold- and dehydration-induced expression of MfHyPRP. Overexpression of MfHyPRP in tobacco led to increased tolerance to freezing, chilling and osmotic stress as well as methyl viologen-induced oxidative stress. The increased cold and osmotic stress tolerance was proposed to be associated with improved protection against oxidative damages. It is suggested that NO mediates cold- and dehydration-induced expression of MfHyPRP that confers tolerance to abiotic stress.

Exploring Motivations Regarding Dietary Intake Intentions in Gestational Diabetes Mellitus: Development and Validation of a Questionnaire.

Purpose: The maintenance of stable blood glucose levels in gestational diabetes patients depends on their ability to make scientific decisions. Decision-making ability is influenced by factors such as preferences, knowledge acquisition, and risk perceptions. At present, problems such as irrational dietary structure, difficulties in decision-making, and poor adherence still exist in clinical practice. The key to guiding gestational diabetes patients in developing their scientific decision-making abilities lies in identifying the weak key points that affect their decision-making abilities. There is a lack of validated tools to assess these patients' perceptions of dietary intake. In this study, we aimed to develop and validate the Dietary Intake Perceived Motivation Questionnaire for Patients with Gestational Diabetes Mellitus with the purpose of accurately identifying the obstacles encountered by gestational diabetes mellitus patients in the development of their scientific decision-making abilities. Patients and Methods: In this study, 304 individuals with gestational diabetes were recruited from a public hospital in Wuxi, China. The questionnaire was developed in 3 stages, consisting of questionnaire development, a pilot study, and a formal test, and the validity and reliability of the questionnaire were tested and confirmed. The content validity index and exploratory factor analysis were completed by expert correspondence to indicate the validity of the content and structure. In addition, Cronbach's α was used to evaluate the internal consistency of each item of the questionnaire, and Spearman-Brown analysis was used to analyze the split-half reliability. In addition to the questionnaire, the study participants were asked to complete a general information questionnaire that included items on various demographic factors such as age, week of gestation, and mode of conception. Results: The questionnaire was validated through principal component analysis, resulting in a 31-item questionnaire named the Dietary Intake Perceived Motivation Questionnaire for Patients with Gestational Diabetes Mellitus. This questionnaire explained 86.267% of the variance and demonstrated good internal consistency (Cronbach's α= 0.929). Conclusion: Our study determined that the questionnaire serves as a valuable tool in evaluating the motivation behind dietary intake in gestational diabetes patients.

Bisphosphonate-Modified Functional Supramolecular Hydrogel Promotes Periodontal Bone Regeneration by Osteoclast Inhibition.

Regeneration of periodontal tissue remains a challenge. Under periodontitis, osteoclasts are overactivated and bone loss occurs. We incorporated sodium alendronate (Alen), a medication commonly used to treat osteoporosis, into a supramolecular hydrogel system in order to create a novel biomaterial that would promote periodontal bone regeneration by inhibiting osteoclast overactivation. The Nap-Gly-Phe-Phe (NapGFF) peptide chain was modified to synthesize the functional Nap-Alen gelator. Afterward, the Nap-Alen/HAP supramolecular hydrogel composite with a suitable hydroxyapatite (HAP) ratio was constructed, which has outstanding mechanical properties and 3D structure. In addition to its good biocompatibility, it can inhibit the proliferation of bone marrow-derived macrophages (BMDMs) and differentiation of osteoclasts. Due to the simultaneous introduction of porous HAP, the hydrogel with a nanofiber structure was formed into a 3D mesh-like sparse porous composite hydrogel. While enhancing the mechanical properties of the gel, the porous structure facilitated the attachment and migration of bone regeneration-related cells. Therefore, it can effectively promote the regeneration of periodontal bone. In the future, by modifying the biophysical properties and loading stem cells or cytokines, this supramolecular hydrogel composite constructed in this study may provide a new strategy for tissue regeneration engineering and provide a preliminary experimental basis for relevant clinical translational studies.

Accumulated biomechanical effects of mandibular molar mesialization using clear aligners with auxiliary devices: an iterative finite element analysis.

BACKGROUND: The biomechanics generated by the clear aligner (CA) material changes continuously during orthodontic tooth movement, but this factor remains unknown during the computer-aid design process and the predictability of molars movement is not as expected. Therefore, the purpose of this study was to propose an iterative finite element method to simulate the long-term biomechanical effects of mandibular molar mesialization (MM) in CA therapy under dual-mechanical systems. METHODS: Three groups including CA alone, CA with a button, and CA with a modified lever arm (MLA) were created. Material properties of CA were obtained by in vitro mechanical experiments. MM was conducted by the rebound force exerted by CA material and the mesial elastic force (2N, 30° to the occlusal plane) applied to the auxiliary devices. Stress intensity and distribution on periodontal ligament (PDL), attachment, button and MLA, and displacement of the second molar (M2) during the iterations were recorded. RESULTS: There was a significant difference between the initial and cumulative long-term displacement. Specifically, compared to the beginning, the maximum stress of PDL decreased by 90% on average in the intermediate and final steps. The aligner was the main mechanical system at first, and then, the additional system exerted by the button and MLA dominated gradually. The stress of attachments and auxiliary devices is mainly concentrated on their interfaces with the tooth. Additionally, MLA provided a distal tipping and extrusive moment, which was the only group that manifested a total mesial displacement of the root. CONCLUSIONS: The innovatively designed MLA was more effective in reducing undesigned mesial tipping and rotation of M2 than the traditional button and CA alone, which provided a therapeutic method for MM. The proposed iterative method simulated tooth movement by considering the mechanical characteristic of CA and its long-term mechanical force changes, which will facilitate better movement prediction and minimize the failure rate.

Erratum: Functionalization of SF/HAP Scaffold with GO-PEI-miRNA inhibitor Complexes to Enhance Bone Regeneration through Activating Transcription Factor 4: Erratum.

[This corrects the article DOI: 10.7150/thno.34676.].

Pancreatic cancer cells upregulate LPAR4 in response to isolation stress to promote an ECM-enriched niche and support tumour initiation.

Defining drivers of tumour initiation can provide opportunities to control cancer progression. Here we report that lysophosphatidic acid receptor 4 (LPAR4) becomes transiently upregulated on pancreatic cancer cells exposed to environmental stress or chemotherapy where it promotes stress tolerance, drug resistance, self-renewal and tumour initiation. Pancreatic cancer cells gain LPAR4 expression in response to stress by downregulating a tumour suppressor, miR-139-5p. Even in the absence of exogenous lysophosphatidic acid, LPAR4-expressing tumour cells display an enrichment of extracellular matrix genes that are established drivers of cancer stemness. Mechanistically, upregulation of fibronectin via an LPAR4/AKT/CREB axis is indispensable for LPAR4-induced tumour initiation and stress tolerance. Moreover, ligation of this fibronectin-containing matrix via integrins α5ß1 or αVß3 can transfer stress tolerance to LPAR4-negative cells. Therefore, stress- or drug-induced LPAR4 enhances cell-autonomous production of a fibronectin-rich extracellular matrix, allowing cells to survive 'isolation stress' and compensate for the absence of stromal-derived factors by creating their own tumour-initiating niche.